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Neurofeedback, sham neurofeedback, and cognitive-behavioural group therapy in adults with attention-deficit hyperactivity disorder: a triple-blind, randomised, controlled trial.

Background: Many studies suggest that electroencephalographic (EEG) neurofeedback might be beneficial in the treatment of attention-deficit hyperactivity disorder (ADHD). However, numbers of well controlled studies are low and neurofeedback techniques are regarded as highly controversial. The present trial examined the efficacy (compared with sham neurofeedback) and efficiency (compared with meta-cognitive therapy) of a standard EEG neurofeedback protocol in adults with ADHD. Methods: We did a concurrent, triple-blind, randomised, controlled trial using authorised deception in adults with ADHD from one centre (University of Tübingen) in Tübingen, Germany. Participants were eligible if they fulfilled the DSM-IV-TR criteria for ADHD, were aged between 18 years and 60 years, and had no or stable use of medication for at least 2 months with no intention to change. We excluded participants who had comorbid schizophrenia or schizoaffective disorder, bipolar disorder, borderline personality disorder, epilepsy, or traumatic brain injury; substance abuse or dependence; or current or planned other psychological treatment. Those eligible were randomly assigned to three groups: a neurofeedback group which received 30 verum θ-to-β neurofeedback sessions over 15 weeks, a sham neurofeedback group which received 15 sham followed by 15 verum θ-to-β neurofeedback sessions over 15 weeks, or a meta-cognitive group therapy group which received 12 sessions over 12 weeks. Participants were assigned equally to one of the three interventions through a computerised minimisation randomisation procedure stratified by sex, age, and baseline symptom severity of ADHD. Participants were masked as to whether they were receiving neurofeedback or sham neurofeedback, but those receiving meta-cognitive therapy were aware of their treatment. Clinical assessors (ie, those assessing outcomes) and research staff who did the neurofeedback training were masked to participants' randomisation status only for neurofeedback and sham neurofeedback. The primary outcome was symptom score on the Conners' adult ADHD rating scale, assessed before treatment, at midtreatment (after 8 weeks), after treatment (after 16 weeks), and 6 months later. All individuals with at least one observation after randomisation were included in the analyses. This trial is registered with ClinicalTrials.gov, number NCT01883765. Findings: Between Feb 1, 2013, and Dec 1, 2015, 761 people were assessed for eligibility. 656 (86%) were excluded and 118 (15%) were eligible for participation in this study. Eligible participants were randomly assigned to neurofeedback (38 [32%]), sham neurofeedback (39 [33%]), or meta-cognitive therapy (41 [35%]). 37 (97%) individuals for neurofeedback, 38 (97%) for sham neurofeedback, and 38 (93%) for meta-cognitive therapy were included in analyses. Self-reported ADHD symptoms decreased substantially for all treatment groups (B=-2·58 [95% CI -3·48 to -1·68]; p<0·0001) between pretreatment and the end of 6 month follow-up, independent of treatment condition (neurofeedback vs sham neurofeedback B=-0·89 [95% CI -2·14 to 0·37], p=0·168; neurofeedback vs meta-cognitive therapy -0·30 [-1·55 to 0·95], p=0·639). No treatment-related or trial-related serious adverse events were reported. Interpretation: Our findings suggest that neurofeedback training is not superior to a sham condition or group psychotherapy. All three treatments were equivalently effective in reducing ADHD symptoms. This first randomised, sham-controlled trial did not show any specific effects of neurofeedback on ADHD symptoms in adults. Funding: German Research Foundation.

The lancet. Psychiatry · randomised controlled trial · 91 citationsread the source →

The prevalence and risk factors of mental problems in medical students during COVID-19 pandemic: A systematic review and meta-analysis.

Background: This meta-analysis and systematic review aimed to evaluate the global prevalence and risk factors of mental problems (i.e., depression, anxiety, stress, sleep disorder, posttraumatic stress disorder (PTSD), burnout, psychological distress, and suicidal ideation) among medical students during the COVID-19 pandemic. Method: We searched PubMed, Embase, Web of Science, psycARTICLES, PsycINFO, CNKI, and Wan Fang for studies on the prevalence of mental problems among medical students from January 1, 2020, to April 1, 2022. The pooled prevalence was calculated by random-effect models. We performed a narrative review to identify the risk factors. Results: The meta-analysis included 201 studies (N = 198,000). The prevalence of depression (41 %, 95 % CI, 37-45 %,), anxiety (38 %,95 % CI, 34 %-42 %), stress (34 %, 95 % CI, 27 %-42 %), sleep disorder (52 %, 95 % CI, 44 %-60 %), psychological distress (58 %, 95 % CI, 51 %-65 %), PTSD (34 %, 95 % CI, 22 %-46 %), suicidal ideation (15 %, 95 % CI, 11 %-18 %) and burnout (38 %, 95 % CI, 25 %-50 %) was high. The major risk factors were being female, being junior or preclinical students, exposure to COVID-19, academic stress, psychiatric or physical disorders history, economic trouble, fear of education impairment, online learning trouble, fear of infection, loneliness, low physical activity, low social support, problematic internet or smartphone use, and young age. Limitations: Most studies were cross-sectional. Few studies provided a reasonable response rate, suggesting potential selection bias. Conclusions: The study demonstrated a high prevalence and risk factors for mental problems during COVID-19, calling for mental health services. Our findings are valuable for college and health authorities to identify high-risk students and provide targeted intervention.

Journal of affective disorders · meta-analysis · 154 citationsread the source →

Group Cognitive Behavioral Therapy and Attention Bias Modification for Childhood Anxiety Disorders: A Factorial Randomized Trial of Efficacy.

Background: The objective of this study is to assess group differences in symptom reduction between individuals receiving group cognitive behavioral therapy (G-CBT) and attention bias modification (ABM) compared to their respective control interventions, control therapy (CT), and attention control training (ACT), in a 2 × 2 factorial design. Methods: A total of 310 treatment-naive children (7-11 years of age) were assessed for eligibility and 79 children with generalized, separation or social anxiety disorder were randomized and received G-CBT (n = 42) or CT (n = 37). Within each psychotherapy group, participants were again randomized to ABM (n = 38) or ACT (n = 41) in a 2 × 2 factorial design resulting in four groups: G-CBT + ABM (n = 21), G-CBT + ACT (n = 21), CT + ABM (n = 17), and CT + ACT (n = 20). Primary outcomes were responder designation as defined by Clinical Global Impression-Improvement (CGI-I) scale (≤2) and change on the Pediatric Anxiety Rating Scale (PARS). Results: There were significant improvements of symptoms in all groups. No differences in response rates or mean differences in PARS scores were found among groups: G-CBT + ABM group (23.8% response; 3.9 points, 95% confidence interval [CI] -0.3 to 8.1), G-CBT + ACT (42.9% response; 5.6 points, 95% CI 2.2-9.0), CT + ABM (47.1% response; 4.8 points 95% CI 1.08-8.57), and CT + ACT (30% response; 0.8 points, 95% CI -3.0 to 4.7). No evidence or synergic or antagonistic effects were found, but the combination of G-CBT and ABM was found to increase dropout rate. Conclusions: We found no effect of G-CBT or ABM beyond the effects of comparison groups. Results reveal no benefit from combining G-CBT and ABM for anxiety disorders in children and suggest potential deleterious effects of the combination on treatment acceptability.

Journal of child and adolescent psychopharmacology · randomised controlled trial · 15 citationsread the source →

Culturally tailored evidence-based substance use disorder treatments are efficacious with an American Indian Southwest tribe: an open-label pilot-feasibility randomized controlled trial.

Background and aims: Many evidence-based treatments (EBTs) for substance use disorder (SUD) exist, yet few are tailored to Indigenous patients. This trial tested the efficacy of a culturally tailored EBT that combined Motivational Interviewing and the Community Reinforcement Approach (MICRA) versus treatment as usual (TAU). Design: A mixed efficacy/effectiveness randomized controlled trial of MICRA (n = 38) and TAU (n = 41) using a parallel design with follow-up assessments at 4-, 8-, and 12- months post baseline. Setting: United States, reservation-based outpatient, addiction specialty care treatment program. Participants: 79 (68% male) American Indian and Alaska Native (AI/AN) Tribal members meeting criteria for SUD and seeking SUD treatment. Interventions: MICRA (individual therapy sessions beginning with MI for 2-3 sessions) compared with TAU (individual and group counseling sessions in a didactic style with Twelve-Step philosophy and elements of relapse prevention). Measures: Demographics, percent days abstinent (PDA; the primary outcome at 12months assessed by Form 90D), Inventory of Drug Use Consequences, Alcohol and Drug Use Self-Efficacy Scale, Native American Spirituality Scale, and SCID-DSM-IV-TR. Findings: There was no evidence for the benefit of MICRA over TAU (MICRA PDA = 72.63%, TAU = 73.62%, treatment effect: B = -4.04 (SE = 5.47); 95% CI = -14.941, 6.866; BF = 3.44) in the primary outcome. Both groups showed improvements in PDA, SUD severity, and negative consequences from baseline to the 12-month follow-up. Neither self-efficacy nor spirituality were significant mediators of MICRA. Conclusions: There were no treatment group differences between culturally tailored evidence-based treatments for substance use disorder and treatment as usual in this randomized controlled trial with American Indian and Alaska Native participants. Nonetheless, participants improved over time on several substance-related outcomes.

Addiction (Abingdon, England) · randomised controlled trial · 33 citationsread the source →

Evaluation of a Whole-School Change Intervention: Findings from a Two-Year Cluster-Randomized Trial of the Restorative Practices Intervention.

This study fills a gap in research on multi-level school-based approaches to promoting positive youth development and reducing bullying, in particular cyberbullying, among middle school youth. The study evaluates the Restorative Practices Intervention, a novel whole-school intervention designed to build a supportive environment through the use of 11 restorative practices (e.g., communication approaches that aim to build stronger bonds among leadership, staff, and students such as using "I" statements, encouraging students to express their feelings) that had only quasi-experimental evidence prior to this study. Studying multilevel (e.g., individual, peer group, school) approaches like the Restorative Practices Intervention is important because they are hypothesized to address a more complex interaction of risk factors than single level efforts, which are more common. Baseline and two-year post survey data was collected from 2771 students at 13 middle schools evenly split between grades 6 (48 percent) and 7 (52 percent), and primarily ages 11 (38 percent) or 12 (41 percent). Gender was evenly split (51 percent male), and 92 percent of students were white. The intervention did not yield significant changes in the treatment schools. However, student self-reported experience with restorative practices significantly predicted improved school climate and connectedness, peer attachment, and social skills, and reduced cyberbullying victimization. While more work is needed on how interventions can reliably produce restorative experiences, this study suggests that the restorative model can be useful in promoting positive behaviors and addressing bullying.

Journal of youth and adolescence · randomised controlled trial · 34 citationsread the source →

A double-blind, randomized clinical trial comparing soybean oil-based versus olive oil-based lipid emulsions in adult medical-surgical intensive care unit patients requiring parenteral nutrition.

Objective: Parenteral nutrition has been associated with metabolic and infectious complications in intensive care unit patients. The underlying mechanism for the high risk of complications is not known but may relate to the proinflammatory effects of soybean oil-based lipid emulsions, the only Food and Drug Administration-approved lipid formulation for clinical use. Design: Prospective, double-blind, randomized, controlled trial. Setting: Medical-surgical intensive care units from a major urban teaching hospital and a tertiary referral university hospital. Patients: Adult medical-surgical intensive care unit patients. Intervention: Parenteral nutrition containing soybean oil-based (Intralipid) or olive oil-based (ClinOleic) lipid emulsions. Measurements: Differences in hospital clinical outcomes (nosocomial infections and noninfectious complications), hospital length of stay, glycemic control, inflammatory and oxidative stress markers, and granulocyte and monocyte functions between study groups. Results: A total of 100 patients were randomized to either soybean oil-based parenteral nutrition or olive oil-based parenteral nutrition for up to 28 days. A total of 49 patients received soybean oil-based parenteral nutrition (age 51 ± 15 yrs, body mass index 27 ± 6 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.5 ± 7 [±SD]), and a total of 51 patients received olive oil-based lipid emulsion in parenteral nutrition (age 46 ± 19 yrs, body mass index 27 ± 8 kg/m2, and Acute Physiology and Chronic Health Evaluation II score 15.1 ± 6 [±SD]) for a mean duration of 12.9 ± 8 days. The mean hospital blood glucose concentration during parenteral nutrition was 129 ± 14 mg/dL, without differences between groups. Patients treated with soybean oil-based and olive oil-based parenteral nutrition had a similar length of stay (47 ± 47 days and 41 ± 36 days, p = .49), mortality (16.3% and 9.8%, p = .38), nosocomial infections (43% vs. 57%, p = .16), and acute renal failure (26% vs. 18%, p = .34). In addition, there were no differences in inflammatory and oxidative stress markers or in granulocyte and monocyte functions between groups. Conclusion: The administration of parenteral nutrition containing soybean oil-based and olive oil-based lipid emulsion resulted in similar rates of infectious and noninfectious complications and no differences in glycemic control, inflammatory and oxidative stress markers, and immune function in critically ill adults.

Critical care medicine · randomised controlled trial · 43 citationsread the source →

Nurses' Workplace Conditions Impacting Their Mental Health during COVID-19: A Cross-Sectional Survey Study.

Among health workers, nurses are at the greatest risk of COVID-19 exposure and mortality due to their workplace conditions, including shortages of personal protective equipment (PPE), insufficient staffing, and inadequate safety precautions. The purpose of this study was to examine the impact of COVID-19 workplace conditions on nurses' mental health outcomes. A cross-sectional correlational design was used. An electronic survey was emailed to nurses in one Canadian province between June and July of 2020. A total of 3676 responses were included in this study. We found concerning prevalence rates for post-traumatic stress disorder (47%), anxiety (38%), depression (41%), and high emotional exhaustion (60%). Negative ratings of workplace relations, organizational support, organizational preparedness, workplace safety, and access to supplies and resources were associated with higher scores on all of the adverse mental health outcomes included in this study. Better workplace policies and practices are urgently required to prevent and mitigate nurses' suboptimal work conditions, given their concerning mental health self-reports during the COVID-19 pandemic.

Healthcare (Basel, Switzerland) · 99 citationsread the source →

Interactive telemedicine: effects on professional practice and health care outcomes.

Background: Telemedicine (TM) is the use of telecommunication systems to deliver health care at a distance. It has the potential to improve patient health outcomes, access to health care and reduce healthcare costs. As TM applications continue to evolve it is important to understand the impact TM might have on patients, healthcare professionals and the organisation of care. Objectives: To assess the effectiveness, acceptability and costs of interactive TM as an alternative to, or in addition to, usual care (i.e. face-to-face care, or telephone consultation). Search methods: We searched the Effective Practice and Organisation of Care (EPOC) Group's specialised register, CENTRAL, MEDLINE, EMBASE, five other databases and two trials registers to June 2013, together with reference checking, citation searching, handsearching and contact with study authors to identify additional studies. Selection criteria: We considered randomised controlled trials of interactive TM that involved direct patient-provider interaction and was delivered in addition to, or substituting for, usual care compared with usual care alone, to participants with any clinical condition. We excluded telephone only interventions and wholly automatic self-management TM interventions. Data collection and analysis: For each condition, we pooled outcome data that were sufficiently homogenous using fixed effect meta-analysis. We reported risk ratios (RR) and 95% confidence intervals (CI) for dichotomous outcomes, and mean differences (MD) for continuous outcomes. Main results: We included 93 eligible trials (N = 22,047 participants), which evaluated the effectiveness of interactive TM delivered in addition to (32% of studies), as an alternative to (57% of studies), or partly substituted for usual care (11%) as compared to usual care alone. The included studies recruited patients with the following clinical conditions: cardiovascular disease (36), diabetes (21), respiratory conditions (9), mental health or substance abuse conditions (7), conditions requiring a specialist consultation (6), co morbidities (3), urogenital conditions (3), neurological injuries and conditions (2), gastrointestinal conditions (2), neonatal conditions requiring specialist care (2), solid organ transplantation (1), and cancer (1).Telemedicine provided remote monitoring (55 studies), or real-time video-conferencing (38 studies), which was used either alone or in combination. The main TM function varied depending on clinical condition, but fell typically into one of the following six categories, with some overlap: i) monitoring of a chronic condition to detect early signs of deterioration and prompt treatment and advice, (41); ii) provision of treatment or rehabilitation (12), for example the delivery of cognitive behavioural therapy, or incontinence training; iii) education and advice for self-management (23), for example nurses delivering education to patients with diabetes or providing support to parents of very low birth weight infants or to patients with home parenteral nutrition; iv) specialist consultations for diagnosis and treatment decisions (8), v) real-time assessment of clinical status, for example post-operative assessment after minor operation or follow-up after solid organ transplantation (8) vi), screening, for angina (1).The type of data transmitted by the patient, the frequency of data transfer, (e.g. telephone, e-mail, SMS) and frequency of interactions between patient and healthcare provider varied across studies, as did the type of healthcare provider/s and healthcare system involved in delivering the intervention. We found no difference between groups for all-cause mortality for patients with heart failure (16 studies; N = 5239; RR:0.89, 95% CI 0.76 to 1.03, P = 0.12; I(2) = 44%) (moderate to high certainty of evidence) at a median of six months follow-up. Admissions to hospital (11 studies; N = 4529) ranged from a decrease of 64% to an increase of 60% at median eight months follow-up (moderate certainty of evidence). We found some evidence of improved quality of life (five studies; N = 482; MD:-4.39, 95% CI -7.94 to -0.83; P < 0.02; I(2) = 0%) (moderate certainty of evidence) for those allocated to TM as compared with usual care at a median three months follow-up. In studies recruiting participants with diabetes (16 studies; N = 2768) we found lower glycated haemoglobin (HbA1c %) levels in those allocated to TM than in controls (MD -0.31, 95% CI -0.37 to -0.24; P < 0.00001; I(2)= 42%, P = 0.04) (high certainty of evidence) at a median of nine months follow-up. We found some evidence for a decrease in LDL (four studies, N = 1692; MD -12.45, 95% CI -14.23 to -10.68; P < 0.00001; I(2 =) 0%) (moderate certainty of evidence), and blood pressure (four studies, N = 1770: MD: SBP:-4.33, 95% CI -5.30 to -3.35, P < 0.00001; I(2) = 17%; DBP: -2.75 95% CI -3.28 to -2.22, P < 0.00001; I(2) = 45% (moderate certainty evidence), in TM as compared with usual care. Seven studies that recruited participants with different mental health and substance abuse problems, reported no differences in the effect of therapy delivered over video-conferencing, as compared to face-to-face delivery. Findings from the other studies were inconsistent; there was some evidence that monitoring via TM improved blood pressure control in participants with hypertension, and a few studies reported improved symptom scores for those with a respiratory condition. Studies recruiting participants requiring mental health services and those requiring specialist consultation for a dermatological condition reported no differences between groups. Authors' conclusions: The findings in our review indicate that the use of TM in the management of heart failure appears to lead to similar health outcomes as face-to-face or telephone delivery of care; there is evidence that TM can improve the control of blood glucose in those with diabetes. The cost to a health service, and acceptability by patients and healthcare professionals, is not clear due to limited data reported for these outcomes. The effectiveness of TM may depend on a number of different factors, including those related to the study population e.g. the severity of the condition and the disease trajectory of the participants, the function of the intervention e.g., if it is used for monitoring a chronic condition, or to provide access to diagnostic services, as well as the healthcare provider and healthcare system involved in delivering the intervention.

The Cochrane database of systematic reviews · meta-analysis · 456 citationsread the source →

Childhood maltreatment and unfavourable clinical outcomes in bipolar disorder: a systematic review and meta-analysis.

Background: Bipolar disorder affects up to one in 25 individuals and identification of early risk indicators of negative outcomes could facilitate early detection of patients with greatest clinical needs and risk. We aimed to investigate the association between childhood maltreatment and key negative outcomes in patients with bipolar disorder. Methods: For this systematic review and meta-analysis we searched MEDLINE, PsycINFO, and Embase to identify articles published before Jan 1, 2015, examining the association of maltreatment (physical, sexual, or emotional abuse, neglect, or family conflict) before age 18 years with clinical features and course of illness in bipolar disorder. Data were extracted from published reports and any missing information was requested from investigators. We did 12 independent random-effects meta-analyses to quantify the associations between childhood maltreatment and course of illness or clinical features. Findings: We initially identified 527 records and after unsuitable studies were removed, our search yielded 148 publications of which 30 were used in the meta-analysis. Patients with bipolar disorder and history of childhood maltreatment had greater mania severity (six studies, 780 participants; odds ratio [OR] 2·02, 95% CI 1·21-3·39, p=0·008), greater depression severity (eight studies, 1007 participants; 1·57, 1·25-1·99, p=0·0001), greater psychosis severity (seven studies, 1494 participants; 1·49, 1·10-2·04, p=0·011), higher risk of comorbidity with post-traumatic stress disorder (eight studies, 2494 participants; 3·60, 2·45-5·30, p<0·0001), anxiety disorders (seven studies, 5091 participants; 1·90, 1·39-2·61, p<0·0001), substance misuse disorders (11 studies, 5469 participants; 1·84, 1·41-2·39, p<0·0001), alcohol misuse disorder (eight studies, 5040 participants; 1·44, 1·13-1·83, p=0·003), earlier age of bipolar disorder onset (14 studies, 5733 participants; 1·85, 1·43-2·40, p<0·0001), higher risk of rapid cycling (eight studies, 3010 participants; 1·89, 1·45-2·48, p<0·0001), greater number of manic episodes (seven studies, 3909 participants; 1·26, 1·09-1·47, p=0·003), greater number of depressive episodes (eight studies, 4025 participants; 1·38, 1·07-1·79, p=0·013), and higher risk of suicide attempt (13 studies, 3422 participants; 2·25, 1·88-2·70, p<0·0001) compared with those with bipolar disorder without childhood maltreatment. Overall, these associations were not explained by publication bias, undue effects of individual studies, or variation in study quality. Interpretation: Childhood maltreatment predicts unfavourable clinical features and course of illness in patients with bipolar disorder. Funding: None.

The lancet. Psychiatry · meta-analysis · 278 citationsread the source →

Cohort Profile: The biopsychosocial religion and health study (BRHS)

In The Secrets of Long Life in the National Geographic1 Buettner explored longevity among three communities in Sardinia Italy, Okinawa Japan, and Loma Linda California. Loma Linda is largely a community of 7th-day Adventists. In 1969 initial research2 found that among individuals surviving past age 35 Adventist women in California lived 3.7 years longer than their counterparts and Adventist men 6.2 years longer. In a later, larger California sample3 the differences were even stronger—4.4 years for women and 7.3 years for men. Exercise, vegetarian diet, not smoking, eating nuts and social support have been found to predict longevity in Adventists.4 Yet even when these and several psychological variables are controlled church attendance still predicts greater longevity.5 Interest has been increasing regarding the association of both mental and physical health with religion or spirituality.6 There have been a number of literature reviews that have concluded that the associations of religion and health are largely positive.7–9 In fact, Hall10 concluded religious attendance was more cost-effective in increasing longevity than statin-type medications. While some have questioned the quality of these research conclusions11 and others have pointed out that the benefits or costs of religion may vary depending on the indicator of religious involvement,12,13 there is general agreement regarding the need for more and better research on the subject. Nonetheless, Hummer and his colleagues14 concluded there was consistent evidence that religious attendance was associated with lower mortality risk in cross-sectional and prospective studies. They also concluded there was a need for more diverse measures of religious involvement, comparison among specific subpopulations, and a better understanding of the pathways by which religion might influence health (p. 1226). It was with this goal in mind that this Biopsychosocial Religion and Health Study was developed. The coverage of the study is best understood in the framework of our conceptual model. Two central concepts in this model are allostatic load and cumulative risk exposure. Allostasis is the process of achieving biologic stability through change—specifically, dynamic adjustments in multiple physiological systems to maintain equilibrium and set points (homeostasis) when responding to environmental demands.15 Healthy functioning requires allostasis, which is adaptive and protective over the short term. However, allostasis ‘has a potential cost to the body when allostasis is either called upon too often or is inefficiently managed, and that cost is referred to as “allostatic load” ’ (p. 174).16 Allostatic load can occur when chronic stressors place a burden on the organism but can also result from a lifetime of exposure to events demanding allostatic adjustment. We refer to this lifetime exposure as cumulative risk exposure. Allostatic load, over the life course, ultimately results in increased morbidity and mortality.17,18 In our model cumulative risk exposure aggregates an individual's risk level across physical risks such as poverty, poor housing quality, and violence exposure (which often co-occur), as well as psychosocial risks such as poor parental or marital bond, or poor job satisfaction.19 Cumulative risk exposure influences allostasis to affect allostatic load. Allostatic load, in turn, produces changes in morbidity, mortality and quality of life. However, the effects of cumulative risk exposure are both mediated and moderated by positive and negative aspects of religion. These positive and negative aspects have at least part of their influence by causing changes in lifestyle, psychological and social factors. We use the term manifestations to refer to beliefs and behaviors as they show themselves in psychosocial and biological responses. Our primary aims were to examine: (i) how religious experience moderates the impact of cumulative risk exposure on quality of life, health, and mortality; (ii) the mechanisms by which these manifestations of religion might operate; (iii) how manifestations of religious experience relate to biologic indicators of allostatic load within the context of cumulative risk exposure, and (iv) whether these manifestations operate differently in non-Blacks and Blacks—Blacks being a group for whom religion may be more central in life and, perhaps, in health.13,20,21 We could answer aims i, ii and iv with new questionnaire data and with the mortality and hospitalization data being collected by AHS-2.22 However, obtaining biologic samples as required by aim iii is much more difficult and expensive. Hence, we divided our study into two sub-studies: the Psychosocial Manifestations of Religion Sub-study (PsyMRS) and the Biological Manifestations of Religion Sub-study (BioMRS). PsyMRS is a large prospective study of approximately 11 000 individuals from the AHS-2 population who completed the supplemental PsyMRS questionnaire. Figure 1 shows our sampling plan. The sample will be surveyed at 3-year intervals while the study continues. AHS-2 will provide data on mortality and hospitalizations as described later. BioMRS is an approximately 530-person sub-study embedded within the larger PsyMRS. All members of BioMRS complete the PsyMRS questionnaire and, in addition, attend a clinic where biologic indicators are assessed. All individuals in both PsyMRS and BioMRS were selected from those participating in AHS-2. The AHS-2 recruitment methods and sampling strategy are described elsewhere.22 Sampling plan. AHS-2 is the Adventist Health Study 2. PsyMRS is the Psychosocial Manifestations of Religion Sub-study involving collection of questionnaire data. BioMRS is the Biological Manifestations of Religion Sub-study that includes assessment of biometrics, blood/saliva/urine markers, and memory/learning ability. Numbers are targets. For example, while our year one target for PsyMRS was 10 000, as August 2007, 11 004 were in the dataset We randomly sampled 20 000 AHS-2 participants and sent each the 20-page religion and health questionnaire with up to three reminder cards. Based on pilot studies we expected response rates of 55% from Caucasian and 26% from African American participants. Our goal was to enroll 3400 Blacks and 6600 Caucasians. Data collection started in September 2006 and was largely completed by August 2007. Our return rate was higher than expected with 60% from Caucasians and 31% from Blacks. Recruitment for BioMRS was through an initial letter followed by phone calls. Our goal was to obtain 300 non-Black and 200 Black participants; this moderately overweighs Black participants when compared with the overall AHS-2 sample and the PsyMRS study. Only individuals living within driving distance of our clinic sites in Loma Linda, Riverside, and Los Angeles were contacted. There were 536 participants (296 Whites, 239 Blacks, and 1 Hispanic). In the 3rd year after the initial sample we aim for a minimum of 3000 PsyMRS participants and 400 BioMRS participants. If further funding is obtained, both PsyMRS and BioMRS data will be collected at additional time points to allow latent growth curve modelling of the relations among study variables.23 Our conceptual framework suggested four categories of variables relevant to the PsyMRS questionnaire: cumulative risk exposure, religion, mediating and outcome variables. Allostatic load cannot be directly assessed from the questionnaire. In almost all cases we have used scales which have been validated in other studies or, where they are not available, validated our own. Cumulative risk exposure variables are included to assess a broad spectrum of cumulative and acute stressors that have been associated with health or quality of life.19,24 Most available single measures do not assess risk exposure at more than one point in the person's life so we broadly sampled cumulative risk across the life course. The measures include physical and socioeconomic stress: housing quality, family size, and poverty; and psychosocial stress: perceived stress, job stress/control/satisfaction, unfair treatment and discrimination, parent bonding, marital satisfaction, and trauma exposure. Religion variables were selected to include four aspects of religion: (i) affective—gratitude, forgiveness, loving vs controlling God, positive and negative eschatological attitudes; (ii) cognitive—intrinsic religiosity, some forms of religious coping, spiritual meaning; (iii) behavioural—church attendance, Sabbath keeping, prayer types, church organizational activity; and (iv) social—congregational sense of community, religious support. Mediating variables were selected based on Ellison and Levin's typology of six mechanisms for the religion/health connection25—(i) health behaviors and personal lifestyle variables (from AHS-2), (ii) social integration and social support, (iii) self-esteem and personal efficacy, (iv) positive vs negative emotions, (v) healthy beliefs (e.g. optimism) and (vi) coping resources and behaviors. Additionally we included measures of neuroticism, impression management and self-deception to serve as control variables. Outcome variables included health related quality of life (the SF-12)26 and life satisfaction as well as various medical history, symptom frequency, medication use and sleep disturbance questions and an adaptation of the Charlson comorbidity index.27 Finally, total and coronary disease mortality will be available on followup. All BioMRS participants completed a PsyMRS questionnaire, provided a waking saliva sample and a 12-h, overnight urine sample. At the clinic, fasting blood and adipose samples were taken; biometrics and percentage body fat (bioimpedence) were also assessed. Participants then provided physical and cognitive function data—Independent Activities of Daily Living; physical performance, based on five separate tests of physical ability—balance, gait, chair stands, manual ability, and grip strength; and the California Verbal Learning Test.28 Our measure of allostatic load (Table 1) is designed to summarize levels of physiological activity across a wide range of regulatory systems pertinent to disease risk, as previously described.29–31 Biological parameters used to determine the allostatic load index Biological parameters used to determine the allostatic load index The AHS-2 questionnaire was completed by BRHS participants 1–3 years before the PsyMRS questionnaire. The AHS-2 data set includes 130 food frequency items, daily physical activity, detailed ethnicity and other demographics, country of birth, religion of mother and father who raised participant, religion at age 15–25, age at baptism, medical history, women's health conditions and history, alcohol and tobacco use, and medications used at baseline. AHS-2 will provide hospitalization history information based on a biennial survey and causes of mortality by matching the sample with the National Death Index.22 Based on previous studies of Adventists in California32 we expect good retention in our sample. With the planned cohort maintenance and retention activities of AHS-222 we hope to trace a high percentage of the participants over at least a 3-year period. The demographics of the PsyMRS sample are shown in Table 2 along with comparisons with the 2006 General Social Survey, a survey based on national probability sample.33 Ages below 35 are omitted as the inclusion criteria for AHS-2 in the first several years was age 35+ for non-Blacks and age 30+ for Blacks. Comparison of demographics in the biopsychosocial religion and health study (BRHS) and the general social survey (GSS) by ethnicity and gender Notes: Only individuals older than 35 were included from both samples since that was an initial inclusion criteria for BRHS. All GSS vs BRHS comparisons on education, marital status, and age within genders are statistically significant. Comparison of demographics in the biopsychosocial religion and health study (BRHS) and the general social survey (GSS) by ethnicity and gender Notes: Only individuals older than 35 were included from both samples since that was an initial inclusion criteria for BRHS. All GSS vs BRHS comparisons on education, marital status, and age within genders are statistically significant. One concern is the relatively small number of Black male Adventist participants. However, there are sufficient numbers for data analysis in the middle ranges of age, education and income. There are no large education differences between male and female or Black and White Adventists. While not shown in Table 2 there are no large percentage differences in income though females and Black Adventists have slightly lower income than males and White Adventists respectively. One interesting figure is the relatively low number of Black Adventist women who are married and a correspondingly high number who are divorced or never married relative to both Black male Adventists and to both male and female White Adventists. Comparing the PsyMRS sample and the GSS sample, the BRHS sample has more females, more college educated individuals especially among the Blacks, more married individuals and more individuals above age 65 in all genders and ethnicities. The educational difference may be the result of the literacy level implied by being able to fill out the 50 page AHS-2 questionnaire and possibly the emphasis on education among 7th-day Adventists—e.g. though in the 2000 Census only the 18th largest denominational group,34 Adventists have the 5th largest number of denominational schools35 and the 9th largest number of students enrolled in such schools.36 The difference between Adventists and the GSS sample is consistently larger for Black males than other groups. Adventists are more likely to be married and less likely to be divorced than the GSS sample. Black Adventist women are also less likely to be widowed (P = 0.022 by Fisher's exact Test) and never married (P < 0.0005) than Black women in the GSS sample. Table 3 compares the BRHS and GSS data for two religious questions. BRHS participants were much more likely to report attending church. On the other hand, while prayer was more frequent for Adventists than for those in the GSS participants, the frequency of daily prayer for Black Adventist females was similar to that found in GSS Black females. Comparison of religion variables in the biopsychosocial religion and health study and the general social survey by ethnicity and gender Notes: All GSS versus BRHS comparisons on church attendance and prayer frequency within genders are statistically significant except for prayer in Black females. Comparison of religion variables in the biopsychosocial religion and health study and the general social survey by ethnicity and gender Notes: All GSS versus BRHS comparisons on church attendance and prayer frequency within genders are statistically significant except for prayer in Black females. Previous research with earlier Adventist cohorts has shown that 7th-day Adventists have lower mortality rates than the general population.4 However, until now we have had no data on quality of life. Figure 2 shows physical and mental quality of life on the SF-12v2 for Black and White Adventists compared with the national norms taken from the 2002 SF-12v2 manual based on data collected in 1999 and 2000.37 Unfortunately, national norms for the SF-12v2 are not available by ethnicity but the comparisons are nonetheless interesting. It appears that both Black and White Adventists in our sample report better physical and mental health than the national norms but the patterns differ by age group. For physical health Adventist females tend to be higher than national norms in the 45–54 age group and the differences tend to get smaller as the age of the groups increase. For males the differences tend to be there at all ages but are more pronounced in the 55- to 74-year old age range. Adventists and non-Adventists have similar levels of mental health in the 35- to 44-year old age group but the mental health of both Black and White Adventists is better in the older age groups. Interestingly, Black Adventists at some ages seem to report better mental health than even White Adventists. Physical and Mental Health based on SF-12 composite scores for 7th-day Adventist Blacks and Whites and for SF-12 national norms.38 Numbers are scale scores (mean 50, SD 10) for individuals over 35 years of age The overall better level of physical and mental health for Adventists could be a volunteer effect since our respondents had to fill out long questionnaires. On the other hand, the national norms were also based on volunteers though the questionnaires involved were not as extensive. Still, the fact that the gaps were bigger for mental health and that that gap is greater at older ages is interesting and harder to explain as a volunteer bias alone. These patterns will warrant further examination as our study progresses. The better physical health of Black Adventists than the national norms also warrants attention given the data on health disparities suggests Blacks score lower on physical health measures.38 One potential weakness of this study is that the data are collected exclusively on 7th-day Adventists. While this means that cross-denominational differences cannot be explored this is no different from other studies which have focused on single denominations such as Baptists,39,40 Catholics,41 Mormons,38–40 and Presbyterians.43 Additionally, our preliminary examination of the data shows a wide range of responses on most religion variables. While other approaches are useful,43–45 examination of the religion-health association within a single denomination has several strengths: (i) single denomination studies eliminate the need to control for denominational differences; (ii) because members of a single denomination have a shared religious tradition they will have less variation in how they interpret more nuanced religious questions, even as they differ in their responses to such questions; (iii) in addition, the examination of Blacks is easier because confounding by socio-economic status is less pronounced and thus easier to control than in the U.S. population due to the Adventist education emphasis;46 (iv) finally, just as one cannot learn about economic mobility and success solely by studying the urban underclass and focusing on barriers to achievement, one cannot learn about health and longevity by focusing exclusively on causes of death and studying persons who die prematurely. It behoves us to examine groups that defy the odds and enjoy better-than-average health and longevity; there is no better source of good biopsychosocial, quality of life and religious data on one of these strategically important groups, the 7th-day Adventists, than the data from this study. This study has a number of strengths. First, it includes a much wider range of religious variables than previous epidemiological studies.14,43–45 Second, we used a systematic theoretical scheme for inclusion of possible mediators of the religion and health relationship and, hence, the study includes a wide range of potential psychosocial- and lifestyle-mediating variables. Third, it includes a variety of biologic and functional assessments of allostatic load that have not been incorporated in previous studies of the religion and health connection. Fourth, the quality of life measures, assessed for the first time on an Adventist population, will allow us to determine whether the longer lives of Adventists are accompanied by a longer span of high quality life or whether these longer lives just stretch out the period of poor quality life. The Biopsychosocial Religion and Health Study has potential to greatly increase our understanding of the religion-health relationship and its implications for public health. We are still in the process of cleaning data and prospective data collection has yet to begin. Thus, the data are not freely available. However, BRHS researchers would welcome contacts from other investigators interested in collaboration on projects relating to specific aspects of the data we are can be through the of this or through the Adventist Health Study at Loma Linda National on for their support of this National for their support of the Adventist Health Study 2 which is the parent study for the Biopsychosocial Religion and Health and have been as on this and to the that the we have in and assessment are good we a We would to a to and for the on the BioMRS biological and to for all aspects of the BioMRS We would also to the students who have in our and on the participants. of

International Journal of Epidemiology · 63 citationsread the source →

Social inequalities in multimorbidity, frailty, disability, and transitions to mortality: a 24-year follow-up of the Whitehall II cohort study.

Background: Social inequalities in mortality persist in high-income countries with universal health care, and the mechanisms by which these inequalities are generated remain unclear. We aimed to examine whether social inequalities were present before or after the onset of adverse health conditions (multimorbidity, frailty, and disability). Methods: Our analysis was based on data from the ongoing Whitehall II cohort study, which enrolled British civil servants aged 35-55 years in 1985-88. Participants were assessed for three indicators of socioeconomic status (education, occupational position, and literacy) at age 50 years. Participants underwent clinical examinations (in 2002-04, 2007-09, 2012-13, and 2015-16) for assessment of frailty (two or more of low physical activity, slow walking speed, poor grip strength, weight loss, and exhaustion) and disability (two or more difficulties in bathing, dressing, going to the toilet, transferring, feeding, and walking). In addition, electronic health records were used to assess the incidence of multimorbidity (two or more of diabetes, coronary heart disease, stroke, chronic obstructive pulmonary disease, depression, arthritis, cancer, dementia, and Parkinson's disease) and mortality. In analyses adjusted for sociodemographic factors, we used multistate models to examine social inequalities in transitions from healthy state to adverse health conditions and subsequently to mortality. Findings: Of 10 308 individuals in the Whitehall II study cohort, 6425 had relevant data available at 50 years and to the end of follow-up on Aug 31, 2017, and were included in our analysis. Participants were followed up for a median of 23·6 years (IQR 19·6-28·9). 1694 (26·4%) of 6425 participants developed multimorbidity, 1733 (27·0%) became frail, 692 (10·8%) had a disability, and 611 (9·5%) died. Multimorbidity (hazard ratio [HR] 4·12 [95% CI 3·41-4·98]), frailty (HR 2·38 [95% CI 1·93-2·93]), and disability (HR 1·73 [95% CI 1·34-2·22]) were associated with increased risk of mortality; these associations were not modified by socioeconomic status. In multistate models, occupation was the socioeconomic status indicator that was most strongly associated with inequalities in the transition from healthy state to multimorbidity (HR 1·54 [95% CI 1·37-1·73]), to frailty (HR 2·08 [95% CI 1·85-2·33]), and to disability (HR 1·44 [95% CI 1·18-1·74]). Socioeconomic status indicators did not affect transitions to mortality in those with multimorbidity, frailty, or disability. Interpretation: Socioeconomic status affects the risk of multimorbidity, frailty, and disability, but does not affect the risk of mortality after the onset of these adverse health conditions. Therefore, primary prevention is key to reducing social inequalities in mortality. Of the three adverse health conditions, multimorbidity had the strongest association with mortality, making it a central target for improving population health. Funding: UK Medical Research Council; National Institute on Aging, National Institutes of Health; British Heart Foundation.

The Lancet. Public health · 239 citationsread the source →

Electronic cigarettes for smoking cessation.

Background: Electronic cigarettes (ECs) are handheld electronic vaping devices which produce an aerosol by heating an e-liquid. Some people who smoke use ECs to stop or reduce smoking, although some organizations, advocacy groups and policymakers have discouraged this, citing lack of evidence of efficacy and safety. People who smoke, healthcare providers and regulators want to know if ECs can help people quit smoking, and if they are safe to use for this purpose. This is a review update conducted as part of a living systematic review. Objectives: To examine the effectiveness, tolerability, and safety of using electronic cigarettes (ECs) to help people who smoke tobacco achieve long-term smoking abstinence. Search methods: We searched the Cochrane Tobacco Addiction Group's Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, and PsycINFO to 1 July 2022, and reference-checked and contacted study authors.  SELECTION CRITERIA: We included randomized controlled trials (RCTs) and randomized cross-over trials, in which people who smoke were randomized to an EC or control condition. We also included uncontrolled intervention studies in which all participants received an EC intervention. Studies had to report abstinence from cigarettes at six months or longer or data on safety markers at one week or longer, or both. Data collection and analysis: We followed standard Cochrane methods for screening and data extraction. Our primary outcome measures were abstinence from smoking after at least six months follow-up, adverse events (AEs), and serious adverse events (SAEs). Secondary outcomes included the proportion of people still using study product (EC or pharmacotherapy) at six or more months after randomization or starting EC use, changes in carbon monoxide (CO), blood pressure (BP), heart rate, arterial oxygen saturation, lung function, and levels of carcinogens or toxicants, or both. We used a fixed-effect Mantel-Haenszel model to calculate risk ratios (RRs) with a 95% confidence interval (CI) for dichotomous outcomes. For continuous outcomes, we calculated mean differences. Where appropriate, we pooled data in meta-analyses. Main results: We included 78 completed studies, representing 22,052 participants, of which 40 were RCTs. Seventeen of the 78 included studies were new to this review update. Of the included studies, we rated ten (all but one contributing to our main comparisons) at low risk of bias overall, 50 at high risk overall (including all non-randomized studies), and the remainder at unclear risk. There was high certainty that quit rates were higher in people randomized to nicotine EC than in those randomized to nicotine replacement therapy (NRT) (RR 1.63, 95% CI 1.30 to 2.04; I2 = 10%; 6 studies, 2378 participants). In absolute terms, this might translate to an additional four quitters per 100 (95% CI 2 to 6). There was moderate-certainty evidence (limited by imprecision) that the rate of occurrence of AEs was similar between groups (RR 1.02, 95% CI 0.88 to 1.19; I2 = 0%; 4 studies, 1702 participants). SAEs were rare, but there was insufficient evidence to determine whether rates differed between groups due to very serious imprecision (RR 1.12, 95% CI 0.82 to 1.52; I2 = 34%; 5 studies, 2411 participants). There was moderate-certainty evidence, limited by imprecision, that quit rates were higher in people randomized to nicotine EC than to non-nicotine EC (RR 1.94, 95% CI 1.21 to 3.13; I2 = 0%; 5 studies, 1447 participants). In absolute terms, this might lead to an additional seven quitters per 100 (95% CI 2 to 16). There was moderate-certainty evidence of no difference in the rate of AEs between these groups (RR 1.01, 95% CI 0.91 to 1.11; I2 = 0%; 5 studies, 1840 participants). There was insufficient evidence to determine whether rates of SAEs differed between groups, due to very serious imprecision (RR 1.00, 95% CI 0.56 to 1.79; I2 = 0%; 8 studies, 1272 participants). Compared to behavioural support only/no support, quit rates were higher for participants randomized to nicotine EC (RR 2.66, 95% CI 1.52 to 4.65; I2 = 0%; 7 studies, 3126 participants). In absolute terms, this represents an additional two quitters per 100 (95% CI 1 to 3). However, this finding was of very low certainty, due to issues with imprecision and risk of bias. There was some evidence that (non-serious) AEs were more common in people randomized to nicotine EC (RR 1.22, 95% CI 1.12 to 1.32; I2 = 41%, low certainty; 4 studies, 765 participants) and, again, insufficient evidence to determine whether rates of SAEs differed between groups (RR 1.03, 95% CI 0.54 to 1.97; I2 = 38%; 9 studies, 1993 participants).  Data from non-randomized studies were consistent with RCT data. The most commonly reported AEs were throat/mouth irritation, headache, cough, and nausea, which tended to dissipate with continued EC use. Very few studies reported data on other outcomes or comparisons, hence evidence for these is limited, with CIs often encompassing clinically significant harm and benefit. Authors' conclusions: There is high-certainty evidence that ECs with nicotine increase quit rates compared to NRT and moderate-certainty evidence that they increase quit rates compared to ECs without nicotine. Evidence comparing nicotine EC with usual care/no treatment also suggests benefit, but is less certain. More studies are needed to confirm the effect size. Confidence intervals were for the most part wide for data on AEs, SAEs and other safety markers, with no difference in AEs between nicotine and non-nicotine ECs nor between nicotine ECs and NRT. Overall incidence of SAEs was low across all study arms. We did not detect evidence of serious harm from nicotine EC, but longest follow-up was two years and the number of studies was small. The main limitation of the evidence base remains imprecision due to the small number of RCTs, often with low event rates, but further RCTs are underway. To ensure the review continues to provide up-to-date information to decision-makers, this review is a living systematic review. We run searches monthly, with the review updated when relevant new evidence becomes available. Please refer to the Cochrane Database of Systematic Reviews for the review's current status.

The Cochrane database of systematic reviews · systematic review · 147 citationsread the source →

Prevalence of spatial neglect post-stroke: A systematic review.

Objective: Spatial neglect (SN) impedes stroke rehabilitation progress, slows functional recovery, and increases caregiver stress and burden. The estimation of SN prevalence varies widely across studies. Background: We aimed to establish the prevalence of SN based on the injured cerebral hemisphere, recovery stage post-stroke, and diagnostic methodology. Materials and methods: All journal articles published up to February 27, 2019 from CINAHL, PsycINFO, PubMed and Web of Science were searched. We selected original research articles that described observational studies, included both individuals with left brain damage (LBD) and those with right brain damage (RBD) post-stroke, and reported specific diagnostic methods for SN. All authors reached consensus for the final selection of 41 articles. Time post-stroke, patient selection criteria, study setting, SN diagnostic methods were extracted. Results: A total of 6324 participants were included: 3411 (54%) with RBD and 2913 (46%) with LBD. Without considering time post-stroke or diagnostic methods, the occurrence rate of SN was 29% (38% after RBD and 18% after LBD). Using ecological assessments resulted in higher prevalence than using tests not directly related to daily life activities (53% vs. 24%). Using methods based on a single-cutoff criterion led to lower occurrence of SN than using multi-test methods (27% vs. 33%). The prevalence decreased from the acute to chronic stage post-stroke. Conclusions: The estimated prevalence of SN after unilateral stroke is 30%. SN is more common after RBD than after LBD, but SN after LBD is still quite common. Using ecological assessments and multi-test methods to detect SN is preferred to using a single-cutoff criterion of a test that is not directly related to daily function. The decrease in SN prevalence over time is evident, but the exact prevalence in later stages cannot be estimated. More research is needed to better understand chronic SN.

Annals of physical and rehabilitation medicine · systematic review · 131 citationsread the source →

Populations and Interventions for Palliative and End-of-Life Care: A Systematic Review.

Importance: Evidence supports palliative care effectiveness. Given workforce constraints and the costs of new services, payers and providers need help to prioritize their investments. They need to know which patients to target, which personnel to hire, and which services best improve outcomes. Objective: To inform how payers and providers should identify patients with "advanced illness" and the specific interventions they should implement, we reviewed the evidence to identify (1) individuals appropriate for palliative care and (2) elements of health service interventions (personnel involved, use of multidisciplinary teams, and settings of care) effective in achieving better outcomes for patients, caregivers, and the healthcare system. Evidence review: Systematic searches of MEDLINE, EMBASE, PsycINFO, Web of Science, and Cochrane Database of Systematic Reviews databases (1/1/2001-1/8/2015). Results: Randomized controlled trials (124) met inclusion criteria. The majority of studies in cancer (49%, 38 of 77 studies) demonstrated statistically significant patient or caregiver outcomes (e.g., p < 0.05), as did those in congestive heart failure (CHF) (62%, 13 of 21), chronic obstructive pulmonary disease (COPD; 58%, 11 of 19), and dementia (60%, 15 of 25). Most prognostic criteria used clinicians' judgment (73%, 22 of 30). Most interventions included a nurse (70%, 69 of 98), and many were nurse-only (39%, 27 of 69). Social workers were well represented, and home-based approaches were common (56%, 70 of 124). Home interventions with visits were more effective than those without (64%, 28 of 44; vs. 46%, 12 of 26). Interventions improved communication and care planning (70%, 12 of 18), psychosocial health (36%, 12 of 33, for depressive symptoms; 41%, 9 of 22, for anxiety), and patient (40%, 8 of 20) and caregiver experiences (63%, 5 of 8). Many interventions reduced hospital use (65%, 11 of 17), but most other economic outcomes, including costs, were poorly characterized. Palliative care teams did not reliably lower healthcare costs (20%, 2 of 10). Conclusions: Palliative care improves cancer, CHF, COPD, and dementia outcomes. Effective models include nurses, social workers, and home-based components, and a focus on communication, psychosocial support, and the patient or caregiver experience. High-quality research on intervention costs and cost outcomes in palliative care is limited.

Journal of palliative medicine · systematic review · 135 citationsread the source →

Prevention of Psychosis: Advances in Detection, Prognosis, and Intervention.

Importance: Detection, prognosis, and indicated interventions in individuals at clinical high risk for psychosis (CHR-P) are key components of preventive psychiatry. Objective: To provide a comprehensive, evidence-based systematic appraisal of the advancements and limitations of detection, prognosis, and interventions for CHR-P individuals and to formulate updated recommendations. Evidence review: Web of Science, Cochrane Central Register of Reviews, and Ovid/PsychINFO were searched for articles published from January 1, 2013, to June 30, 2019, to identify meta-analyses conducted in CHR-P individuals. MEDLINE was used to search the reference lists of retrieved articles. Data obtained from each article included first author, year of publication, topic investigated, type of publication, study design and number, sample size of CHR-P population and comparison group, type of comparison group, age and sex of CHR-P individuals, type of prognostic assessment, interventions, quality assessment (using AMSTAR [Assessing the Methodological Quality of Systematic Reviews]), and key findings with their effect sizes. Findings: In total, 42 meta-analyses published in the past 6 years and encompassing 81 outcomes were included. For the detection component, CHR-P individuals were young (mean [SD] age, 20.6 [3.2] years), were more frequently male (58%), and predominantly presented with attenuated psychotic symptoms lasting for more than 1 year before their presentation at specialized services. CHR-P individuals accumulated several sociodemographic risk factors compared with control participants. Substance use (33% tobacco use and 27% cannabis use), comorbid mental disorders (41% with depressive disorders and 15% with anxiety disorders), suicidal ideation (66%), and self-harm (49%) were also frequently seen in CHR-P individuals. CHR-P individuals showed impairments in work (Cohen d = 0.57) or educational functioning (Cohen d = 0.21), social functioning (Cohen d = 1.25), and quality of life (Cohen d = 1.75). Several neurobiological and neurocognitive alterations were confirmed in this study. For the prognosis component, the prognostic accuracy of CHR-P instruments was good, provided they were used in clinical samples. Overall, risk of psychosis was 22% at 3 years, and the risk was the highest in the brief and limited intermittent psychotic symptoms subgroup (38%). Baseline severity of attenuated psychotic (Cohen d = 0.35) and negative symptoms (Cohen d = 0.39) as well as low functioning (Cohen d = 0.29) were associated with an increased risk of psychosis. Controlling risk enrichment and implementing sequential risk assessments can optimize prognostic accuracy. For the intervention component, no robust evidence yet exists to favor any indicated intervention over another (including needs-based interventions and control conditions) for preventing psychosis or ameliorating any other outcome in CHR-P individuals. However, because the uncertainty of this evidence is high, needs-based and psychological interventions should still be offered. Conclusions and relevance: This review confirmed recent substantial advancements in the detection and prognosis of CHR-P individuals while suggesting that effective indicated interventions need to be identified. This evidence suggests a need for specialized services to detect CHR-P individuals in primary and secondary care settings, to formulate a prognosis with validated psychometric instruments, and to offer needs-based and psychological interventions.

JAMA psychiatry · systematic review · 369 citationsread the source →

Different doses, durations and modes of delivery of nicotine replacement therapy for smoking cessation.

Background: Nicotine replacement therapy (NRT) aims to replace nicotine from cigarettes to ease the transition from cigarette smoking to abstinence. It works by reducing the intensity of craving and withdrawal symptoms. Although there is clear evidence that NRT used after smoking cessation is effective, it is unclear whether higher doses, longer durations of treatment, or using NRT before cessation add to its effectiveness. Objectives: To determine the effectiveness and safety of different forms, deliveries, doses, durations and schedules of NRT, for achieving long-term smoking cessation, compared to one another. Search methods: We searched the Cochrane Tobacco Addiction Group trials register, and trial registries for papers mentioning NRT in the title, abstract or keywords. Date of most recent search: April 2018. Selection criteria: Randomized trials in people motivated to quit, comparing one type of NRT use with another. We excluded trials that did not assess cessation as an outcome, with follow-up less than six months, and with additional intervention components not matched between arms. Trials comparing NRT to control, and trials comparing NRT to other pharmacotherapies, are covered elsewhere. Data collection and analysis: We followed standard Cochrane methods. Smoking abstinence was measured after at least six months, using the most rigorous definition available. We extracted data on cardiac adverse events (AEs), serious adverse events (SAEs), and study withdrawals due to treatment. We calculated the risk ratio (RR) and the 95% confidence interval (CI) for each outcome for each study, where possible. We grouped eligible studies according to the type of comparison. We carried out meta-analyses where appropriate, using a Mantel-Haenszel fixed-effect model. Main results: We identified 63 trials with 41,509 participants. Most recruited adults either from the community or from healthcare clinics. People enrolled in the studies typically smoked at least 15 cigarettes a day. We judged 24 of the 63 studies to be at high risk of bias, but restricting the analysis only to those studies at low or unclear risk of bias did not significantly alter results, apart from in the case of the preloading comparison. There is high-certainty evidence that combination NRT (fast-acting form + patch) results in higher long-term quit rates than single form (RR 1.25, 95% CI 1.15 to 1.36, 14 studies, 11,356 participants; I2 = 4%). Moderate-certainty evidence, limited by imprecision, indicates that 42/44 mg are as effective as 21/22 mg (24-hour) patches (RR 1.09, 95% CI 0.93 to 1.29, 5 studies, 1655 participants; I2 = 38%), and that 21 mg are more effective than 14 mg (24-hour) patches (RR 1.48, 95% CI 1.06 to 2.08, 1 study, 537 participants). Moderate-certainty evidence (again limited by imprecision) also suggests a benefit of 25 mg over 15 mg (16-hour) patches, but the lower limit of the CI encompassed no difference (RR 1.19, 95% CI 1.00 to 1.41, 3 studies, 3446 participants; I2 = 0%). Five studies comparing 4 mg gum to 2 mg gum found a benefit of the higher dose (RR 1.43, 95% CI 1.12 to 1.83, 5 studies, 856 participants; I2 = 63%); however, results of a subgroup analysis suggest that only smokers who are highly dependent may benefit. Nine studies tested the effect of using NRT prior to quit day (preloading) in comparison to using it from quit day onward; there was moderate-certainty evidence, limited by risk of bias, of a favourable effect of preloading on abstinence (RR 1.25, 95% CI 1.08 to 1.44, 9 studies, 4395 participants; I2 = 0%). High-certainty evidence from eight studies suggests that using either a form of fast-acting NRT or a nicotine patch results in similar long-term quit rates (RR 0.90, 95% CI 0.77 to 1.05, 8 studies, 3319 participants; I2 = 0%). We found no evidence of an effect of duration of nicotine patch use (low-certainty evidence); 16-hour versus 24-hour daily patch use; duration of combination NRT use (low- and very low-certainty evidence); tapering of patch dose versus abrupt patch cessation; fast-acting NRT type (very low-certainty evidence); duration of nicotine gum use; ad lib versus fixed dosing of fast-acting NRT; free versus purchased NRT; length of provision of free NRT; ceasing versus continuing patch use on lapse; and participant- versus clinician-selected NRT. However, in most cases these findings are based on very low- or low-certainty evidence, and are the findings from single studies.AEs, SAEs and withdrawals due to treatment were all measured variably and infrequently across studies, resulting in low- or very low-certainty evidence for all comparisons. Most comparisons found no evidence of an effect on cardiac AEs, SAEs or withdrawals. Rates of these were low overall. Significantly more withdrawals due to treatment were reported in participants using nasal spray in comparison to patch in one trial (RR 3.47, 95% CI 1.15 to 10.46, 922 participants; very low certainty) and in participants using 42/44 mg patches in comparison to 21/22 mg patches across two trials (RR 4.99, 95% CI 1.60 to 15.50, 2 studies, 544 participants; I2 = 0%; low certainty). Authors' conclusions: There is high-certainty evidence that using combination NRT versus single-form NRT, and 4 mg versus 2 mg nicotine gum, can increase the chances of successfully stopping smoking. For patch dose comparisons, evidence was of moderate certainty, due to imprecision. Twenty-one mg patches resulted in higher quit rates than 14 mg (24-hour) patches, and using 25 mg patches resulted in higher quit rates than using 15 mg (16-hour) patches, although in the latter case the CI included one. There was no clear evidence of superiority for 42/44 mg over 21/22 mg (24-hour) patches. Using a fast-acting form of NRT, such as gum or lozenge, resulted in similar quit rates to nicotine patches. There is moderate-certainty evidence that using NRT prior to quitting may improve quit rates versus using it from quit date only; however, further research is needed to ensure the robustness of this finding. Evidence for the comparative safety and tolerability of different types of NRT use is of low and very low certainty. New studies should ensure that AEs, SAEs and withdrawals due to treatment are both measured and reported.

The Cochrane database of systematic reviews · systematic review · 126 citationsread the source →

Prediction and prevention of schizophrenia: what has been achieved and where to go next?

Since the traditional clinical paradigm has been replaced by the modern molecular one, medicine set off into new directions. “Prediction”, “prevention” and “personalization” are the programmatic key words of this new approach. Like other medical disciplines, psychiatry has broadened its focus from diagnosis and treatment to the detection and estimation of the risk of disease development, the prediction of its onset and strategies to avoid its manifestation 1,2,3,4. Although treatment of schizophrenia has greatly advanced over the last decades, a significant number of patients continue to take an unfavorable chronic course 5,6. This makes schizophrenia the leading cause for permanent occupational disability among people under 40 years of age in Germany 7, and the 8th most common cause for disability adjusted life years (DALYs) lost among the 15 to 34-year olds worldwide 8, despite its low prevalence. Moreover, schizophrenia involves tremendous direct and indirect societal costs 9 and a huge burden on patients and their families 8,10. It is becoming increasingly clear that schizophrenia is a complex disorder with polygenic heredity and that its pathogenesis is greatly influenced by interactions between different genes and between genes and environment. Associations to variants of the genes for dysbindin and neuregulin-1, the genetic locus G72 and the DAOA (D-amino acid oxidase activator) gene have now been repeatedly confirmed. As with all other complex diseases, research is focusing now on characterizing the polygenetic predisposition and clarifying its influence on the development of the phenotype 11. Research methods range from molecular genetics via proteome research to cell biology, neurophysiology, brain structural and functional imaging and neuropsychology. With all these methods, several indicators for an increased risk of schizophrenia have been identified. However, the currently recognized neurobiological risk factors are not sufficiently predictive to allow the development and application of “selective” prevention measures targeting asymptomatic persons at risk. For neuro-psychological risk factors, this has just become evident in the large-scale attempt of the North American Prodrome Longitudinal Study (NAPLS) group to improve their multivariate model by integrating the examined neurocognitive variables 12. There are also established environmental risk factors for schizophrenia, such as pregnancy or birth complications, growing up in a large city, IQ low but normal and drug consumption. However, with odds ratios around 2, each of these factors appears to increase the lifetime risk of the disease only slightly 13. Thus, the currently known risk factors, either alone or taken together, cannot be used for prediction and prevention without knowledge of the complete predispositional basis and the gene-gene and gene-environment interactions, which are probably numerous. In view of this situation, it may be argued that the current efforts towards prediction and prevention are still premature and that further progress of etiological research is needed. However, a different perspective has emerged from the work of the centers for early recognition and prevention, established first in Melbourne, Australia and in Cologne, Germany in the mid 1990s, and later on in many other places around the world. This resulted from retrospective research of the early course of psychosis, in which the pathophysiologically active disturbances in brain development extend beyond early abnormalities in behavior into psychopathologically definable early risk and ultra high risk (UHR) symptoms, depending on the individual combination of stressors and resilience factors. First episode psychosis (FEP) research has shown that the outbreak of the disease is preceded in about 70% to nearly 100% of cases by an initial prodrome, which lasts for an average of five to six years. Even in highly developed health care systems, an average of one year thereafter elapses from the first manifestation of psychotic positive symptoms to the initiation of adequate treatment 14,15. The period over which the FEP remains untreated (duration of untreated psychosis, DUP) correlates with: delayed and incomplete remission of the symptoms; necessity of more protracted treatment and greater risk of relapse; lower compliance, greater burden on the family, and a higher level of “expressed emotion”; increased risk of depression and suicide; greater impact on the individual's employment or education; increased drug abuse and delinquent behavior; markedly increased costs of treatment 16. These correlations have recently been confirmed by a meta-analysis 17, with coefficients ranging from 0.285 to 0.434 (95% CI). This does not only provide strong arguments in favor of treating the FEP as early as possible, but has also led to a systematic effort to decrease the incidence of psychosis through indicated prevention. Two important studies concerning the early stage prior to the conversion to FEP have demonstrated that the earliest and most common symptoms, which generally dominate during the prodrome, are unspecific and cannot be distinguished from impairment in mood, drive, contact, and concentration of depressive episodes. These are the Age-Beginning-Course (ABC) study of schizophrenia, a retrospective study with optimized methods 14, and the Cologne Early Recognition (CER) Study, a long-term prospective study with an average follow-up period just below 10 years 18. These studies also found striking cognitive impairments in the form of self-experienced disturbances in thought, speech, and perception processes. This subgroup of so-called basic symptoms, which were found in more than a quarter of patients, had high specificity and a high positive predictive power, accompanied by only low rates of false positive predictions 19,20,21. Basic symptoms were first operationalized in the Bonn Scale for the Assessment of Basic Symptoms (BSABS). Shorter versions of the scale for adults and for children and adolescents — the Schizophrenia Proneness Instrument, Adult version (SPI-A) and the Schizophrenia Proneness Instrument, Child and Youth version (SPI-CY) — were later developed from dimensional analyses 22,23,24. While the BSABS only allows an assessment of the current state, the SPI-A and the SPI-CY also allow severity ratings according to the maximum frequency of occurrence within the past 3 months. In the CER study, 385 patients who were presumably in the prodromal phase of schizophrenia were followed up for an average of 9.6 (±7.6) years past baseline. Twenty percent of the initial criterion-positive cases (1 of 66 basic symptoms) who agreed to be followed up developed schizophrenia after 12 months, a further 17% after 24 months, a further 13% after 36 months, and finally a total of 70% after an average of 4.5 years. Thus, only 30% did not convert to schizophrenia. The overall presence/absence of at least one basic symptom correctly predicted presence/absence of a subsequent transition to schizophrenia in 78.1% of cases. From further analyses, two partially overlapping basic symptom criteria for defining at risk mental states (ARMS) for psychosis, primarily schizophrenia, were developed (Table 1). The first criterion, which consists of ten cognitive-perceptive basic symptoms and is abbreviated as COPER, was based on findings concerning the predictive accuracy of individual basic symptoms 18,25. The second was based on a methodological re-analysis of the same data set, in which a cluster of nine cognitive basic symptoms had repeatedly been selected as the most predictive. This cluster was called “cognitive disturbances” (COGDIS). In terms of general predictive accuracy, the two criteria slightly differed in the CER study, as COGDIS tended to be more conservative than COPER, i.e. to perform better in ruling in subsequent schizophrenia at the cost of performing worse in ruling it out. The transition rate throughout the average follow-up period of roughly 10 years was 65% for COPER and 79% for COGDIS, with the majority of transitions occurring within the first 3 years past baseline. In a second prospective study 26, conducted with the SPI-A and with a systematic follow-up of 24 months, 38% of the initially included 146 at-risk subjects developed a frank psychosis, mainly schizophrenia, within 12.3 (±10.4) months on average (1–48; median=9) according to COPER. Thus, the positive results of the CER study were confirmed. Again, COGDIS appeared to be more specific but less sensitive than COPER. As a consequence of these findings, predictive basic symptoms have been established as a set of criteria for risk assessment in international research on the early recognition of psychosis. In particular, the German Research Network on Schizophrenia used these symptoms, together with a combined criterion of functional deterioration and biological risk, in defining an “early at-risk of psychosis state” (ERPS), thereby suggesting a clinical risk staging model (Figure 1). Early and late initial prodromal state: a clinical staging approach The positive symptoms typical of schizophrenia — such as delusions, hallucinations or formal thought disorders — often first appear in an attenuated or transient form during the initial prodromal phase. These symptoms provide a valid prediction of conversion into FEP, particularly in the short term. Warning signs of this sort have been used as ultra-high risk (UHR) criteria 27,28. Notwithstanding their differences across studies, these criteria are generally composed of three alternative elements: attenuated positive symptoms (APS), brief limited intermittent psychotic symptoms (BLIPS), or a combination of one or more risk factors (always including genetic risk) and functional decline within a certain recent period. For the ascertainment of the UHR criteria, the Melbourne group gradually developed a specific instrument, the Comprehensive Assessment of At Risk Mental States (CAARMS) 29. Based on the Australian definition of the UHR criteria, the Structured Interview for Prodromal Syndromes (SIPS), the Scale for Prodromal Syndromes (SOPS) and, subsequently, the Criteria of Prodromal Syndromes (COPS) were developed 30,31. Different UHR-related approaches to an early detection of FEP, particularly schizophrenia, were developed by the Hillside Recognition and Prevention (RAP) program in New York 32 and the Basel Früherkennung von Psychosen (FEPSY) study 33. There have been at least 15 prediction studies using UHR criteria, some of which with large samples 34,35,36,37,38,39,40,41. The 12-month rates of transition into FEP published so far range between approximately 13% and 50%. A substantial variance is even observed with comparable observation periods in the same center 34,35. Yet, as the annual incidence for all forms of psychosis in the general population is only about 0.034% 42, even the lowest conversion rates still indicate a dramatic increase in the relative risk of illness, at least in the help-seeking samples of specialized centers. Table 2 depicts the predictive accuracy measures published so far, with the last five listed studies representing secondary predictor analyses of samples meeting at risk criteria. As a result, in the German Research Network on Schizophrenia, the UHR approach was combined with the basic symptom approach and applied in a slightly modified form for the definition of “late at-risk of psychosis state” (LRPS) (Figure 1). This clinical staging model, which suggests a syndromal sequence for the development of FEP progressing from unspecific prodromal symptoms to predictive basic symptoms, and then to APS, to BLIPS and to full-blown psychotic symptoms, was recently strongly supported 15. Universal or selective prevention measures target healthy population groups or clinically still healthy risk carriers, respectively 43. Indicated prevention, instead, targets individuals with basic symptoms and UHR symptoms. Even at the early stages when these individuals seek advice and help at the early recognition and prevention centers, they must be regarded as ill and in need of treatment. Furthermore, the impending deterioration of psychosocial performance in schizophrenia often already occurs in the initial prodromal phase, even prior to the conversion into FEP 14,15. These clinical and psychosocial impairments justify defining the interventions in EPRS and LPRS as indicated prevention, pursuing the following three objectives: a) improvement in the current burden of prodromal symptoms; b) avoidance or perhaps delay in the development of psychosocial handicap; c) prevention of or at least delay or attenuation of psychosis. Five international intervention studies have attempted to find out whether or to what extent these three objectives can be reached 44,45,46,47,48,49,50,51 (Table 3). The preventive measures used were either cognitive behavioral therapy (CBT), adapted to the requirements of the persons at risk, or atypical antipsychotics (risperidone, olanzapine, and amisulpride). These were randomized controlled studies, but there were problems with the blinding condition in the two CBT interventions. This and other methodological shortcomings currently limit conclusions and have encouraged the research groups working in this area to set up new, optimized intervention studies. For example, the protocol of the ongoing parallel group PREVENT study includes careful comparative analyses and superiority and inferiority tests of the psychological and pharmacological treatments 52. A staging of risk, thereby implying a temporal dimension, was considered for the first time in the two intervention studies of the German Research Network on Schizophrenia. One of these studies covered ERPS and only offered CBT as a preventive measure 49,50. The other study was designed for LRPS and used only preventive treatment with amisul-pride 51. When the symptom development in the initial prodromal state follows the sequence shown in Figure 1, it would be beneficial for scientific and especially ethical reasons to focus on psychological interventions in ERPS, which are well tolerated and highly accepted. As soon as the first attenuated or transient psychotic symptoms occur, it seems justifiable to apply well tolerated antipsychotics with few side effects. This differential prevention strategy is now pursued in all German early recognition centers and is also increasingly gaining support in other countries. Another pharmacological option is aripiprazole, tested in a pilot study in UHR states 53. Its possible preventive effects are currently being analyzed in the PREVENT study. Antidepressants were used in a naturalistic, non-randomized observational study of an adolescent sample employing only the APS criterion for inclusion, but, for methodological reasons, this study does not allow any conclusion about differential preventive effects of these medications 54. A critical evaluation of the achievements over the past 15 years through continuous efforts to enhance prediction and prevention of psychoses, particularly of schizophrenia, reveals quite impressive results. However, the results achieved thus far need to be evaluated in the light of the ambitious, initially mentioned objectives of modern predictive and preventive medicine. Once predictive basic symptoms and UHR symptoms have occurred, the underlying pathophysiological process might have already progressed. For such a complex disease with a long-term course and a pre-dispositional basis, this kind of risk identification and risk-oriented prevention may possibly come too late. A more substantial reduction in incidence could be reached with selective and universal prevention measures. Therefore, symptom-based prediction and prevention need to be further developed into the direction of selective prevention for symptom-free risk carriers. In the future, it is necessary to strive for: a) an improvement of risk enrichment with the inclusion of biological risk factors; b) a stronger individualization of the risk estimation by stratification; c) the inclusion of sub-psychotic mental states, as cross-sectionally by current at risk criteria, in the the application of prevention strategies more with the of the the initial prodromal phase for as as then most of the follow-up periods shown in Table 2 are not to the transition A significant number of later may be as and, the predictive of the risk may be 12. Therefore, the first and most important is to out new, optimized large-scale studies with follow-up periods the of the initial prodromal phase, as in the CER study 18. The risk enrichment can also be advanced through the inclusion of following the of recent research on the prediction of through the cognitive impairment This condition a risk for with a conversion rate comparable to the risk for the patients certain imaging and the predictive risk enrichment may be possible for using brain but also impairments of and which are with the psychosis risk and are more and in cases with a later transition to schizophrenia and other new large-scale studies with sufficiently observation periods could whether the risk enrichment can be achieved by of such The of this strategy is on the progress of research on biological and environmental risk factors and their interactions, as is currently attempted in the Network of schizophrenia study In other medical disciplines, such as or a risk which does not in a of is using for multivariate clinical staging by risk In the of study, this approach was into psychosis prediction research for the first time A clinical model was developed based on a including six variables positive disturbances Assessment of in the past and years of Based on the individual a multivariate for further the risk of transition to psychosis into risk was each a increased relative risk to the general with each This model was argued to improve the prediction of psychosis by a of the individual risk in terms of and a more risk estimation or clinical staging of risk, in studies, could the development of risk adapted inclusion criteria for randomized preventive In the first application of this approach in the only clinical and variables were It remains to be whether a model including or environmental variables would increase the predictive accuracy even In studies have to whether such can also be applied to the prediction of psychosis within different time The currently ongoing of the has a about the inclusion of a risk for psychosis in to prevention initially argued this and to the that the application of as criteria could that the high rate of predictions in would be to increase up to in general This is and prior to whether to the in the of the The on the predictive of at risk criteria, thereby the persons meeting at risk criteria already from mental and functional for which they seek Moreover, they psychological and cognitive with and functional the majority of help-seeking at risk persons general criteria for mental disorder a clinically significant behavioral or psychological with disability and have to be considered as i.e. as people with the need and to be these in there are reasons for the inclusion of a clinical in the as by current at risk criteria, not as a prodromal risk for first psychosis, but as an to medical the of such an diagnosis would have the of the by the current mental state to a and Although an increased risk of psychosis would continue to be a of such a the psychological and medical focus would be from an to and At this current state of the criteria would be the for the inclusion of this A for the and of a new of international and studies would be with this inclusion in and later on also in A new prevention approach is by the of and studies a of the onset of psychosis the with the first results are for and The transition rate was lower in an group of UHR adolescents than in a group and this was at a an was evaluated in 10 patients in an pilot and a significant improvement in different was In an study, time was in an UHR group with as with a group suggesting a of This was the first study imaging data on effects in individuals at risk. The preventive of is currently in the process of in the Australian Prodrome study With the of schizophrenia is the first mental disorder to which the prediction and prevention program of modern medicine has been The results are and justify the that in the years to come it be possible to provide preventive strategies to the individual risk of of each In to a reduction in risk assessment has to be by neurobiological and psychosocial risk factors, and indicated prevention has to be further developed towards selective prevention. This a new of large sample studies for prediction as well as prevention, with observation In these studies, of risk selected to predictive must be psychological and pharmacological interventions need to be on a long-term basis, more prevention strategies have to be In to be to and such studies, it would be to mental states, as by the currently used risk symptoms, in the of the

World Psychiatry · 127 citationsread the source →

Collaborative Care for Opioid and Alcohol Use Disorders in Primary Care: The SUMMIT Randomized Clinical Trial.

Importance: Primary care offers an important and underutilized setting to deliver treatment for opioid and/or alcohol use disorders (OAUD). Collaborative care (CC) is effective but has not been tested for OAUD. Objective: To determine whether CC for OAUD improves delivery of evidence-based treatments for OAUD and increases self-reported abstinence compared with usual primary care. Design, setting, and participants: A randomized clinical trial of 377 primary care patients with OAUD was conducted in 2 clinics in a federally qualified health center. Participants were recruited from June 3, 2014, to January 15, 2016, and followed for 6 months. Interventions: Of the 377 participants, 187 were randomized to CC and 190 were randomized to usual care; 77 (20.4%) of the participants were female, of whom 39 (20.9%) were randomized to CC and 38 (20.0%) were randomized to UC. The mean (SD) age of all respondents at baseline was 42 (12.0) years, 41(11.7) years for the CC group, and 43 (12.2) yearsfor the UC group. Collaborative care was a system-level intervention, designed to increase the delivery of either a 6-session brief psychotherapy treatment and/or medication-assisted treatment with either sublingual buprenorphine/naloxone for opioid use disorders or long-acting injectable naltrexone for alcohol use disorders. Usual care participants were told that the clinic provided OAUD treatment and given a number for appointment scheduling and list of community referrals. Main outcomes and measures: The primary outcomes were use of any evidence-based treatment for OAUD and self-reported abstinence from opioids or alcohol at 6 months. The secondary outcomes included the Healthcare Effectiveness Data and Information Set (HEDIS) initiation and engagement measures, abstinence from other substances, heavy drinking, health-related quality of life, and consequences from OAUD. Results: At 6 months, the proportion of participants who received any OAUD treatment was higher in the CC group compared with usual care (73 [39.0%] vs 32 [16.8%]; logistic model adjusted OR, 3.97; 95% CI, 2.32-6.79; P < .001). A higher proportion of CC participants reported abstinence from opioids or alcohol at 6 months (32.8% vs 22.3%); after linear probability model adjustment for covariates (β = 0.12; 95% CI, 0.01-0.23; P = .03). In secondary analyses, the proportion meeting the HEDIS initiation and engagement measures was also higher among CC participants (initiation, 31.6% vs 13.7%; adjusted OR, 3.54; 95% CI, 2.02-6.20; P < .001; engagement, 15.5% vs 4.2%; adjusted OR, 5.89; 95% CI, 2.43-14.32; P < .001) as was abstinence from opioids, cocaine, methamphetamines, marijuana, and any alcohol (26.3% vs 15.6%; effect estimate, β = 0.13; 95% CI, 0.03-0.23; P = .01). Conclusions and relevance: Among adults with OAUD in primary care, the SUMMIT collaborative care intervention resulted in significantly more access to treatment and abstinence from alcohol and drugs at 6 months, than usual care. Trial registration: clinicaltrials.gov Identifier: NCT01810159.

JAMA internal medicine · randomised controlled trial · 174 citationsread the source →

Digital Cognitive Behavioral Therapy for Insomnia Using a Smartphone Application in China: A Pilot Randomized Clinical Trial.

Importance: Digital cognitive behavioral therapy for insomnia (DCBT-I) requires adaptation to different sociocultural contexts. Moreover, studies comparing DCBT-I and sleep education in the same operating interface are lacking. Objective: To investigate the efficacy of a smartphone-based Chinese culture-adapted DCBT-I application (app) for insomnia compared with sleep education using the same app. Design, setting, and participants: This was a single-blinded, randomized clinical trial conducted from March 2021 to January 2022. Screening and randomization were conducted at Peking University First Hospital. Follow-up visits were performed online or in the same hospital. After assessing for eligibility, eligible participants were enrolled and allocated (1:1) to DCBT-I or sleep education groups. Data were analyzed from January to February 2022. Interventions: A Chinese smartphone-based app with the same interface was used in both DCBT-I and sleep education groups over 6 weeks, with 1-, 3-, and 6-month follow-ups. Main outcomes and measures: The primary outcome was Insomnia Severity Index (ISI) scores with the intention-to-treat principle. Secondary and exploratory outcomes included sleep diary measures; self-reported scales assessing dysfunctional beliefs about sleep, mental health, and quality of life; and smart bracelet measures. Results: Of 82 participants (mean [SD] age, 49.67 [14.49] years; 61 [74.4%] females), with 41 randomized to sleep education and 41 randomized to DCBT-I; 77 participants completed the 6-week intervention (39 participants in the sleep education group and 38 participants in the DCBT-I group; full analysis data set) and 73 completed the 6-month follow-up (per protocol data set). Mean (SD) ISI scores in the DCBT-I group were significantly lower than those in the sleep education group after the 6-week intervention (12.7 [4.8] points vs 14.9 [5.0] points; Cohen d = 0.458; P = .048) and at the 3-month follow-up (12.1 [5.4] points vs 14.8 [5.5] points; Cohen d = 0.489; P = .04). There were significant improvements from before to after the intervention for both the sleep education and DCBT-I groups, with large effect sizes(sleep education: d = 1.13; DCBT-I: d = 1.71). Some of the sleep diary measures and self-reported scales showed more improvements in the DCBT-I group than sleep education group, such as total sleep time (mean [SD]: 3 months, 403.9 [57.6] minutes vs 363.2 [72.3] minutes; 6 months, 420.3 [58.0] minutes vs 389.7 [59.4] minutes) and sleep efficiency (mean [SD]: 3 months, 87.4% [8.3%] vs 76.7% [12.1%]; 6 months, 87.5% [8.2%] vs 78.1% [10.9%]). Conclusions and relevance: In this randomized clinical trial, the smartphone-based Chinese culture-adapted DCBT-I improved insomnia severity compared with sleep education. Future multicenter clinical trials with large sample sizes are needed to validate its effectiveness in the Chinese population. Trial registration: ClinicalTrials.gov Identifier: NCT04779372.

JAMA network open · randomised controlled trial · 36 citationsread the source →

Short-course radiotherapy followed by chemotherapy before total mesorectal excision (TME) versus preoperative chemoradiotherapy, TME, and optional adjuvant chemotherapy in locally advanced rectal cancer (RAPIDO): a randomised, open-label, phase 3 trial.

Background: Systemic relapses remain a major problem in locally advanced rectal cancer. Using short-course radiotherapy followed by chemotherapy and delayed surgery, the Rectal cancer And Preoperative Induction therapy followed by Dedicated Operation (RAPIDO) trial aimed to reduce distant metastases without compromising locoregional control. Methods: In this multicentre, open-label, randomised, controlled, phase 3 trial, participants were recruited from 54 centres in the Netherlands, Sweden, Spain, Slovenia, Denmark, Norway, and the USA. Patients were eligible if they were aged 18 years or older, with an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1, had a biopsy-proven, newly diagnosed, primary, locally advanced rectal adenocarcinoma, which was classified as high risk on pelvic MRI (with at least one of the following criteria: clinical tumour [cT] stage cT4a or cT4b, extramural vascular invasion, clinical nodal [cN] stage cN2, involved mesorectal fascia, or enlarged lateral lymph nodes), were mentally and physically fit for chemotherapy, and could be assessed for staging within 5 weeks before randomisation. Eligible participants were randomly assigned (1:1), using a management system with a randomly varying block design (each block size randomly chosen to contain two to four allocations), stratified by centre, ECOG performance status, cT stage, and cN stage, to either the experimental or standard of care group. All investigators remained masked for the primary endpoint until a prespecified number of events was reached. Patients allocated to the experimental treatment group received short-course radiotherapy (5 × 5 Gy over a maximum of 8 days) followed by six cycles of CAPOX chemotherapy (capecitabine 1000 mg/m2 orally twice daily on days 1-14, oxaliplatin 130 mg/m2 intravenously on day 1, and a chemotherapy-free interval between days 15-21) or nine cycles of FOLFOX4 (oxaliplatin 85 mg/m2 intravenously on day 1, leucovorin [folinic acid] 200 mg/m2 intravenously on days 1 and 2, followed by bolus fluorouracil 400 mg/m2 intravenously and fluorouracil 600 mg/m2 intravenously for 22 h on days 1 and 2, and a chemotherapy-free interval between days 3-14) followed by total mesorectal excision. Choice of CAPOX or FOLFOX4 was per physician discretion or hospital policy. Patients allocated to the standard of care group received 28 daily fractions of 1·8 Gy up to 50·4 Gy or 25 fractions of 2·0 Gy up to 50·0 Gy (per physician discretion or hospital policy), with concomitant twice-daily oral capecitabine 825 mg/m2 followed by total mesorectal excision and, if stipulated by hospital policy, adjuvant chemotherapy with eight cycles of CAPOX or 12 cycles of FOLFOX4. The primary endpoint was 3-year disease-related treatment failure, defined as the first occurrence of locoregional failure, distant metastasis, new primary colorectal tumour, or treatment-related death, assessed in the intention-to-treat population. Safety was assessed by intention to treat. This study is registered with the EudraCT, 2010-023957-12, and ClinicalTrials.gov, NCT01558921, and is now complete. Findings: Between June 21, 2011, and June 2, 2016, 920 patients were enrolled and randomly assigned to a treatment, of whom 912 were eligible (462 in the experimental group; 450 in the standard of care group). Median follow-up was 4·6 years (IQR 3·5-5·5). At 3 years after randomisation, the cumulative probability of disease-related treatment failure was 23·7% (95% CI 19·8-27·6) in the experimental group versus 30·4% (26·1-34·6) in the standard of care group (hazard ratio 0·75, 95% CI 0·60-0·95; p=0·019). The most common grade 3 or higher adverse event during preoperative therapy in both groups was diarrhoea (81 [18%] of 460 patients in the experimental group and 41 [9%] of 441 in the standard of care group) and neurological toxicity during adjuvant chemotherapy in the standard of care group (16 [9%] of 187 patients). Serious adverse events occurred in 177 (38%) of 460 participants in the experimental group and, in the standard of care group, in 87 (34%) of 254 patients without adjuvant chemotherapy and in 64 (34%) of 187 with adjuvant chemotherapy. Treatment-related deaths occurred in four participants in the experimental group (one cardiac arrest, one pulmonary embolism, two infectious complications) and in four participants in the standard of care group (one pulmonary embolism, one neutropenic sepsis, one aspiration, one suicide due to severe depression). Interpretation: The observed decreased probability of disease-related treatment failure in the experimental group is probably indicative of the increased efficacy of preoperative chemotherapy as opposed to adjuvant chemotherapy in this setting. Therefore, the experimental treatment can be considered as a new standard of care in high-risk locally advanced rectal cancer. Funding: Dutch Cancer Foundation, Swedish Cancer Society, Spanish Ministry of Economy and Competitiveness, and Spanish Clinical Research Network.

The Lancet. Oncology · randomised controlled trial · 1212 citationsread the source →

Effectiveness of a brief lay counsellor-delivered, problem-solving intervention for adolescent mental health problems in urban, low-income schools in India: a randomised controlled trial.

Background: Mental health problems are a leading cause of disability in adolescents worldwide. Problem solving is a well-tested mental health intervention in many populations. We aimed to investigate the effectiveness of a brief, transdiagnostic problem-solving intervention for common adolescent mental health problems when delivered by non-specialist school counsellors in New Delhi, India. Methods: This randomised trial was done in six government-run schools (three all-boys schools, two all-girls schools, and one co-educational school) that serve low-income communities. We recruited participants from grades 9 to 12 (ages 12-20 years) by selecting students with persistently elevated mental health symptoms accompanied by distress or functional impairment. Clinical eligibility criteria were assessed by research assistants using the Hindi-language version of the Strengths and Difficulties Questionnaire (SDQ), with reference to locally validated borderline cutoff scores of 19 or greater for boys and 20 or greater for girls on the SDQ Total Difficulties scale, an abnormal score of 2 or more on the SDQ Impact scale, and persistence of more than 1 month on the SDQ Chronicity index. Participants were randomly allocated (1:1) to problem solving delivered through a brief (2-3 week) counsellor-led intervention with supporting printed materials (intervention group), or problem solving delivered via printed booklets alone (control group). Primary outcomes were adolescent-reported mental health symptoms (SDQ Total Difficulties scale) and idiographic psychosocial problems (Youth Top Problems [YTP]) at 6 weeks. Primary analyses were done on an intention-to-treat basis at the 6-week endpoint. The trial is registered with ClinicalTrials.gov, NCT03630471. Findings: Participants were enrolled between Aug 20, and Dec 4, 2018. 283 eligible adolescents were referred to the trial, and 251 (89%) of these were enrolled (mean age 15·61 years; 174 [69%] boys). 125 participants were allocated to each group (after accounting for one participant in the intervention group who withdrew consent after randomisation). Primary outcome data were available for 245 (98%) participants. At 6 weeks, the mean YTP scores were 3·52 (SD 2·66) in the intervention group and 4·60 (2·75) in the control group (adjusted mean difference -1·01, 95% CI -1·63 to -0·38; adjusted effect size 0·36, 95% CI 0·11 to 0·61; p=0·0015). The mean SDQ Total Difficulties scores were 17·48 (5·45) in the intervention group and 18·33 (5·45) in the control group (-0·86, -2·14 to 0·41; 0·16, -0·09 to 0·41; p=0·18). We observed no adverse events. Interpretation: A brief lay counsellor-delivered problem-solving intervention combined with printed booklets seemed to have a modest effect on psychosocial outcomes among adolescents with diverse mental health problems compared with problem-solving booklets alone. This counsellor-delivered intervention might be a suitable first-line intervention in a stepped care approach, which is being evaluated in ongoing studies. Funding: Wellcome Trust.

The Lancet. Child & adolescent health · randomised controlled trial · 69 citationsread the source →

Promoting school climate and health outcomes with the SEHER multi-component secondary school intervention in Bihar, India: a cluster-randomised controlled trial.

Background: School environments affect health and academic outcomes. With increasing secondary school retention in low-income and middle-income countries, promoting quality school social environments could offer a scalable opportunity to improve adolescent health and wellbeing. Methods: We did a cluster-randomised trial to assess the effectiveness of a multi-component whole-school health promotion intervention (SEHER) with integrated economic and process evaluations in grade 9 students (aged 13-14 years) at government-run secondary schools in the Nalanda district of Bihar state, India. Schools were randomly assigned (1:1:1) to three groups: the SEHER intervention delivered by a lay counsellor (the SEHER Mitra [SM] group), the SEHER intervention delivered by a teacher (teacher as SEHER Mitra [TSM] group), and a control group in which only the standard government-run classroom-based life-skills Adolescence Education Program was implemented. The primary outcome was school climate measured with the Beyond Blue School Climate Questionnaire (BBSCQ). Students were assessed at the start of the academic year (June, 2015) and again 8 months later at the end of the academic year (March, 2016) via self-completed questionnaires. This study is registered with ClinicalTrials.gov, number NCT02484014. Findings: Of the 112 eligible schools in the Nalanda district, 75 were randomly selected to participate in the trial. We randomly assigned 25 schools to each of the three groups. One school subsequently dropped out of the TSM group, leaving 24 schools in this group. The baseline survey included a total of 13 035 participants, and the endpoint survey included 14 414 participants. Participants in the SM-delivered intervention schools had substantially higher school climate scores at endpoint survey than those in the control group (BBSCQ baseline-adjusted mean difference [aMD] 7·57 [95% CI 6·11-9·03]; effect size 1·88 [95% CI 1·44-2·32], p<0·0001) and the TSM-delivered intervention (aMD 7·57 [95% CI 6·06-9·08]; effect size 1·88 [95% CI 1·43-2·34], p<0·0001). There was no effect of the TSM-delivered intervention compared with control (aMD -0·009 [95% CI -1·53 to 1·51], effect size 0·00 [95% CI -0·45 to 0·44], p=0·99). Compared with the control group, participants in the SM-delivered intervention schools had moderate to large improvements in the secondary outcomes of depression (aMD -1·23 [95% CI -1·89 to -0·57]), bullying (aMD -0·91 [95% CI -1·15 to -0·66]), violence victimisation (odds ratio [OR] 0·62 [95% CI 0·46-0·84]), violence perpetration (OR 0·68 [95% CI 0·48-0·96]), attitude towards gender equity (aMD 0·41 [95% CI 0·21-0·61]), and knowledge of reproductive and sexual health (aMD 0·29 [95% CI 0·06-0·53]). Similar results for these secondary outcomes were noted for the comparison between SM-delivered intervention schools and TSM-delivered intervention schools (depression: aMD -1·23 [95% CI -1·91 to -0·55]; bullying: aMD -0·83 [95% CI -1·08 to -0·57]; violence victimisation: OR 0·49 [95% CI 0·35-0·67]; violence perpetration: OR 0·49 [95% CI 0·34-0·71]; attitude towards gender equity: aMD 0·23 [95% CI 0·02-0·44]; and knowledge of reproductive and sexual health: aMD 0·22 [95% CI -0·02 to 0·47]). However, no effects on these secondary outcomes were observed for the TSM-delivered intervention schools compared with the control group (depression: aMD -0·03 [95% CI -0·70 to 0·65]; bullying: aMD -0·08 [95% CI -0·34 to 0·18]; violence victimisation: OR 1·27 [95% CI 0·93-1·73]; violence perpetration: OR 1·37 [95% CI 0·95-1·95]; attitude towards gender equity: aMD 0·17 [95% CI -0·09 to 0·38]; and knowledge of reproductive and sexual health: aMD 0·06 [95% CI -0·18 to 0·32]). Interpretation: The multi-component whole-school SEHER health promotion intervention had substantial beneficial effects on school climate and health-related outcomes when delivered by lay counsellors, but no effects when delivered by teachers. Future research should focus on the evaluation of the scaling up of the SEHER intervention in diverse contexts and delivery agents. Funding: John D. and Catherine T. MacArthur Foundation, USA and the United Nations Population Fund India Office.

Lancet (London, England) · randomised controlled trial · 121 citationsread the source →

Smoking cessation for people with severe mental illness (SCIMITAR+): a pragmatic randomised controlled trial.

Background: People with severe mental illnesses such as schizophrenia are three times more likely to smoke than the wider population, contributing to widening health inequalities. Smoking remains the largest modifiable risk factor for this health inequality, but people with severe mental illness have not historically engaged with smoking cessation services. We aimed to test the effectiveness of a combined behavioural and pharmacological smoking cessation intervention targeted specifically at people with severe mental illness. Methods: In the smoking cessation intervention for severe mental illness (SCIMITAR+) trial, a pragmatic, randomised controlled study, we recruited heavy smokers with bipolar disorder or schizophrenia from 16 primary care and 21 community-based mental health sites in the UK. Participants were eligible if they were aged 18 years or older, and smoked at least five cigarettes per day. Exclusion criteria included substantial comorbid drug or alcohol problems and people who lacked capacity to consent at the time of recruitment. Using computer-generated random numbers, participants were randomly assigned (1:1) to a bespoke smoking cessation intervention or to usual care. Participants, mental health specialists, and primary care physicians were unmasked to assignment. The bespoke smoking cessation intervention consisted of behavioural support from a mental health smoking cessation practitioner and pharmacological aids for smoking cessation, with adaptations for people with severe mental illness-such as, extended pre-quit sessions, cut down to quit, and home visits. Access to pharmacotherapy was via primary care after discussion with the smoking cessation specialist. Under usual care participants were offered access to local smoking cessation services not specifically designed for people with severe mental illnesses. The primary endpoint was smoking cessation at 12 months ascertained via carbon monoxide measurements below 10 parts per million and self-reported cessation for the past 7 days. Secondary endpoints were biologically verified smoking cessation at 6 months; number of cigarettes smoked per day, Fagerström Test for Nicotine Dependence (FTND) and Motivation to Quit (MTQ) questionnaire; general and mental health functioning determined via the Patient Health Questionnaire-9 (PHQ-9), the Generalised Anxiety Disorder-7 (GAD-7) questionnaire, and 12-Item Short Form Health Survey (SF-12); and body-mass index (BMI). This trial was registerd with the ISRCTN registry, number ISRCTN72955454, and is complete. Findings: Between Oct 7, 2015, and Dec 16, 2016, 526 eligible patients were randomly assigned to the bespoke smoking cessation intervention (n=265) or usual care (n=261). 309 (59%) participants were male, median age was 47·2 years (IQR 36·3-54·5), with high nicotine dependence (mean 24 cigarettes per day [SD 13·2]), and the most common severe mental disorders were schizophrenia or other psychotic illness (n=343 [65%]), bipolar disorder (n=115 [22%]), and schizoaffective disorder (n=66 [13%]). 234 (88%) of intervention participants engaged with the treatment programme and attended 6·4 (SD 3·5) quit smoking sessions, with an average duration of 39 min (SD 17; median 35 min, range 5-120). Verified quit data at 12 months were available for 219 (84%) of 261 usual care and 223 (84%) of 265 intervention participants. The proportion of participants who had quit at 12 months was higher in the intervention group than in the usual care group, but non-significantly (34 [15%] of 223 [13% of those assigned to group] vs 22 [10%] of 219 [8% of those assigned to group], risk difference 5·2%, 95% CI -1·0 to 11·4; odds ratio [OR] 1·6, 95% CI 0·9 to 2·9; p=0·10). The proportion of participants who quit at 6 months was significantly higher in the intervention group than in the usual care group (32 [14%] of 226 vs 14 [6%] of 217; risk difference 7·7%, 95% CI 2·1 to 13·3; OR 2·4, 95% CI 1·2 to 4·6; p=0·010). The incidence rate ratio for number of cigarettes smoked per day at 6 months was 0·90 (95% CI 0·80 to 1·01; p=0·079), and at 12 months was 1·00 (0·89 to 1·13; p=0·95). At both 6 months and 12 months, the intervention group was non-significantly favoured in the FTND (adjusted mean difference 6 months -0·18, 95% CI -0·53 to 0·17, p=0·32; and 12 months -0·01, -0·39 to 0·38, p=0·97) and MTQ questionnaire (adjusted mean difference 0·58, -0·01 to 1·17, p=0·056; and 12 months 0·64, 0·04 to 1·24, p=0·038). The PHQ-9 showed no difference between the groups (adjusted mean difference at 6 months 0·20, 95% CI -0·85 to 1·24 vs 12 months -0·12, -1·18 to 0·94). For the SF-12 survey, we saw evidence of improvement in physical health in the intervention group at 6 months (adjusted mean difference 1·75, 95% CI 0·21 to 3·28), but this difference was not evident at 12 months (0·59, -1·07 to 2·26); and we saw no difference in mental health between the groups at 6 or 12 months (adjusted mean difference at 6 months -0·73, 95% CI -2·82 to 1·36, and 12 months -0·41, -2·35 to 1·53). The GAD-7 questionnaire showed no difference between the groups (adjusted mean difference at 6 months -0·32 95% CI -1·26 to 0·62 vs 12 months -0·10, -1·05 to 0·86). No difference in BMI was seen between the groups (adjusted mean difference 6 months 0·16, 95% CI -0·54 to 0·85; 12 months 0·25, -0·62 to 1·13). Interpretation: This bespoke intervention is a candidate model of smoking cessation for clinicians and policy makers to address high prevalence of smoking. The incidence of quitting at 6 months shows that smoking cessation can be achieved, but the waning of this effect by 12 months means more effort is needed for sustained quitting. Funding: National Institute for Health Research Health Technology Assessment Programme.

The lancet. Psychiatry · randomised controlled trial · 134 citationsread the source →

Whither the Attenuated Psychosis Syndrome?

After 4 years of debate, a decision has been made. The attenuated psychosis syndrome (APS) will not be a coded diagnosis in the Diagnostic and Statistical Manual of Mental Disorders (DSM-5). Formerly known as the psychosis risk syndrome, the proposed diagnosis was based on criteria developed in the mid-1990s that were informed by a comprehensive review of retrospective studies on the prodromal phase of nonaffective psychosis.1 These criteria aimed to identify prospectively people in the prodrome of schizophrenia and other psychotic disorders and have been variously titled “ultra high risk (UHR),” “clinical high risk (CHR),” “at risk mental state (ARMS),” and the “prodromal stage,” and included a group with attenuated (subthreshold) positive psychotic symptoms.2 The criteria are associated with rates of onset of psychotic disorder substantially higher than in the general population3 and other clinical populations.4 A recent meta-analysis reported the rate of onset of a psychotic disorder to be 36% after 3 years.5 About 73% of those developing a psychotic disorder fulfill criteria for schizophrenia spectrum psychoses.6 It should be noted that these data are from treated samples consisting of patients referred to specialist clinical services. Despite the consistent finding that there is a high risk of developing a psychotic disorder associated with the APS group,5 there has been considerable controversy around the idea of formally codifying it into a DSM5 diagnosis. Indeed, we, the authors of this communication, all active researchers in the area, have had differences in opinion about the merits of including APS as a new diagnosis in the DSM.7–12 One issue debated was the tension between the possibility of early intervention to prevent progression of disorder vs potential unnecessary diagnosis and treatment of what might be a self-limiting phase. The possibility of stigma and discrimination was also raised.10,11 Some speculated that a formal diagnosis would be assumed to equate to an indication for antipsychotic medication and so increase the likelihood of antipsychotic prescription.11 Others argued that the absence of an APS diagnosis has led to some clinicians using the term psychosis NOS (not otherwise specified), which may lead to antipsychotic prescription. The APS as an alternative to this diagnosis could then actually reduce antipsychotic prescribing.9,12 Importantly, an APS diagnosis will enable evidence-based treatments to be developed, including psychological therapies, and could therefore decrease antipsychotic use.12 Ultimately, the decision to exclude APS as a coded diagnosis was made not in response to any of the above issues or in the light of data addressing the principal disputes but because data on the diagnostic reliability of APS in clinical practice were limited and inconclusive. Following this decision, some critics have been quick to denounce the whole APS/ultra high-risk/clinical high-risk/prodromal concept.13–15 We, therefore, feel it is timely, as a group involved in high-risk (prodromal) research, to document some points of consensus between us and highlight areas for future research. Attempts to recognize the prodrome of schizophrenia prospectively have been active for nearly 20 years.2 Many samples of persons meeting high-risk criteria have been seen and evaluated. A strong consensus exists that individuals meeting APS criteria (which includes a criterion for help-seeking) are symptomatic and in need of clinical care.16–18 People meeting the criteria do in fact fulfill the broad definition of mental disorder: “a clinically significant behavioral and psychological syndrome or pattern … that is associated with present distress … or disability … or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom,”19 (p. xxi). Thus, treatment is clearly justified, regardless of the justification of reduction of risk or prevention. We agree that this treatment should include monitoring of mental state, supportive therapy, and attention to current practical needs. Cognitive therapy and omega-3 fatty acids may also be helpful. On current evidence, antipsychotic medication is no more effective than other more benign treatments and so is typically not recommended.20 A second point of consensus is that people meeting APS criteria have a greatly increased risk of developing a psychotic disorder within a brief time frame.3,5,21,22 Despite evidence that the transition rate (conversion from high-risk state to first-episode psychosis) may be declining in the short term23 and the finding of low rate of psychosis in recent intervention trials,24,25 its magnitude is similar to other risk syndromes,26,27 and still in the order of hundreds fold above the risk of the general population. Given this, we agree that regular assessment of mental state to detect first episode of psychosis is indicated. The monitoring of mental state and early detection of psychosis allow prompt treatment and the minimization of the duration of untreated psychosis, which, if prolonged, is harmful to both patients and their families and is known to be associated with a poor outcome.28,29 Finally, we agree that more research into the APS is needed. We support the Psychotic Disorders Workgroup in its recommendation to include the APS as a category in the appendix (Section 3) of DSM-5 as a condition for further study. Collectively, we have devoted many hours into thinking about this condition. Through our research and clinical experience with these patients, we have evolved our thinking and our conceptualization of APS. Initially, the high-risk criteria were developed, as the name suggests, to detect individuals at high risk of psychotic disorder. However, the use of the criteria should not be thought of as identifying and treating an asymptomatic group at risk of a poor outcome, analogous to detecting and treating hyperlipidemia to prevent myocardial infarction (MI). APS patients are symptomatic and distressed. Thus, angina may be a more apt analogy. However, better still is to think of the criteria as detecting chest pain. The condition is distressing, symptomatic, and leads to help seeking. It may indicate the early signs or risk for a serious cardiac disease such as MI, a serious but noncardiac disease, such as pneumonia or a benign self-limiting condition such as esophageal spasm or costochondritis. Likewise, APS may indicate the early signs or risk for illnesses such as nonaffective and affective psychotic disorder, presence or risk for a serious but nonpsychotic illness such as severe unipolar depression, or it may indicate something that is not serious and which may resolve, with or without treatments such as psychological support, stress reduction family interventions, and practical help. This way of conceptualizing APS leads to many different paths for research. Suggestions for the future research agenda follow. Investigation of different outcomes in both the short and long term including psychotic disorders, nonpsychotic disorders, persistence or remission of APS, and social and cognitive functioning is needed. Refining risk factors for these different outcomes is another avenue of research. It may be that added criteria are necessary to enrich the sample for schizophrenia, such as basic and negative symptoms and decline in cognitive and social skills.30,31 Other methods of enrichment for other outcomes can also be studied, including multiple subclinical symptoms plus depression,32 presence of personality disorder, family history of mental disorder, and childhood trauma and adversity.33 Examining recovery and remission of the high-risk state as outcomes is another area that is currently understudied. Searching for predictors of these positive outcomes can then lead to adding such factors to ascertainment criteria as exclusions, which would result in a reduced false positive rate and increased positive predictive power. Examining associated neurobiological,34–36 cognitive,37 physiological,38 metabolic,39 and genetic40,41 associations with the APS and its different outcomes is needed so that subgroups can be more sharply delineated. Longitudinal follow-up is needed to elucidate whether the biological markers that are observed in the APS group are indicative of a trait vulnerability to psychotic disorder or whether they are state markers. Comparison with other psychiatric groups without APS will determine whether biological findings are specific to APS and represent a continuum with psychotic disorders such as schizophrenia or whether they are associated with general psychiatric distress. Research is also needed as to what harms and benefits are associated with an APS diagnosis. This should include assessing any perceived stigma, and comparison made with the stigma, stereotypes, and wish for social distance associated with overt psychiatric symptoms that may occur prior to help seeking and diagnosis. Whether clinical care that provides information, treatment, and hope of a good outcome can minimize stigma should also be studied. The effects of creating a new diagnosis, on patients, their families, and the wider health system, needs to be better understood. While reliability of assessment has been demonstrated in previous studies using structured interviews,42,43 the clinical utility and reliability of assessment in routine practice needs to be assessed and improved and the impact of the proposed diagnosis on prescribing practice examined. Investigation of factors that lead APS patients to seek help will also be useful. Currently, it is unclear how much of the distress that leads to seeking help is related to the psychotic-like symptoms or to associated nonpsychotic mental disorders, such as depression and anxiety.44 Little is known about the prevalence of APS in adolescent and adult clinical populations and in the general community and this also needs further study. Further intervention research is also needed. Omega-3 fatty acids have shown promise in reducing symptoms as well as decreasing the risk of transition to psychotic disorder in one study.45 This requires replication. Other novel treatments such as psychological treatments, vitamin D, glycine, and other neuroprotective agents are also worth testing. Finally, with increasing the knowledge of risk factors for different outcomes (see above), the APS model could also be extended to a more general a strategy for early intervention in a range of mental disorders. It may be that many disorders develop from initial nonspecific symptoms and syndromes, from a background of specific and nonspecific risk factors (such as genes and early environment). Worsening of symptoms and acquisition of new symptoms may occur, together with progressive neurobiological abnormalities, and related neurobehavioral deficits, until clear-cut recognizable mental disorders appear.46 Progression of symptoms and neurobiological abnormalities could continue after “threshold” diagnosis, with development of chronic symptoms, relapses, and ongoing functional deterioration. Transition from one stage to the next is not inevitable, either due to different risk and resilience factors or due to nonspecific or specific intervention. Thus, preventive possibilities exist across this spectrum of evolving illness. This concept of a pluripotent risk syndrome opens up a range of research possibilities. Studying genetic and environmental risk factors and gene and environment interactions for different outcomes, further work on resilience and protective factors, and examination of different trajectories are all future avenues of research. Whether any specific markers for particular course and outcome can be detected early is another area and leads to the possibility of early specific treatments. Novel methods such as multimodal imaging and neurocognitive analysis, single subject methods to predict individual disease course are also possible. APS concept remains a useful one. It identifies people with significant mental health problems that justify treatment in their own right, as well as having a higher likelihood of developing a psychotic disorder (mostly schizophrenia) within a few years. Research into this group will increase our understanding of psychotic-like symptoms and their trajectories and the emerging phase of psychotic disorders. The APS concept is consistent with the continuum view of psychosis and is probably a reflection of biologic reality. Outcomes other than psychotic disorder are also clearly worthy of study. The placement of APS in the DSM-5 appendix should be a clarion call to the field to focus attention on these patients and families in need. National Health and Medical Research Council (Australia) Senior Research Fellowship (#566593), and the Colonial Foundation (to A.R.Y.); National Institute for Mental Health (NIMH) grants (#5U01MH081857 and #5R01 MH061523 to B.A.C.); German Research Foundation, NARSAD, the German Ministry of Education and Research, the Faculty of Medicine of the University of Cologne (to A.B.); the National Institute for Health Research (NIHR) Birmingham and Black Country Collaboration for Leadership in Applied Health Research and Care (to M.B.); NIHR Biomedical Research Centre for Mental Health at the South London and Maudsley NHS Foundation Trust and Institute of Psychiatry King’s College London (to P.F.-P., P.M., and L.V.); the German Research Foundation, the European Commission, the German Ministry of Education and Research, and the Faculty of Medicine of the University of Cologne (to J.K.); the University of Basel (to S.B. and A.R.-R.), Swiss National Foundation, Stanley Foundation, European Union FP7, Österreichische Forschungsförderungsgesellschaft, Foundation Alamaya (to A.R.-R.); NIMH (U01 MH081928, P50 MH080272), Massachusetts Department of Mental Health, R21 MH093294, R01 MH096027 (to L.S.); and NIMH and the Norwegian Research Council (to T.H.M.). A.B. and J.K. have received investigator-initiated grant support from Bristol Myers Squibb. A.B. has received speaker fees and travel support from Bristol Myers Squibb, Eli Lilly, Janssen Cilag, and Servier. P.D.M. has received unrestricted research grant support from Janssen Cilag, honoraria for educational events and consultancies from Janssen-Cilag and Roche, and unrestricted Research Grant Support from Astra Zeneca. As these sources of funding have not influenced the content of this article, all authors have declared that there are no conflicts of interest in relation to the subject of this article.

Schizophrenia Bulletin · 97 citationsread the source →

Emotion regulation in schizophrenia: affective, social, and clinical correlates of suppression and reappraisal.

Individuals can exert considerable control over their experience and expression of emotion by applying different regulatory strategies such as reappraisal and suppression. However, although it has been suggested that blunted affect in schizophrenia, characterized by markedly reduced emotion expressivity alongside apparently normal emotion experience, may reflect overuse of suppression, no study to date has assessed self-reported use of these different emotion regulatory strategies in relation to this disorder. In the present study, 41 individuals with schizophrenia and 38 control participants completed a self-report measure that differentiated between use of suppression and reappraisal. Symptom severity and various aspects of cognitive and psychosocial functioning were also assessed. Relative to controls, individuals with schizophrenia did not differ with regard to their reported use of suppression and reappraisal, and reported use of both strategies was unrelated to clinical ratings of blunted affect. However, whereas (lower) use of reappraisal was associated with greater social function impairment for both groups, only for controls was (greater) use of suppression associated with reduced social functioning. Implications for understanding blunted affect and social dysfunction in schizophrenia are discussed.

Journal of abnormal psychology · 83 citationsread the source →

An interdisciplinary meta-analysis of the potential antecedents, correlates, and consequences of protégé perceptions of mentoring.

This meta-analysis summarized youth, academic, and workplace research on the potential antecedents (demographics, human capital, and relationship attributes), correlates (interaction frequency, relationship length, performance, motivation, and social capital), and consequences (attitudinal, behavioral, career-related, and health-related outcomes) of protégé perceptions of instrumental support, psychosocial support, and relationship quality to the mentor or to the relationship. A total of 173 meta-analytic correlations were computed based on data from 173 samples and a combined N of 40,737. Among antecedents, positive protégé perceptions were most strongly associated with greater similarity in attitudes, values, beliefs, and personality with their mentors (ρ ranged from .38 to .59). Among correlates, protégé perceptions of greater instrumental support (ρ = .35) and relationship quality (ρ = .54) were most strongly associated with social capital while protégé perceptions of greater psychosocial support were most strongly associated with interaction frequency (ρ = .25). Among consequences, protégé perceptions of greater instrumental support (ρ = .36) and relationship quality (ρ = .38) were most strongly associated with situational satisfaction while protégé perceptions of psychosocial support were most highly associated with sense of affiliation (ρ = .41). Comparisons between academic and workplace mentoring generally revealed differences in magnitude, rather than direction, of the obtained effects. The results should be interpreted in light of the methodological limitations (primarily cross-sectional designs and single-source data) and, in some instances, a small number of primary studies.

Psychological bulletin · meta-analysis · 126 citationsread the source →

The Social Epidemiology of Human Immunodeficiency Virus/Acquired Immunodeficiency Syndrome

Social epidemiology is defined as the study of the distribution of health outcomes and their social determinants (1). It builds on the classic epidemiologic triangle of host, agent, and environment to focus explicitly on the role of social determinants in infectious disease transmission and progression. These determinants are the “features of and pathways by which societal conditions affect health” (2, p. 697). Early studies of human immunodeficiency virus (HIV)/acquired immunodeficiency syndrome (AIDS) focused on individual characteristics and behaviors in determining HIV risk, an approach that Fee and Krieger (3) refer to as “biomedical individualism.” Biomedical individualism is the basis of risk factor epidemiology; by contrast, the social epidemiology perspective emphasizes social conditions as fundamental causes of disease (4) (table 1). Social epidemiologists examine how persons become exposed to risk or protective factors and under what social conditions individual risk factors are related to disease. Social factors are thus the focus of analysis and are not simply adjusted for as potentially confounding factors or used as proxies for unavailable individual-level data. Social factors are indeed critical to understanding nonuniform infectious disease patterns that emerge as a result of the dependent nature of disease transmission or the idea that an outcome in one person is dependent upon outcomes and exposures in others (5, 6). Contact patterns that enhance HIV/AIDS vulnerability may be conceptualized at multiple levels. Figure 1 distinguishes determinants of HIV/AIDS at three levels: individual, social, and structural. Individual factors include biologic, demographic, and behavioral risk factors that may influence the risk of HIV acquisition and disease progression. Social-level factors include critical pathways by which community and network structures link persons to society. These structures are central to understanding the diffusion and differential distribution of HIV/AIDS in population subgroups. Structural-level factors include social and economic factors, as well as laws and policies. These factors, in turn, affect HIV transmission dynamics and the differential distribution of HIV/AIDS. Infectious disease epidemiology provides models of the mechanisms through which social determinants affect HIV transmission (7). For example, the basic reproductive number of an infectious disease, R0 (8), describes secondary infections that arise from a primary infection. In the equation R0 = βCD, β is the probability of infection per contact, C is the number of contacts, and D is the duration of infectivity. The goal of intervention efforts is to reduce the empirical value of these terms by modifying the social conditions under which individual risk factors lead to disease. Examples of factors that affect the component terms of R0 in HIV epidemiology are presented in table 2. In this review, we present existing evidence linking social and structural determinants to HIV/AIDS. In addition, we discuss the implications of these findings for future social epidemiology research on HIV/AIDS as well as the design of more effective HIV/AIDS interventions. We searched the published literature to identify conceptual and empirical research reports on the social epidemiology of HIV/AIDS. Five databases were searched: PsycINFO (American Psychological Association, Washington, DC), PubMed (MEDLINE; National Institutes of Health, Bethesda, Maryland), Social Science Citation Index (Web of Science; Thomson ISI, Stamford, Connecticut), Sociological Abstracts (CSA, Bethesda, Maryland), and Digital Dissertations (ProQuest; UMI, Ann Arbor, Michigan). Searches were designed to include the factors we specified in our framework as social or structural factors (figure 1). Searches were limited to published articles in the English language for the period 1981–2003. The following keywords were included in each search: AIDS/acquired immunodeficiency syndrome, HIV, and epidemiol*. Additional searches were conducted by using combinations of keywords listed in Appendix table 1 corresponding with our framework. We identified four categories of social-level factors of importance to HIV/AIDS epidemiology: cultural context, social networks, neighborhood effects, and social capital. Each uses different conceptual and methodological approaches to examine the effects of social forces on population HIV/AIDS vulnerability. Anthropologist Edward Tylor defined culture as “that complex whole which includes knowledge, belief, art, law, morals, custom, and any other capabilities and habits acquired by man as a member of society” (9, p. 1). Anthropologic and epidemiologic approaches may be integrated in a variety of ways to identify features of the social environment that affect HIV/AIDS risk. One way to explore how the social environment affects HIV/AIDS epidemiology is through the use of mixed research methods. Mixed-methods study designs integrate qualitative and quantitative research methods either sequentially or concurrently (10). In sequential study designs, qualitative methods may be used to explore a topic under study or to explain quantitative epidemiologic findings. Concurrent study designs are meant to confirm, cross-validate, or corroborate findings within a single study. A common type of concurrent mixed methods study is “triangulation,” and this approach has been used extensively in rapid assessments of illicit drug use and HIV/AIDS (11–13). Mixed methods approaches are particularly well suited to the investigation of the often hidden and stigmatizing behavioral and social factors underlying HIV epidemics. One exemplary study combining qualitative methods with quantitative methods was conducted by Beyrer et al. (14) to examine the role of overland heroin trafficking routes in shaping explosive HIV/AIDS epidemics among injection drug users in Southeast Asia. Piecing together data from a variety of sources, including existing epidemiologic data, key informant interviews, and laboratory data, this study revealed that distinct HIV subtypes emerged and recombined along drug trafficking routes originating in Myanmar, one of the world’s largest heroin producers. Along these trafficking routes, communities of injection drug users formed, facilitating the spread of HIV into local communities in Laos, Thailand, Vietnam, India, and China (refer, for example, to Panda et al. (15)). This illustration highlights the broader understanding of HIV/AIDS epidemiology that can be achieved by examining the interplay between contextual factors and social and behavioral factors. Investigation of social networks in HIV/AIDS began with the mapping of relationships between one of the first identified AIDS cases, an airline steward, and a large number of his male sex partners in the early 1980s (16). Social network analysis generates measures of the quality, density, position, and structure of relationships between persons, including dyads (partnerships), personal networks (“egocentric” networks), and larger communities (“sociometric” networks) (17, 18). Social networks can influence health outcomes in direct and indirect ways, including 1) social influence, 2) social engagement and participation, 3) prevalence of infectious disease and network member mixing, 4) access to material goods and informational resources, and 5) social support (19). Researchers have demonstrated that patterns in the structure of relationships—rather than differences in individual risk behaviors alone—explain observed HIV patterns (20, 21). The theoretical foundation for examining social networks in HIV research is closely tied to advances in sexually transmitted disease (STD) epidemiology. A key concept from STD epidemiology is the notion of the “core group,” a small group of disease transmitters responsible for a large proportion of cases (22). Friedman et al. (23) found that individuals’ locations within sociometric risk networks were associated with HIV risk among a group of injection drug users in New York City. Other concepts from STD epidemiology, such as partner concurrency, bridging, and mixing patterns, are also important in understanding HIV risk (24–29). Specific network characteristics that have been associated with HIV/AIDS include the size of subgroups and their distribution in a network (23), the centrality of HIV-positive persons within networks (30), partner selection patterns (24, 31–33), and concurrent sexual partnerships (28). Inclusion of these variables has been shown to improve transmission estimates in mathematical modeling (34, 35). Social and normative influences have also been associated with individual HIV risks (36, 37). Network-related social and normative influences are predictive of illicit drug use (38) and condom use behavior (37, 39), highlighting the importance of network-based interventions for HIV prevention (18). Kelly et al. (40, 41) developed a popular opinion leader model that has been effective in reducing HIV risk in several populations, including men who have sex with men and women in low-income housing (42). The success of this model has led to its adaption for international use by the National Institute of Mental Health Collaborative HIV/STD Prevention Trial in China, India, Peru, Russia, and Zimbabwe. Neighborhoods represent the intersection of social networks and physical spatial locations, a confluence Wallace (43) has called the “sociogeographic networks” through which infectious diseases spread. Early interest in the role of neighborhood social environment in disease transmission was sparked by a study in Colorado Springs, Colorado, in which researchers found that gonorrhea was highly focused geographically in core residential neighborhoods (44). Both direct and indirect mechanisms may determine how neighborhood-level factors shape population HIV/AIDS patterns. Direct mechanisms are those that increase the likelihood of a person coming into contact with someone who is HIV positive, for example, through residential segregation and the social isolation of marginalized populations. Indirect mechanisms include those that increase population vulnerability to HIV/AIDS, such as exposure to poor socioeconomic conditions, high unemployment, or the proliferation of illicit drug markets. A range of neighborhood-level factors have been examined in relation to infectious disease, including poverty and income (45, 46), residential segregation (47), and neighborhood physical environment (48, 49). Current research in neighborhood and area effects on health emphasizes the importance of moving beyond documentation of associations to analyze the social and epidemiologic mechanisms through which neighborhood effects might operate (50–54). Increasing concentrations of affluence and poverty are contributing to what demographer Douglas Massey has called “a radical change in the geographic basis of human society” (55, p. 395). Powerful social and economic forces in US cities are increasing neighborhood segregation by class and race/ethnicity (56, 57). Resulting social disorganization and loss of resources and services in poor neighborhoods are in turn shaping HIV/AIDS patterns at the neighborhood level. In a number of studies in New York City, for example, Wallace (58–63) has examined the complex interplay of public policies such as “planned shrinkage” with HIV epidemic dynamics in the Bronx, documenting the “synergy of plagues” that has accompanied rapid social change and the destruction of essential protective networks in poor communities. Using AIDS surveillance data, ecologic studies conducted in various US cities have also consistently found significant associations between income and poverty measures and neighborhood-level AIDS incidence and prevalence rates, and these findings have been consistent across census block groups (46), census tracts (64), and zip codes (65, 66). Length of survival an AIDS has also been with neighborhood measures of income and the of highly a of health at the population may also a role in shaping HIV/AIDS patterns, associations between HIV/AIDS and income at the neighborhood have not been well segregation by race/ethnicity is neighborhood-level that may an important role in HIV/AIDS may affect infectious disease patterns through the and isolation of persons in one increasing the probability of transmission within that For example, found that measures of residential isolation were protective for at risk of disease. 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Epidemiologic Reviews · meta-analysis · 394 citationsread the source →

Long-term quality-of-life outcomes after radical prostatectomy or watchful waiting: the Scandinavian Prostate Cancer Group-4 randomised trial.

Background: For men with localised prostate cancer, surgery provides a survival benefit compared with watchful waiting. Treatments are associated with morbidity. Results for functional outcome and quality of life are rarely reported beyond 10 years and are lacking from randomised settings. We report results for quality of life for men in the Scandinavian Prostate Cancer Group Study Number 4 (SPCG-4) after a median follow-up of more than 12 years. Methods: All living Swedish and Finnish men (400 of 695) randomly assigned to radical prostatectomy or watchful waiting in SPCG-4 from 1989 to 1999 were included in our analysis. An additional 281 men were included in a population-based control group matched for region and age. Physical symptoms, symptom-induced stress, and self-assessed quality of life were evaluated with a study-specific questionnaire. Longitudinal data were available for 166 Swedish men who had answered quality-of-life questionnaires at an earlier timepoint. Findings: 182 (88%) of 208 men in the radical prostatectomy group, 167 (87%) of 192 men in the watchful-waiting group, and 214 (76%) of 281 men in the population-based control group answered the questionnaire. Men in SPCG-4 had a median follow-up of 12·2 years (range 7-17) and a median age of 77·0 years (range 61-88). High self-assessed quality of life was reported by 62 (35%) of 179 men allocated radical prostatectomy, 55 (34%) of 160 men assigned to watchful waiting, and 93 (45%) of 208 men in the control group. Anxiety was higher in the SPCG-4 groups (77 [43%] of 178 and 69 [43%] of 161 men) than in the control group (68 [33%] of 208 men; relative risk 1·42, 95% CI 1·07-1·88). Prevalence of erectile dysfunction was 84% (146 of 173 men) in the radical prostatectomy group, 80% (122 of 153) in the watchful-waiting group, and 46% (95 of 208) in the control group and prevalence of urinary leakage was 41% (71 of 173), 11% (18 of 164), and 3% (six of 209), respectively. Distress caused by these symptoms was reported significantly more often by men allocated radical prostatectomy than by men assigned to watchful waiting. In a longitudinal analysis of men in SPCG-4 who provided information at two follow-up points 9 years apart, 38 (45%) of 85 men allocated radical prostatectomy and 48 (60%) of 80 men allocated watchful waiting reported an increase in number of physical symptoms; 50 (61%) of 82 and 47 (64%) of 74 men, respectively, reported a reduction in quality of life. Interpretation: For men in SPCG-4, negative side-effects were common and added more stress than was reported in the control population. In the radical prostatectomy group, erectile dysfunction and urinary leakage were often consequences of surgery. In the watchful-waiting group, side-effects can be caused by tumour progression. The number and severity of side-effects changes over time at a higher rate than is caused by normal ageing and a loss of sexual ability is a persistent psychological problem for both interventions. An understanding of the patterns of side-effects and time dimension of their occurrence for each treatment is important for full patient information. Funding: US National Institutes of Health; Swedish Cancer Society; Foundation in Memory of Johanna Hagstrand and Sigfrid Linnér.

The Lancet. Oncology · randomised controlled trial · 277 citationsread the source →

Social capital and health during pregnancy; an in-depth exploration from rural Sri Lanka.

Background: Dimensions of social capital relevant to health in pregnancy are sparsely described in the literature. This study explores dimensions of social capital and the mechanisms in which they could affect the health of rural Sri Lankan pregnant women. Methods: An exploratory qualitative study of solicited diaries written by pregnant women on their social relationships, diary interviews and in-depth interviews with key informants was conducted. A framework approach for qualitative data analysis was used. Results: Pregnant women (41), from eight different communities completed diaries and 38 post-diary interviews. Sixteen key informant interviews were conducted with public health midwives and senior community dwellers. We identified ten cognitive and five structural constructs of social capital relevant to health in pregnancy. Domestic and neighborhood cohesion were the most commonly expressed constructs. Social support was limited to support from close family, friends and public health midwives. A high density of structural social capital was observed in the micro-communities. Membership in local community groups was not common. Four different pathways by which social capital could influence health in pregnancy were identified. These include micro-level cognitive social capital by promoting mental wellbeing; micro-level structural social capital by reducing minor ailments in pregnancy; micro-level social support mechanisms promoting physical and mental wellbeing through psychosocial resources and health systems at each level providing focused maternal care. Conclusion: Current tools available may not contain the relevant constructs to capture the unique dimensions of social capital in pregnancy. Social capital can influence health during pregnancy, mainly through improved psychosocial resources generated by social cohesion in micro-communities and by the embedded neighborhood public health services.

Reproductive health · 27 citationsread the source →

Maternity Leave in Residency: A Multicenter Study of Determinants and Wellness Outcomes.

Purpose: To characterize determinants of resident maternity leave and the effect of length of leave on maternal well-being. Method: In 2017, the authors sent a voluntary, anonymous survey to female residents at 78 programs, in 25 unique specialties, at 6 institutions. Survey items included personal, partner, and child demographics, and logistics of leave, including whether leave was paid or vacation or sick leave was used. Outcomes were maternity leave length; duration of breastfeeding; burnout and postpartum depression screens; perceptions of support; and satisfaction with length of leave, breastfeeding, and childbearing during residency. Results: Fifty-two percent (804/1,537) of residents responded. Among 16% (126) of respondents who were mothers, 50% (63) had their first child during residency. Seventy-seven maternity leaves were reported (range, 2-40 weeks), with most taking 6 weeks (32% of leaves; 25) and including vacation (81%; 62) or sick leave (64%; 49). Length of leave was associated with institution, use of sick leave or vacation, and amount of paid leave. The most frequently self-reported determinant of leave was the desire not to extend residency training (27%; 59). Training was not extended for 53% (41) of mothers; 9% (7) were unsure. Longer breastfeeding duration and perceptions of logistical support from program administration were associated with longer maternity leaves. Burnout affected approximately 50% (38) of mothers regardless of leave length. Conclusions: This study illustrates variability in administration of resident maternity leaves. Targets for intervention include policy clarification, improving program support, and consideration of parent wellness upon return to work.

Academic medicine : journal of the Association of American Medical Colleges · cohort or longitudinal · 58 citationsread the source →

Hand Posturing Is a Nonverbal Indicator of Catastrophic Thinking for Finger, Hand, or Wrist Injury.

Background: Prior research documents that greater psychologic distress (anxiety/depression) and less effective coping strategies (catastrophic thinking, kinesophobia) are associated with greater pain intensity and greater limitations. Recognition and acknowledgment of verbal and nonverbal indicators of psychologic factors might raise opportunities for improved psychologic health. There is evidence that specific patient words and phrases indicate greater catastrophic thinking. This study tested proposed nonverbal indicators (such as flexion of the wrist during attempted finger flexion or extension of uninjured fingers as the stiff and painful finger is flexed) for their association with catastrophic thinking. Questions/purposes: (1) Do patients with specific protective hand postures during physical examination have greater pain interference (limitation of activity in response to nociception), limitations, symptoms of depression, catastrophic thinking (protectiveness, preparation for the worst), and kinesophobia (fear of movement)? (2) Do greater numbers of protective hand postures correlate with worse scores on these measures? Methods: Between October 2014 and September 2016, 156 adult patients with stiff or painful fingers within 2 months after sustaining a finger, hand, or wrist injury were invited to participate in this study. Six patients chose not to participate as a result of time constraints and one patient was excluded as a result of inconsistent scoring of a possible hand posture, leaving 149 patients for analysis. We asked all patients to complete a set of questionnaires and a sociodemographic survey. We used Patient Reported Outcomes Measurement Information System (PROMIS) Depression, Upper Extremity Physical Function, and Pain Interference computer adaptive test (CAT) questionnaires. We used the Abbreviated Pain Catastrophizing Scale (PCS-4) to measure catastrophic thinking in response to nociception. Finally, we used the Tampa Scale of Kinesophobia (TSK) to assess fear of movement. The occurrence of protective hand postures during the physical examination was noted by both the physician and researcher. For uncertainty or disagreement, a video of the physical examination was recorded and a group decision was made. Results: Patients with one or more protective hand postures did not score higher on the PROMIS Pain Interference CAT (hand posture: 59 [56-64]; no posture: 59 [54-63]; difference of medians: 0; p = 0.273), Physical Function CAT (32 ± 8 versus 34 ± 8; mean difference: 2 [confidence interval {CI}, -0.5 to 5]; p = 0.107), nor the Depression CAT (48 [41-55] versus 48 [42-53]; difference of medians: 0; p = 0.662). However, having at least one hand posture was associated with a higher degree of catastrophic thinking (PCS scores: 13 [6-26] versus 10 [3-16]; difference of medians: 3; p = 0.0104) and a higher level of kinesophobia (TSK: 40 ± 6 versus 38 ± 6; mean difference: -2 [CI, -4 to -1]; p = 0.0420). Greater catastrophic thinking was associated with a greater number of protective hand postures on average (rho: 0.20, p = 0.0138). Conclusions: Protective hand postures and (based on prior research) specific words and phrases are associated with catastrophic thinking and kinesophobia, less effective coping strategies that hinder recovery. Surgeons can learn to recognize these signs and begin to treat catastrophic thinking and kinesophobia starting with compassion, empathy, and patience and be prepared to add formal support (such as cognitive-behavioral therapy) to help facilitate recovery. Level of evidence: Level III, diagnostic study.

Clinical orthopaedics and related research · cohort or longitudinal · 35 citationsread the source →

Healthy lifestyle and life expectancy at age 30 years in the Chinese population: an observational study.

Background: The improvement of life expectancy is one of the aims of the Healthy China 2030 blueprint. We aimed to investigate the extent to which healthy lifestyles are associated with life expectancy in Chinese adults. Methods: We used the prospective China Kadoorie Biobank (CKB) study to examine the relative risk of mortality associated with individual and combined lifestyle factors (never smoking or quitting not for illness, no excessive alcohol use, being physically active, healthy eating habits, and healthy body shape). Participants with coronary heart disease, stroke, cancer, or missing values for body-mass index were excluded. For analysis of chronic respiratory diseases, participants with chronic obstructive pulmonary disease or asthma were excluded. We estimated the national prevalence of lifestyle factors using data from the China Nutrition and Health Surveillance (CNHS; 2015) and derived mortality rates from the Global Burden of Diseases, Injuries, and Risk Factors Study (2015). All three data sources were combined to estimate the life expectancy of individuals at age 30 years following different levels of lifestyle factors by using the life table method. The cause-specific decomposition of the life expectancy differences was analysed using Arriaga's method. Findings: After the exclusion of CKB participants with coronary heart disease, stroke, cancer, or missing BMI data at baseline, 487 209 were included in the primary analysis. Participants with COPD or asthma at baseline were additionally excluded for chronic respiratory disease-related analysis, leaving 451 233 participants with data available for analysis. Data from 171 127 adults aged 30-84 years from the CNHS 2015 were used to estimate the sex-specific and age-specific prevalence of lifestyle-related factors. There were 42 496 deaths documented over a median follow-up of 11·1 years (IQR 10·2-12·1) in CKB. The adjusted hazard ratios (aHRs) of participants adopting five versus 0-1 low-risk factors was 0·38 (95% CI 0·34-0·43) for all-cause mortality, aHR 0·37 (0·30-0·46) for cardiovascular disease mortality, aHR 0·47 (0·39-0·56) for cancer mortality, and aHR 0·30 (0·14-0·64) for chronic respiratory disease mortality. The life expectancy at age 30 years for individuals with 0-1 low-risk factors was on average 41·7 years (95% CI 41·5-42·0) for men and 47·3 years (46·6-48·0) for women. For individuals with all five low-risk factors, the life expectancy at age 30 was 50·5 years (95% CI 48·5-52·4) for men and 55·4 years (53·5-57·4) for women; meaning a difference of 8·8 years (95% CI 6·8-10·7) for men and 8·1 years (6·5-9·9) for women. The estimated extended life expectancy for men and women was mainly attributable to reduced death from cardiovascular disease (2·4 years [27% of the total extended life expectancy] for men and 3·7 years [46%] for women), cancer (2·6 years [30%] for men and 0·9 years [11%] for women), and chronic respiratory disease (0·6 years [7%] for men and 1·2 years [15%] for women). Interpretation: Our findings suggest that increasing the adoption of these five healthy lifestyle factors through public health interventions could be associated with substantial gains in life expectancy in the Chinese population. Funding: National Natural Science Foundation of China, National Key Research and Development Program of China, Kadoorie Charitable Foundation, UK Wellcome Trust.

The Lancet. Public health · cohort or longitudinal · 129 citationsread the source →

Cytotoxicity of Nigella sativa seed oil and extract against human lung cancer cell line.

Nigella sativa (N sativa), commonly known as black seed, has been used in traditional medicine to treat many diseases. The antioxidant, anti-inflammatory, and antibacterial activities of N sativa extracts are well known. Therefore, the present study was designed to investigate the anticancer activity of seed extract (NSE) and seed oil (NSO) of N sativa against a human lung cancer cell line. Cells were exposed to 0.01 to 1 mg/ml of NSE and NSO for 24 h, then percent cell viability was assessed by 3-(4, 5-dimethylthiazol-2yl)-2, 5-biphenyl tetrazolium bromide (MTT) and neutral red uptake (NRU) assays, and cellular morphology by phase contrast inverted microscopy. The results showed NSE and NSO significantly reduce the cell viability and alter the cellular morphology of A-549 cells in a concentration dependent manner. The percent cell viability was recorded as 75%, 50%, and 26% at 0.25, 0.5, and 1 mg/ml of NSE by MTT assay and 73%, 48%, and 23% at 0.25, 0.5, and 1 mg/ml of NSE by NRU assay. Exposure to NSO concentrations of 0.1 mg/ml and above for 24 h was also found to be cytotoxic. The decrease in cell viability at 0.1, 0.25, 0.5, and 1 mg/ml of NSO was recorded to be 89%, 52%, 41%, and 13% by MTT assay and 85%, 52%, 38%, and 11% by NRU assay, respectively. A-549 cells exposed to 0.25, 0.5 and 1 mg/ml of NSE and NSO lost their typical morphology and appeared smaller in size. The data revealed that the treatment of seed extract (NSE) and seed oil (NSO) of Nigella sativa significantly reduce viability of human lung cancer cells.

Asian Pacific journal of cancer prevention : APJCP · 35 citationsread the source →

Parental Educational Attainment and Mental Well-Being of College Students; Diminished Returns of Blacks.

Background: According to the Minorities' Diminished Returns (MDR) theory, the health returns of socioeconomic status (SES) are systemically smaller for Blacks compared to Whites. Less is known, however, about trans-generational aspects of such diminished gains. For example, the differential impact of parental educational attainment on differences in mental well-being between White versus Black college students remains unknown. Aims: With a national scope, this study explored racial differences in the effect of parental educational attainment on the mental well-being of college students in the United States. Methods: The Healthy Mind Study (HMS), 2016⁻2017, is a national telephone survey that included 41,898 college students. The sample was composed of Whites (n = 38,544; 92.0%) and Blacks (n = 3354; 8.0%). The independent variable was highest parental educational attainment. The dependent variable was mental well-being (mentally healthy days in the past month) which was measured using a single item. Age and gender were covariates. Race was the moderator. Logistic regression was used for data analysis. Results: In the pooled sample, high parental educational attainment was associated with better mental wellbeing, independent of race, age, and gender. Race, however, showed a significant interaction with parental educational attainment on students' mental wellbeing, indicating a smaller effect of parent education on the mental wellbeing of Black compared to White college students. Conclusions: The returns of parental educational attainment in terms of mental well-being is smaller for Black college students compared to their White counterparts. To minimize the diminished returns of parental education in Black families, policies should go beyond equalizing SES and reduce the structural barriers that are common in the lives of Black families. Policies should also aim to reduce extra costs of upward social mobility, prevent discrimination, and enhance the quality of education for Blacks. As the mechanisms that are involved in MDR are multi-level, multi-level solutions are needed to minimize the racial gaps in gaining mental health benefits from higher socioeconomic levels.

Brain sciences · 111 citationsread the source →

Developmental Coordination Disorder

For the last 100 years, poor motor coordination in children has been recognized as a developmental problem.1 As early as 1937, these children were classified as “clumsy.”1 Since then, other terms such as “motorically awkward,” “motor impaired,” and “physically awkward” have been used to describe these children, and the terms “developmental apraxia” and “perceptual motor difficulties” have been used to characterize this developmental problem.2,3 Since the 1994 International Consensus Conference on Children and Clumsiness, the term “developmental coordination disorder” (DCD) has been used to describe the condition of children with motor incoordination.1,4 The purpose of this article is to provide the following information about DCD: (1) definition, (2) prevalence, (3) etiology, (4) discussion regarding the difficulties in classifying these children, (5) common characteristics, (6) long-term prognosis, and (7) brief review of treatment approaches. Developmental coordination disorder, a chronic and usually permanent condition found in children, is characterized by motor impairment that interferes with the child's activities of daily living and academic achievement.3,5 In order for a child to be diagnosed with DCD, these motor impairments must negatively affect some other aspect of his or her life.6 Impairment alone, however, does not qualify a child for the diagnosis of DCD; the motor impairment must not be caused by or have the symptoms of an identifiable neurological problem.2,5 That is, the child must not have any disturbances of muscle tone (ataxia or spasticity), sensory loss, or involuntary movements. If mental retardation is present, the testable IQ of the child must be greater than 70 and the motor impairments must be greater than what would normally be expected for children with mental retardation.5 Finally, a child diagnosed with DCD must not meet the criteria for a diagnosis of pervasive developmental disorder.6 Developmental coordination disorder appears to be a fairly common disorder of childhood and is usually identified in children between 6 and 12 years of age. Ten years ago, researchers7,8 estimated that DCD occurred in 10% to 19% of school-aged children. With a more precise definition of DCD, the current prevalence is estimated to be between 5% and 8% of all school-aged children,5,9–11 with more boys than girls (2:1) being diagnosed with DCD.12 This difference may reflect higher referral rates for boys, because the behavior of boys with motor incoordination may be more difficult to manage at home and in the classroom.8 In addition, a higher incidence of DCD may be found among children with a history of prenatal or perinatal difficulties.3 Due to the heterogeneity of DCD, finding its cause has been difficult.3 Several theories speculate that the etiology of DCD is part of the continuum of cerebral palsy5,13; is secondary to prenatal, perinatal, or neonatal insult3; or is secondary to neuronal damage at the cellular level in the neurotransmitter or receptor systems.14 Hadders-Algra14 based her view that DCD is a result of damage at the cellular level on evidence that cerebral palsy is often caused by prenatal damage that cannot be identified by current diagnostic techniques. Developmental coordination disorder, a chronic and usually permanent condition found in children, is characterized by motor impairment that interferes with the child’s activities of daily living. Although both standard and nonstandard functional tests are available to identify the specific disabilities experienced by a child with DCD, relating the observed disabilities to the primary impairment(s) or any possible neuropathology is not easily accomplished. The problems experienced by children with DCD are believed to emanate from abnormalities in neurotransmitter or receptor systems rather than from damage to specific groups of neurons or brain regions.15 Children's difficulties with coordination can result from a combination of one or more impairments in proprioception, motor programming, timing, or sequencing of muscle activity. A number of theories have evolved in an attempt to shed light on the specific neuronal processing deficits that contribute to DCD. Current models used to explain the neural regulation of posture and movement during development can serve as a basis for the examination and management of individuals with DCD. Using these models, many of the deficits of motor control observed in these children can be described. A variety of theoretical models exist to explain the role of the nervous system in motor development. Forty years ago, the primitive reflex model was a generally accepted theory used to explain how the brain regulates early motor behavior.16 As development proceeded, the higher centers exerted increasing control over the lower reflexes.16 These earlier models were based on a hierarchy of motor control in which higher centers were capable of planning and executing a motor plan without external or internal feedback from lower centers of the central nervous system (CNS). The more recently proposed systems model suggests a more complex interaction among various levels of the CNS. In the systems model, sensory feedback is interpreted by the CNS, and the appropriate movement strategy is selected based on current experience, the state of the internal and external environment, and memory of similar movements. Edelman's neuronal group selection theory includes aspects of both of these models and proposes that functional groups of neurons exist at all levels of the CNS.17 These neuronal groups are determined by evolution, but their functional integrity is dependent on afferent information produced by movement and experience.17 In this regard, these genetically determined collections of interconnected neurons (neuronal groups) in both cortical and subcortical structures serve as an early repertoire for motor behavior or receipt of specific sensory information.14,17,18 According to neuronal group selection theory, motor development proceeds in 2 phases.15 The first, the phase of primary variability, is characterized by crude and erratic motor activity that does not require sensory information for its initiation or guidance. These self-generated movements give rise to afferent (visual, kinesthetic) inputs that reinforce more specific synaptic connections within each group. An intermediate period in which effective patterns are selected is followed by the secondary variability phase. In this phase, sensory and motor factors interact to establish the intercellular connections that produce the specific and complex muscle contraction patterns that characterize coordinated, goal-directed movement. Reciprocal connections between groups subserving movements in various body parts and representing different parts of visual space are reinforced with each repetition of a particular function. As the more efficient movement patterns are practiced, the appropriate synaptic circuits are reinforced and subsequently established.14,17,19,20 The literature includes a wide variation in terminology and criteria to describe DCD. This variation has made studying the causes of DCD and developing treatment approaches for the child with DCD difficult. In their analysis of clinical trial data, Macnab et al21 identified 5 different subtype profiles of DCD. The first subtype included children with better gross motor than fine motor skills, although both were still below normal while standing balance and visual-perceptual skills were both within normal ranges. Compared with children of the same age with DCD, children in the second subtype scored high on measures of upper-limb speed and dexterity, visuomotor integration, and visual-perception skills, but they demonstrated poor performance on measures of kinesthetic ability (accuracy in discriminating movement and position of the upper limbs) and balance. Children in subtype 3 demonstrated the greatest overall motor involvement and were the only subtype to have difficulty with both kinesthetic and visual skills. Compared with their peers with DCD, children in subtype 4 performed well on kinesthetic tasks but demonstrated poor performance on tasks requiring visual and dexterity skills. Children in subtype 5 demonstrated poor performance on measurements of running speed and agility compared with their peers with DCD; however, they performed well relative to their peers with DCD in the tasks involving visual-perception skills. The development of different classification systems for DCD may have been influenced by the design of motor tests.21 For example, items testing one motor skill may be influenced by a related motor skill (eg, ball-throwing skills cannot be separated from visuomotor skills). In addition, a test may have an over-representation of one skill that could unduly influence the child's performance on the test. For example, having a greater number of items testing gross motor rather than fine motor skills could either positively or negatively influence a child's score, depending on the child's specific strengths and weaknesses. Another difficulty in interpreting the literature on DCD is the lack of inclusion criteria. Geuze et al22 reviewed 164 publications on the study of DCD and found that only 60% of the studies had objective inclusion criteria. Because of this lack of inclusion criteria, Geuze et al recommended that a child scoring below the 15th percentile on standardized tests of motor skills and having an IQ score above 69 would qualify for a diagnosis of DCD. The inconsistency among standardized motor tests used to identify children with DCD is another problem. In one study,5 the Bruininks-Oseretsky Test of Motor Proficiency (BOTMP) and the Movement Assessment Battery for Children (M-ABC) were administered to 157 children with DCD and 155 children with no motor difficulties; the test results were in agreement 82% (kappa=.62) of the time in distinguishing children who had DCD from children who did not have DCD. This is considered a substantial level of agreement.23 In a study of 202 children (101 with DCD and 101 without DCD), the BOTMP and M-ABC agreed only 67% of the time (kappa=.41), which was considered a moderate level of agreement.24 Because the BOTMP and the M-ABC are 2 of the most commonly used tests for identifying children with DCD, the potential lack of agreement by these tests in identifying children who have DCD is a concern. Two primary factors may explain the difference in outcomes between the BOTMP and M-ABC when used to identify children with DCD.24 First, the BOTMP allows the tester to verbally prompt and correct the child during the testing procedure, allowing the child who is dependent on more external controls to do better on the BOTMP. The BOTMP tends to under-identify children with DCD. Second, the M-ABC requires more careful instruction on the part of the examiner and allows more opportunities for the examinee to practice, but does not allow any verbal or physical prompting by the examiner. Children with attention problems may have more difficulty with the careful instructions for the M-ABC. Another difficulty in classifying children with DCD is the overlap with other disorders. Approximately 41% of children with attention-deficit/hyperactivity disorder (ADHD) and 56% of children with learning disabilities also have DCD.5,21 Further confusing the classification scheme is that the terms “developmental coordination disorder,” for which no identifiable organic brain damage is present, and “apraxia,” which is caused by identifiable brain damage, have been used interchangeably.3 Children with DCD may have a wide range of dysfunctions. These dysfunctions can be grouped into 3 areas: gross motor, fine motor, and psychosocial. Many children with DCD have neurological soft signs such as hypotonia, persistence of primitive reflexes, and immature balance reactions that interfere with gross motor development.5,25 These children also may demonstrate an awkward running pattern, fall frequently, drop items, and have difficulty imitating body positions and following 2- to 3-step motor commands.8 Because of their gross motor problems, children with DCD also perform poorly in sporting events,2 possibly due, in part, to their slow reaction and movement times.7 Their decreased participation in sports may result in decreased muscle force.8 Difficulty with handwriting or drawing often is the first identifiable sign of a fine motor problem and is the most frequently mentioned motor problem experienced by children with DCD. Children with DCD frequently have difficulty planning and executing other fine motor skills such as gripping and dressing.26–29 Unfortunately, children with DCD may experience problems not limited to fine or gross motor areas. These children also may experience psychosocial problems at school. Children with DCD may have learning disabilities or reading problems and may be at increased risk for lower intelligence.5,8 They may act out in class more than other children,13 may be the class clown, and may exhibit less socially desirable means of gaining recognition and friends.8 Adolescents with DCD have been found to have fewer friends, and they have more feelings of low self-worth and more anxiety than peers without DCD and younger children with DCD.30 Historically, parents have been told not to worry about their child's clumsiness because the child will outgrow the problem.31 However, current researchers in the area of DCD report that the children do not outgrow clumsiness and that, without intervention, they will not improve.1,8,12,27,31 Losse et al31 tested 17 children aged 6 years and retested them at age 16 years. The children with motor difficulties at 6 years of age continued to exhibit problems at 16 years of age. In another study,32 818 children with DCD were tested for reading comprehension at age 7 years and then again at age 10 years. A positive correlation in poor reading comprehension existed for children with DCD at 7 and 10 years of age. A follow-up study was conducted on 22-year-old individuals (N=55) who at age 7 years had either DCD or attention-deficit/hyperactivity disorder (ADHD), or both.33 The children with DCD and those with both DCD and ADHD had poorer outcomes than their similarly aged peers without DCD and children with ADHD only. The children with DCD and those with both DCD and ADHD were found to have had more criminal offenses, more incidences of substance abuse and other psychiatric disorders, and lower levels of schooling. Treatment approaches used by occupational therapists and physical therapists can be broadly categorized into either bottom-up or top-down approaches (Tab. 1).10,12,34–36 Bottom-up approaches are based on hierarchical theories of motor control. These theories tend to explain the remediation of motor dysfunction through activation of higher levels of neuronal functioning in a child. The bottom-up approaches frequently used in managing children with DCD are sensory integration, the process-oriented treatment approach, and perceptual motor training.34 Summary of Bottom-Up Versus Top-Down Approaches Summary of Bottom-Up Versus Top-Down Approaches In sensory integration therapy, the child is provided sensory stimulation designed to promote motor development and higher cortical learning. A child undergoing sensory integration therapy may show some gains in motor development, but these gains often do not generalize to functional skills.34 Kinesthesia (the perception of one's own body parts, weight, and movement) is integral to the acquisition of motor skills in process-oriented treatment approaches. Therapeutic intervention with process-oriented treatment is based on specifically designed kinesthetic training activities. As described by Laszlo and Bairstow,37 this approach has an inherent reward system built into it through its use of positive reinforcement, presentation of desirable activities within the capabilities of the child, and judicious progression of the level of difficulty. The usefulness of the process-oriented treatment approach has been the subject of considerable study.9,10,37,38 Sims and colleagues35 suggested that much of the success of this approach can be attributed to a strong motivation effect, fostered by positive feedback and a sense of self-competence. Perceptual motor training, an eclectic approach, offers the child with DCD a wide range of motor experiences along with ample opportunities to practice these skills. Often, in outcome studies, children who receive perceptual motor training are compared with children who receive either sensory integration therapy or process-oriented treatment. Children perceptual motor training have been found to demonstrate motor to or greater than those of children either sensory integration therapy or process-oriented perceptual motor training, process-oriented may promote learning through positive feedback and reinforcement, these do not and to the that top-down approaches approaches use a approach to motor skill development and have been influenced by the systems approach to motor learning and control. This approach suggests that motor skills from an interaction of many both internal and external to the approaches also the in which motor behavior intervention and approaches or are the 2 most commonly intervention on of a The theoretical for intervention in a child's motor performance is the result of learning on a specific Motor tasks are into with each and then to the Children with this approach have demonstrated gains in motor skills.34 approaches to motor development problem The approach strategy the to to the and perform the well did plan The child verbal to the to motor learning. In this approach, the as a by the child out how to his or her motor performance on various motor intervention, the results of studies of approaches are In one 10 children with DCD who were with a approach to motor development were compared with 10 children who were with a bottom-up The children were for and groups on various standardized motor tests 10 treatment However, children in the approach group motor skill and to better than children who were the bottom-up and the approach both provide repetition and practice of specific motor skills, and the approach has the of problem The greater success of top-down when compared with bottom-up be a result of the top-down inclusion of both and motor learning with for attention to and memory as the child in activities. The results of these studies, in to outcome measures of the different approaches in children with DCD, would that approaches that systems theory on sensory information being only part of the and motor learning theory be most effective for these 2 a brief of clinical the of various treatment approaches used with children with of Treatment Approaches for Children With Developmental approach to daily occupational performance treatment approach treatment group integration, perceptual motor, gross and fine motor integration Assessment Battery for Test of Motor Test of for of Motor and of of Treatment Approaches for Children With Developmental approach to daily occupational performance treatment approach treatment group integration, perceptual motor, gross and fine motor integration Assessment Battery for Test of Motor Test of for of Motor and of The neuronal group selection theory can provide a for interpreting the in outcomes among the various approaches. children with moderate to cerebral palsy have a limited repertoire of primary neuronal which children with DCD are believed to experience difficulty at the level of secondary variability, that is, in and the most efficient and effective for a normal development, experience a primary role in the neuronal group selection that the for and According to the neuronal group selection theory, this of motor skill during the of secondary variability as a result of of neuronal selection of specific neurons within each repetition of synaptic within and among neuronal and sensory synaptic which act in and cortical and subcortical and following to a variety of motor of these connections is dependent on sensory Bottom-up approaches such as sensory integration, process-oriented and perceptual motor training sensory experience, with less on processing and motor Although an intervention based on information processing may provide the experience to the most effective neuronal bottom-up approaches may not provide for motor practice of and goal-directed tasks in order to reinforce and establish these approaches less on the specific impairments to decreased coordination and more on the of that is, the among a number of structures and systems and the within which the is Treatment based on a top-down approach that provide the child the to in problem while afferent subcortical structures the feedback and to identify and the most efficient movement for the Because integration, internal of motor and appropriate motor at the level of secondary the on sensory rather than factors by the bottom-up approaches in part, be for the observed in outcomes following treatment. A number of motor learning theories have been proposed in an attempt to explain the through which are into more complex According to the motor control and learning theory proposed by and motor circuits that the and following long-term these and functioning neuronal circuits through practice, the child is to motor into more complex movements. and proposed 2 to such the first of which on sensory to neuronal is during the second that the to the specific motor tasks through the and involving the and in the first of learning requires attention and The motor then in the of learning through repetition and top-down approaches meet both of these bottom-up approaches information processing only. the and of the neural in children with DCD is a not Motor control are complex and on functioning of and motor only are children with DCD a group in terms of functional disabilities the specific of the problems observed can from one child to the Because of these an approach to the management of children with DCD is Developmental coordination disorder is a complex disorder 5% to of school-aged children. intervention, these children will to exhibit poor motor skills and show deficits in other as for may (1) the most appropriate level of intervention (2) which produce results that generalize to the and provide long-term in motor (3) what have on the child's motor and (4) motor skills to the that to the

Physical Therapy · review · 472 citationsread the source →

Metastasis Suppressor Proteins: Discovery, Molecular Mechanisms, and Clinical Application

Clinically and experimentally, primary tumor formation and metastasis are distinct processes — locally growing tumors can progress without the development of metastases. This observation prompted the hypothesis that the molecular processes regulating tumorigenicity and metastasis are distinguishable and could be targeted therapeutically. During the process of transformation and subsequent progression to a malignant phenotype, both genetic and epigenetic alterations alter a cell's ability to perceive and respond to signals that regulate normal tissue homeostasis. A minority of tumorigenic cells accrue the full complement of alterations that enables them to disseminate from the primary tumor, survive insults from the immune system and biophysical forces, and respond to growth-promoting and/or inhibitory signals from the distant tissues and thrive there. Identification of genes and proteins that specifically inhibit the ability of cells to form metastases (e.g., metastasis suppressors) is providing new insights into the molecular mechanisms that regulate this complex process. This review will highlight: (a) the functional identification of metastasis suppressors, (b) the signaling cascades and cellular phenotypes which are controlled or modulated by metastasis suppressors, and (c) opportunities for translation and clinical trials that are based on mechanistic studies regarding metastasis suppressors. The identification of nm23, the first metastasis suppressor gene, provided functional evidence for the existence of genes that specifically regulate metastasis (1, 2). Subsequent to this initial discovery, researchers used in vivo studies to identify additional metastasis suppressors. These pioneering studies used an unbiased approach to identify such candidates by demonstrating that ectopic expression of the putative suppressor gene inhibited the development of spontaneous macroscopic metastases without significantly affecting primary tumor growth (3–5). Recently, this definition has been extended to include genes which specifically inhibit metastatic colonization (i.e., experimental metastasis formation using i.v. injection). The use of in vivo assays is required because in vitro assays are often of inadequate complexity to sufficiently model the entire process of metastasis. Furthermore, there are currently no in vitro models that allow the study of preferential growth within different target tissues. Table 1 lists the proteins which have bona fide metastasis suppressor activity in vivo (i.e., suppression of metastasis following ectopic expression into metastatic cell lines). It is interesting to note that metastasis suppressor activity for many of these genes would not have been predicted a priori based on their known cellular function(s). Furthermore, the unbiased, functional strategy identified novel genes for which no cellular function was known at the time of discovery. Metastasis suppressors can impart their suppressive activity at one or more of the steps in the metastatic cascade (6). For example, in vivo studies showed that metastatic cancer cells which express ectopic KISS1, JNKK1/MKK4, MKK6, MKK7, TXNIP, nm23-H1, or SSeCKS proteins could successfully disseminate and lodge at secondary sites, but are suppressed in their ability to colonize (i.e., form overt metastases) target tissues (7–12). After lodging at secondary sites, disseminated cells may die, persist as nondividing cells, or initiate growth (13). Such pivotal cellular decisions depend on both the expression of a specific gene profile as well as the activation status of key signaling pathways and the cumulative inputs of timing, amplitude, and duration of signaling responses. In short, cells expressing metastasis suppressors grow at primary sites, but fail to proliferate at secondary or metastatic sites, suggesting differential responses to site-specific external signals. Although the observation that a gene of interest functions as a metastasis suppressor is an excellent starting point, research is now focused on the biochemical and molecular mechanisms by which metastasis suppressor proteins execute their in vivo functions. Metastasis suppressors vary widely in their cellular locations and biochemical functions. Such proteins could display either extracellular (e.g., KISS1) or intracellular localization patterns. Within the cell, they are located in various cellular compartments, from the plasma membrane (e.g., cadherin, KAI1, CD44), cytoskeleton (e.g., RhoGDI2, gelsolin), cytosol (e.g., JNKK1/MKK4, nm23-H1, RKIP), mitochondria (e.g., caspase 8), and nucleus (e.g., BRMS1, CRSP3, TXNIP) (14–21).Cells respond to external stimuli by using a limited number of signaling pathways. Signaling specificity is achieved, at least in part, by combinatorial spatiotemporal activation of signaling proteins. The summation of these signaling events, enabled by a cell-specific gene expression profile, is a tailored, situation-appropriate response. During the process of transformation and progression to a malignant phenotype, both genetic and epigenetic alterations influence a cell's ability to perceive and respond to signals which regulate normal tissue homeostasis. The accumulation of such alterations during progressive rounds of cell division could endow a minority of tumorigenic cells with the ability to disseminate from the primary tumor. It is likely that as a result of these changes, metastatic cells are no longer bound by tissue-of-origin–derived signaling specificity and acquire the ability to modulate their responses to the changing environments encountered throughout the metastatic cascade. Current data supports a model in which ectopic expression of metastasis suppressor proteins may restore, at least in part, the endogenous signaling repertoire of earlier, more benign cellular generations, thereby blocking metastasis formation. In this light, metastasis formation can be viewed as the result of a cell's ability to respond to multiple growth milieus as opposed to being restricted to growth in the microenvironment of the tissue of origin. Defining pathways regulating metastatic growth requires the integration and interpretation of data obtained over experimental settings ranging from the molecular interactions of specific proteins, to communication between signaling networks within single cells, and ultimately cellular interactions among populations of cells that yield a particular disease state. This line of inquiry is a particular challenge in studies of metastasis regulation because of the complexity and diversity of downstream events that take place in metastasis formation. The majority of metastasis suppressors identified participate in highly conserved eukaryotic signal transduction pathways. Based on their known biochemical functions, we have divided the metastasis suppressors into four general signaling categories: cytoskeletal signaling, mitogenic pathways, stress-activated pathways, and survival pathways (Fig. 1). Although it may seem straightforward to place a metastatic suppressor into a linear signaling pathway, it is important to be mindful that these pathways are, in fact, dynamic networks that exist in series and parallel leading to crosstalk and interplay; phenomena known as emergent properties. The cytoskeleton is a dynamic structure that enables motility, deformability, and flexibility, while maintaining cellular architecture. For most nonhematopoietic cells, motility is an ancillary function; however, as a nonhematopoietic cell transitions from the benign to the invasive to the metastatic state, motility becomes an increasingly paramount ability. Without a dynamic actin cytoskeleton, a tumor cell would be incapable of intravasation or extravasation, and the cellular deformability is necessary to complete the metastatic cascade. Not surprisingly, several proteins involved in cellular motility have been implicated as metastasis suppressors. The Rho family of GTP-binding proteins, which include Rho, Rac, and Cdc42, are central players in the regulation of actin dynamics. The Rho-GTPase family consists of small 20 to 30 kDa monomeric GTP-binding proteins that bind GDP/GTP and hydrolyze GTP, leading to the activation of downstream effector molecules (22). In this signaling scheme, metastasis suppressors have been identified as upstream inhibitors of the Rho family (23), or downstream effectors (24). RhoGDIs inhibit Rho family members by impeding the dissociation of GDP from Rho proteins, thereby locking the Rho protein in its inactive state, preventing Rho proteins from interacting with effector targets, and/or sequestering Rho-GTPases in the cytosol (25). RHOGDI2 was shown to suppress experimental lung metastasis but not affect in vitro growth or in vivo tumorigenicity. The Src-suppressed C kinase substrate is a protein kinase C substrate with protein scaffolding properties that have been shown to be a negative regulator of Rho family members (26). Reexpression of Src-suppressed C kinase substrate suppressed secondary lung metastases in nude mice and increased cell-cell adhesion, yet had little effect on primary tumor growth (10). Furthermore, Src-suppressed C kinase substrate reexpression at physiologic levels suppresses podosome formation and correlates with the induction of normal actin cytoskeletal structures and cell morphology, but not with the inhibition of Src kinase activity in cells (26).The finding that RhoGDI displayed the ability to suppress metastasis suggested that the downstream molecules it inhibits may have metastasis-promoting activities. This hypothesis seems to hold true in that mice deficient in RhoC, a target of RhoGDI, displayed a marked decrease in metastasis potential (27). Furthermore, specific inhibition of a downstream effector of Rho, ROCK, decreased tumor cell invasiveness in vitro and reduced the dissemination of tumor cells implanted in the peritoneal cavity in vivo (28). RhoGDI2 has also been shown to regulate secreted growth factors such as endothelin 1 (ET-1), which contribute to metastasis and will be discussed below (29). This prometastasic activation of effectors downstream of the Rho family is not universal. Gelsolin is a downstream effector of Rac that regulates the length of actin via its filament severing and capping activities. Overexpression of gelsolin has been shown to inhibit metastasis in vivo (24). Counterintuitively, gelsolin is an indispensable protein of podosomes, which are thought to play an active role in tissue invasion and matrix remodeling through their regulation of matrix metalloprotease (MMP) activity (30, 31).Cell interactions with the extracellular matrix and with neighboring cells trigger numerous responses that have essential roles in the regulation of behavior and fate. Integrin-mediated cell adhesions provide bidirectional links between the microenvironment and the cytoskeleton. This crosstalk between a cell and its local environment occurs whether the cell is benign, malignant, or metastatic. In this light, the cytoskeleton serves as a conduit for the integration and processing of intracellular and extracellular information; however, changes in the cytoskeletal program during pathologic progression may alter how this information is integrated and processed. Two metastasis suppressors have been shown to have interactions with integrins. Connective tissue growth factor is a 38-kDa cysteine-rich heparin-binding protein which is a secreted growth factor that can bind to integrins on the cell surface (32). Ectopic expression of connective tissue growth factor inhibited metastatic colonization by lung cancer cells (33). In contrast, the KAI1 metastasis suppressor protein is a member of the tetraspanin family of proteins and has been shown to interact with a myriad of cell surface proteins including other tetraspans (i.e., CD9, CD81), integrins β1 and β2, MHCII growth factor receptors, and intracellular signaling proteins such as protein kinase C (34). It has been hypothesized that KAI1 modulates integrin and growth receptor signaling by accelerating the rate of internalization via a protein kinase C–dependent pathway, thereby modulating cell adhesion and cell migration (34). Furthermore, KAI1 has been shown to decrease the integrin- and ligand-induced activation of the receptor tyrosine kinase c-Met, and independently decreases integrin-induced Src activation. Both c-Met and Src are thought to be required for invasion (35). A final observation with respect to the involvement of integrins in metastasis suppressor activity concerns caspase-8 function. Loss of caspase-8 in neuroblastoma cells leads to increased survival and an increased incidence of metastasis. The induction of caspase-8-mediated apoptosis seems to be due to unligated integrins because decreased expression of unligated integrins enhanced cell survival (36–38).Claudin-4 is a component of tight junctions which form the most apical component of intercellular junctional complexes where they establish cell polarity and cellular functions such as permeability (39, 40). These intercellular junctions not only carry out adhesive functions but also contain crucial components of signaling pathways that regulate epithelial proliferation and differentiation. Complementary in vitro and in vivo studies identified claudin-4 as an inhibitor of invasion and metastasis in pancreatic cancer cells and a target of transforming growth factor-β and extracellular signal-regulated kinase (ERK) signaling (40, 41).RECK, a membrane glycoprotein that encodes a GPI-anchored glycoprotein harboring three protease inhibitor–like domains, has been shown to negatively regulate MMP-2, MMP-9, and MT1-MMPs in vitro, suggesting that it is an important regulator of extracellular matrix remodeling. Furthermore, RECK-null mouse embryos displayed markedly elevated MMP activity. Interestingly, RECK is down-regulated by Ras signaling, a commonly altered pathway in many malignant cells (42).The role of some putative metastasis suppressors is more complex. There are several of a protein as a metastasis suppressor in one model and a potential tumor suppressor in For example, is a glycoprotein that responses of the cell to their cellular Although it has been in the that of has been shown to suppress metastasis in the cancer system other have that may metastatic activity a of the invasion and of and has been suggested to be a is not the only protein to have an role in metastasis. are a of that cell-cell adhesion in various tissues in a function is controlled by its Both and seem to inhibit cell migration and the in vivo metastatic potential of cells other studies have suggested that may invasion It is important to note that cancer cells of tissue used in several of the The tissue specificity of metastasis suppressor function is with the and integration information through signal transduction is a secreted protein and is hypothesized to processing by The are known as or not be secreted in to its metastatic suppressor activity has yet to be at the identification of upstream of identified a metastasis suppressor activity for CRSP3, a of the receptor of cells with suppressed metastasis and was with an of providing a potential between these and metastasis regulation stress-activated protein and pathways in parallel to the protein kinase In to the of with and have been with cell and apoptosis in to and changes, and growth factor specifically either or The protein is a kinase that has been shown to and the and in to a of extracellular can function as a metastasis suppressor in both and cancer Complementary in vitro and in vivo assays showed that the kinase activity of is required for the suppression of overt metastases and is to Subsequent studies identified metastasis suppressor for and in and interest is the finding that in cancer signals through the of the pathway to suppress metastasis in cancer signals through the of the pathway to suppress metastasis In vivo studies that both and suppress the formation of overt metastases by the ability of disseminated cells to colonize the lung identification of a metastasis suppressor function for protein also or protein mechanistic between the to cellular and of metastatic ability. is an endogenous inhibitor of a component of a system that has been implicated in cancer progression The levels of in cells are by endogenous as the in to to and including The primary of cellular is the is through of membrane or in to to with molecular or thereby highly or a of events that result in cell and of metastasis. this and ectopic expression of modulates these events to suppress metastasis formation is currently pathway is by mitogenic such as growth growth or which receptor tyrosine and The of mitogenic factors to cell surface a series of that with the activation of various factors and proteins and regulation may at in this is through both the of a kinase for a as well as protein expression levels of regulation are by intracellular localization and with scaffolding or proteins. These events may be important for regulating metastatic In the of metastasis the protein with the by to and the kinase suppressor of Ras a protein that has a role in the regulation of Ras activity and activation of the pathway has been shown to regulate signaling, suggesting that metastasis suppression activity may be by the inhibition of signaling kinase inhibitor protein was identified as a metastasis suppressor gene in functions as a negative upstream regulator of signaling and kinase interact with at sites, and of either inhibits of the Both be in to inhibition may suppress metastasis by of metastasis suppressors, and are with the signaling The signaling pathway a key role in many of cell survival and 1 are of an inhibitory and a and signals from various cellular proteins such as and an integration for the activation of and downstream to a that a of downstream targets, the and also regulates a of target proteins that cell proliferation and survival The levels of are and several particular interest is the which to signaling metastasis suppressor protein has been with the of cells showed decreases in endogenous levels of (i.e., of This finding is with a model in which changes in signaling the ability of disseminated cells to survive in the and grow at secondary In contrast, expression of the metastasis suppressor is modulated by clinical is the finding that expression correlates significantly with in both and cancer and that the in as a significantly of and cancer survival either evidence from the cell molecular and genetic studies that the metastatic process requires many steps to The of only one in this of in vivo events the process and a This enabled the identification of metastasis suppressor proteins. the of the however, the is not as straightforward because which signaling in the metastatic process are is not have insights into this by metastatic colonization as the in the metastatic cascade that is from a of A clinical will this to of invasive are with metastatic and (i.e., These that many with invasive disease disseminated cancer cells at preventing the of disseminated cells into the metastatic (i.e., the process of would a for cancer This approach more at preventing cancer cells from the primary tumor for the that this process has place the is first with In where this process has not yet local such as and can the the for additional at the an for metastasis preventing the growth of disseminated tumor cells into an overt clinical metastasis or the metastases. the approach not the in hold disease in providing increased of the with both of these is the identification of at for disease that they may at metastatic that can be to this include both tumor as well as molecular of the primary tumor to the development of metastasis a it has been to of the disseminated tumor cells at a secondary as the and as being distinct from that at the primary with to the tumor tumor cells distinct in the primary and secondary sites, and these interactions can or include locally and as well as cell-cell interactions in environments such as the and these with the of metastasis suppressor protein one can to there are to metastasis suppressor proteins. The of these on of the leading to of metastasis suppressor protein For example, the gene is it that of a normal gene would be the In contrast, was secondary to suppressed for example, at the endogenous gene seem we will provide an of approach from that have the of the first identified metastasis a of metastasis suppressor protein function in disseminated tumor In many cancer is with metastasis that occurs A study used gene to and whether this would cancer metastasis in an model of this A cell line of metastatic potential to the by in vivo was used to the of reexpression on metastasis. of these cells, an expressing was This in expression of the gene in most of the tumor cells in in and was with a in the number of metastases and a of This of of the of induction as a approach The of this approach are also to the of which is a disease that the In with gene is and the with i.v. development from the also the of the metastasis gene but the approach reexpression of the endogenous gene as a the was to a that would expression and allow at to on at of the This of would a that is and with an and have been to For example, was to expression in a cell line elevated the expression of cells out an of the the that elevated the expression of metastatic cell is a used at in and as well as at in cancer Furthermore, elevated expression and inhibited colonization and this effect was through The effect of on the of expression was in an in vivo model system for the of metastases the cell line to lung mice to or in of mice to of The number of metastases mouse was reduced by to on the metastases in reduced by to in the inhibited the number and of metastases in this This in metastases was with reexpression in the lung a of in with metastases and and tumors is of gene expression alterations with of metastasis suppressor protein A would be that functional of metastasis suppressor proteins is with gene expression changes, and cellular Recently, this with the that of metastasis suppressor proteins is with the of was used to a novel These studies focused on RhoGDI2, a suppressor of metastasis in an model of cancer metastasis reduced expression was to be with decreased survival for with cancer that RhoGDI2 as a on the expression of genes and to identify such genes in a of the lung metastasis model and primary clinical of RhoGDI2 protein is currently they to proteins or pathways downstream of These genes required to be following the of RhoGDI2 protein from the cells, and be of being inhibited by or to the changes in gene expression following of RhoGDI2 expression in metastatic cells, several proteins including This finding was by the between RhoGDI2 expression levels and of in tumor (29). Furthermore, inhibition of the endothelin with of the endothelin receptor such as to metastatic suppression in cells deficient for RhoGDI2 (29). The endothelin has been shown to regulate tissue cell cell and remodeling also has on cells in the and lung important of cancer metastasis In to such may growth factor and factor and growth factor one in the proliferation of and cells tumor also a role for in metastases from and and supports a model in which cells, in providing a microenvironment for these that trials with endothelin may be for with cancer following of the primary The for its use in the from the effect these have had in preventing experimental metastasis. These however, not the of these in metastatic but this is yet to be The molecular shown between and RhoGDI2 is because of endothelin receptor A such as with clinical In fact, in with in a the most events and that is well In this there was no at to in other of was not by this the of this effector approach to other metastasis suppressor proteins could identify potential novel for in other for and during the of key of this

Clinical Cancer Research · review · 131 citationsread the source →

Heart rate variability

IN FOCUSHeart rate variabilityHarald M. StaussHarald M. StaussDepartment of Exercise Science, University of Iowa, Iowa City, Iowa 52242Published Online:01 Nov 2003https://doi.org/10.1152/ajpregu.00452.2003MoreSectionsPDF (59 KB)Download PDF ToolsExport citationAdd to favoritesGet permissionsTrack citations the rhythm of the heart has not only fascinated cardiologists but also inspired poets and musicians. Indeed, the periodic beat of the heart was used to define the speed of music. In music notation, the traditional Italian term "moderato" originally referred to one beat of the measure per walking pace (76-80 paces/min) or heartbeat (∼72 beats/min). The use of the heartbeat to define the speed of music may imply that the periodicity of the beat of the heart is very constant. However, this is not necessarily the case. In fact, loss of heart rate variability can indicate severe cardiovascular diseases and reliably predict poor outcome of such conditions (18, 22, 27, 47a). This In Focus article reviews sources of heart rate variability, its role as a prognostic marker for cardiovascular diseases, and its application in estimation of cardiac autonomic nervous system activity. All of these topics have been addressed intensely in articles published in the American Journal of Physiology-Regulatory, Integrative and Comparative Physiology during the last two years. In healthy subjects, the sinoatrial node located at the posterior wall of the right atrium initiates each beat of the heart. Due to the unstable membrane potential of the myocytes located in this region, action potentials are generated periodically at a fairly constant frequency. This relatively constant frequency generated by the autorhythmicity of the sinoatrial node is modulated by many factors that add variability to the heart rate signal at different frequencies. According to the Task Force of The European Society of Cardiology and The North American Society of Pacing and Electrophysiology (47a) these frequencies are classified into 1) ultra-low frequencies (ULF; >5-h cycle length) that include the circadian rhythm (6, 9, 34, 54); 2) very low frequencies (VLF; >25-s cycle length) that are supposed to be affected by temperature regulation (1, 7, 34, 52, 54) and humoral systems (9, 36); 3) low frequencies (LF; >6-s cycle length in humans) that are sensitive to changes in cardiac sympathetic (and presumably parasympathetic) nerve activity (27, 30); and 4) high frequencies (HF; 2.5- to 6.0-s cycle length in humans) that are synchronized to the respiratory rhythm (5) and are primarily modulated by cardiac parasympathetic innervation (38).The most prominent oscillation in the ULF band of the heart rate spectrum is the circadian rhythm. The autonomic nervous system contributes significantly to circadian heart rate variability. Using long-term recordings in conscious rabbits, Barrett et al. (6) demonstrated a strong circadian rhythm in heart rate, mean arterial blood pressure, renal blood flow, and renal sympathetic nerve activity. The importance of this study is that it clearly demonstrates that sympathetic nerve discharges exhibit a strong circadian rhythmicity. The paraventricular nucleus of the hypothalamus (PVN) appears to play a central role in mediating the circadian rhythm of autonomic nervous system activity. First, GABAergic and glutamatergic neurons project from the suprachiasmatic nuclei of the hypothalamus (SCN) to spinal-projecting neurons of the PVN (12). The SCN is the major central oscillator that triggers the day/night cycle. It receives photic input from the retina (47) and drives many neuroendocrine, metabolic, autonomic, and behavioral circadian rhythms (14, 16, 21, 31, 35, 44, 46, 50). In addition, microinjections of the inhibitory neurotransmitter GABA into the PVN of anesthetized rats elicit dose-dependent decreases in renal sympathetic nerve activity, whereas bicuculline (a GABA antagonist) increases renal sympathetic nerve activity (56). Second, from the PVN, neurons project to the nucleus of the solitary tract (that integrates inputs from the baroreceptors), the nucleus ambiguus (origin of preganglionic parasympathetic neurons to the heart), the rostroventrolateral medulla (location of sympathetic premotor neurons), and the intermediolateral cell column of the thoracolumbar spinal cord (location of preganglionic sympathetic neurons). Thus PVN neurons can modulate autonomic nervous system activity by sending inputs to major sites of autonomic nervous system regulation. As an example, a pivotal role of the PVN for sympathoexcitation during parturition was recently demonstrated in sheep. The increase in sympathetic nerve activity that accompanies birth in maternal animals was prevented by stereotactic lesioning of the PVN (43). Taken together, a major component of the circadian heart rate variability is elicited by diurnal fluctuations in autonomic nervous system activity, generated by corresponding fluctuations of neuronal activity within the PVN, which depend on circadian inputs originating from the SCN.It has been suggested that thermoregulation affects VLF heart rate variability (10, 26). Cooling the heart causes bradycardia, a mechanism used in heart surgeries. Conversely, fever is known to increase heart rate. Raising body core temperature from 36.0 to 36.6°C caused an increase in heart rate by almost 40 beats/min in male subjects (1), whereas acutely reducing ambient temperature from thermoneutral conditions (35°C) to 29, 23, and 17°C, reduced heart rate from 400 to 250 beats/min in 8-day-old rats (7). In addition, lowering temperature in the isolated working rat heart from 37 to 31°C reduced heart rate from 332 to 215 beats/min and markedly increased heart rate variability (28), indicating that parts of the temperature effects on heart rate and heart rate variability are independent from the autonomic nervous system. In contrast to the tachycardia that accompanies acute elevations in temperature, chronically raising ambient temperature in adult rodents from a standard housing temperature of 21-23°C to thermoneutral conditions (29-30°C) reduced heart rate by roughly 50 beats/min in rats (34) and by 200-300 beats/min in mice (54). The authors of these articles (34, 54) suggested that standard housing temperatures are associated with cold stress that causes parallel activation of brown adipose tissue, cardiac, and vasomotor sympathetic drives that elicits nonshivering thermogenesis and tonically elevates heart rate and arterial blood pressure. These and other studies indicate that both direct effects of temperature on pacemaker activity of the sinus node (28) and indirect effects mediated via the autonomic nervous system (11, 25, 51, 55) mediate temperature effects on heart rate and heart rate variability. Thus fluctuation in temperature is an important source of heart rate variability that should not be underestimated. In a more recent study, this was taken into account by core body temperature correction of heart rate variability (3).Endocrine factors affecting heart rate variability include thyroxine, reproductive hormones, the renin-angiotensin system, steroids, and others. Chronic subcutaneous infusion of angiotensin II in rats markedly increased blood pressure and heart rate variability, expressed as standard deviation (9). In contrast, chronic corticosterone treatment is likely to reduce baroreflex-mediated heart rate variability, because baroreceptor-heart rate (39) and baroreceptor-renal sympathetic nerve activity reflex sensitivity (41) were blunted in chronically corticosterone-treated rats. Furthermore, an interaction between angiotensin II and glucocorticoids was recently described. Intracerebro-ventricular microinjections of angiotensin II AT1 receptor antagonists caused marked decreases in mean blood pressure and heart rate in rats chronically treated with corticosterone but not in control animals (40). This interaction is likely to take place in the central nervous system, because peripheral angiotensin II AT1 receptor blockade did not alter the effects of betamethasone treatment on blood pressure, heart rate, and baroreceptor-heart rate reflex sensitivity in newborn lambs (42).Adenosine is a substance less known to affect heart rate variability. It is produced locally in the heart (53) and binds to A1-adenosinergic receptors, which are among the earliest expressed G protein-coupled receptors in the heart (36). The A1-adenosinergic agonist N6-cyclopentyladenosine dose dependently reduced heart rate in murine embryos, whereas 1,3-dipropyl-8-cyclopentylxanthine, an A1-adenosinergic antagonist, increased heart rate (36). Adenosine also exerts central nervous system effects in various brain areas (15, 20). Microinjections of adenosine into the nucleus of the solitary tract of awake rats caused dose-dependent changes in heart rate: low doses (0.01 nmol) produced a bradycardic response, whereas high doses (2.5-5.0 nmol) elicited a tachycardic response (15). Thus adenosine may indeed be involved in the regulation of heart rate and modulate heart rate variability via local cardiac and central nervous system effects. It has been proposed that the intrinsic cardiac nervous system plays an active role in regulating cardiac function (4, 37, 45, 57). This nervous system consists of sympathetic and parasympathetic neurons and interconnecting local circuits (37). Neurons in the canine right atrial ganglionated plexus (RAGP) spontaneously generate activity even after chronic cardiac autonomic denervation (45). Right atrial neurons in patients undergoing coronary artery bypass surgery generated spontaneous activity that was unrelated to the cardiac cycle but sensitive to changes in systemic arterial pressure, indicating that these neurons receive pressure-sensitive sensory inputs (4). In addition, it has been suggested that substance P acts as a neuromodulator and neurotransmitter in intracardiac ganglia of the guinea pig, modulates the response to vagal inputs, and triggers action potentials at the site of parasympathetic ganglia independent of acetylcholine (57). Furthermore, the right atrial (RAGP) and the posterior atrial ganglionated plexus (PAGP) appear to have different functions. Ablation of the PAGP reduced vagally mediated bradycardia by 26%, whereas RAGP ablation completely abolished this response. Inhibition of sympathetically mediated tachycardia by vagal stimulation was attenuated by ablation of either plexus (37). Thus parasympathetic efferent neurons are primarily located in the RAGP, whereas prejunctional parasympathetic-sympathetic interactions also involve neurons within the PAGP (37). The spontaneous activity of neurons in the intrinsic cardiac nervous system, even after cardiac denervation (45), suggests an active role of this system in regulating heart rate. However, the impact of the intrinsic cardiac nervous system on heart rate variability remains to be elucidated. The importance of the autonomic nervous system for heart rate variability in humans becomes apparent in patients following cardiac transplantation, in whom heart rate variability is markedly reduced (49). Although reinnervation is possible after months and years, initially transplanted hearts can be considered to be denervated. Thus the reduced heart rate variability in cardiac transplanted patients (49) underlines the importance of an intact autonomic innervation for spontaneously occurring heart rate variability. A major component of the chronotropic effect of the autonomic nervous system is linked to cAMP. Intracellular cAMP increases the inward current of Na+ (funny current, If), which determines the rate of the slow diastolic depolarization that precedes each action potential. The activity of adenylate cyclase and thus intracellular cAMP levels are increased by stimulation of sympathetic β1-adrenergic receptors and decreased (via a Gi protein) by stimulation of parasympathetic muscarinic receptors. Thus cardiac sympathetic innervation increases the rate of the slow diastolic depolarization and accelerates heart rate, while cardiac parasympathetic innervation elicits opposite effects. Interestingly, parasympathetic-mediated changes in heart rate occur much faster than sympathetic-mediated effects on heart rate (27, 30, 47a). As a result, cardiac sympathetic nervous system activity can only affect LF components of heart rate variability, whereas the parasympathetic nervous system can also modulate HF components. A hitherto unsolved question in this context is if the rapid heart rate response to parasympathetic stimulation compared with the slow effect of sympathetic inputs is due to 1) different kinetics of β1-adrenergic vs. muscarinic receptors, 2) different kinetics of adenylate cyclase vs. phosphodiesterase, the enzyme that cleaves cAMP, or 3) fast parasympathetic-mediated opening of KACh channels (via muscarinic receptors and a GK protein). Support for the latter possibility comes from experiments in the rabbit sinoatrial node that demonstrated that activation of KACh channels contributes to the initial slowing of heart rate as a result of vagal stimulation (8).On the basis of the different frequency response characteristics of sympathetic and parasympathetic modulation of heart rate, frequency analysis of heart rate variability is often used as a tool to determine "autonomic balance" or sympathetic and parasympathetic nervous system activity (27, 47a). As an example, the wavelet transform was recently used to determine cardiac autonomic responses to reperfusion in patients with thrombolysis after coronary thrombosis. Depending on the location of the infarct, marked alterations in LF or HF spectral power of heart rate or in the LF/HF ratio was observed in all successful reperfusions (48).The HF component corresponds to the frequency of respiration and is driven by the vagus as indicated by the strong respiratory pattern of cardiac vagal motoneurons in the nucleus ambiguus (38). The LF component has been ascribed to sympathetic modulation of cardiac pacemaker activity, because a variety of studies demonstrated that acute interventions that increase sympathetic nervous system activity, such as orthostatic perturbations (17, 19, 33), mental stress (32), or handgrip exercise (13, 24) increases LF spectral power of heart rate (27, 30). In addition to acute perturbations of cardiac sympathetic nerve activity, feedback oscillations generated by the baroreceptor reflex also appear to contribute to LF spectral power of heart rate as it was demonstrated that sinoaortic denervation markedly reduces the LF component (27, 30). Despite the strong modulation of heart rate by the autonomic nervous system, the LF and HF spectral components of heart rate variability may not always be very reliable markers for cardiac sympathetic and parasympathetic "tone" (30). In a recent study, muscle sympathetic nerve activity was recorded together with heart rate variability during application of lower body negative pressure that is known to increase muscle sympathetic nerve activity (17, 33). At higher levels of lower body negative pressure (-15 mmHg), both muscle sympathetic nerve activity and relative LF spectral power of heart rate increased significantly, whereas HF spectral power decreased (17). These findings suggest that LF spectral power reflects cardiac sympathetic "tone." However, no correlation within subjects was found between changes in LF/HF ratio and muscle sympathetic nerve activity (17). Thus heart rate variability does not reliably reflect the sympathetic response to orthostatic stress. Respiration-related fluctuation of heart rate (respiratory sinus arrhythmia) is probably the most often investigated component of heart rate variability, as it is believed that this component reflects respiration-driven vagal modulation of sinus arrhythmia (27). In a recent study, Rentero et al. (38) recorded the electrical activity from cardiac vagal motoneurons in the nucleus ambiguus. Firing of these neurons was modulated by the central respiratory cycle. This and other studies support the view that respiratory sinus arrhythmia is generated by central coupling of the respiratory oscillator with autonomic centers in the brain stem. However, a mechanical cardiopulmonary coupling as a source of respiration-related heart rate variability has also been suggested (5). The Bainbridge reflex causes a tachycardia in response to hypervolemia. This reflex is initiated by atrial mechanoreceptors and uses efferent sympathetic and parasympathetic pathways to modulate heart rate in response to changes in central venous pressure (23). Thus respiratory changes in central blood volume cause corresponding respiratory fluctuations in cardiac autonomic nervous system activity via the Bainbridge reflex. Only the parasympathetic component of the efferent pathway of the reflex can contribute to respiratory sinus arrhythmia, because sympathetic actions on heart rate are too damped to follow the respiratory frequency. The gain and phase of the transfer function between respiratory changes in lung volume and R-R intervals of the ECG were calculated in human subjects during graded changes in central blood volume (5). At the respiratory frequency, the phase was -180 degree, indicating that an inspiratory increase in central blood volume was associated with a decrease in R-R interval (increase in heart rate). Furthermore, the gain of the transfer function at the respiratory frequency steadily increased with increasing central volumes (except at the highest volume). Both of these findings confirm the presence of the Bainbridge reflex in humans (5). Thus, in addition to the central coupling of respiratory oscillators with cardiovascular centers, the Bainbridge reflex may contribute to respiration-related heart rate variability by mechanical cardiopulmonary coupling. There is general agreement that low heart rate variability is an unfavorable prognostic marker for cardiovascular diseases, such as diabetic autonomic neuropathy, hypertension, myocardial infarction, and heart failure (18, 22, 27, 29, 47a). Heart rate variability (variance of R-R intervals) was reduced in patients with mild hypertension (29) compared with normal values (1,134 ± 202 vs. 3,466 ± 1,018 ms2) provided by the Task Force (47a). In the rat model of myocardial infarction-induced congestive heart failure, Francis and colleagues (18) reported loss of spontaneous heart rate variability 6 wk after coronary artery ligation. Interestingly, reduced heart rate variability was also observed in a rat model of depression that is based on chronic (4 wk) mild stress application (22). Because depression is an independent risk factor for coronary artery disease, this finding may realistically model a human disease process. The reduction in heart rate variability was abolished by β-adrenergic receptor blockade, indicating that the reduced heart rate variability in this model of depression is related to elevated cardiac sympathetic tone (22).In summary, heart rate variability is generated by multiple factors not exclusively limited to the autonomic nervous system. Specific frequency components of heart rate variability mirror acute perturbations of the autonomic nervous system but do not always reflect autonomic nervous system activity. Simple statistics of heart rate variability, such as the standard deviation of R-R intervals in the ECG, can reliably predict the prognosis of cardiovascular diseases.I thank Dr. R. McAllen for critically reviewing the manuscript. References 1 Aoki K, Stephens DP, and Johnson JM. Diurnal variation in cutaneous vasodilator and vasoconstrictor systems during heat stress. 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American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · review · 309 citationsread the source →

Prevalence of depressive disorders and treatment in China: a cross-sectional epidemiological study.

Background: In China, depressive disorders have been estimated to be the second leading cause of years lived with disability. However, nationally representative epidemiological data for depressive disorders, in particular use of mental health services by adults with these disorders, are unavailable in China. The present study, part of the China Mental Health Survey, 2012-15, aims to describe the socioeconomic characteristics and the use of mental health services in people with depressive disorders in China. Methods: The China Mental Health Survey was a cross-sectional epidemiological survey of mental disorders in a multistage clustered-area probability sample of adults of Chinese nationality (≥18 years) from 157 nationwide representative population-based disease surveillance points in 31 provinces across China. Trained investigators interviewed the participants with the Composite International Diagnostic Interview 3.0 to ascertain the presence of lifetime and 12-month depressive disorders according to DSM-IV criteria, including major depressive disorder, dysthymic disorder, and depressive disorder not otherwise specified. Participants with 12-month depressive disorders were asked whether they received any treatment for their emotional problems during the past 12 months and, if so, the specific types of treatment providers. The Sheehan Disability Scale (SDS) was used to assess impairments associated with 12-month depressive symptoms. Data-quality control procedures included logic check by computers, sequential recording check, and phone-call check by the quality controllers, and reinterview check by the psychiatrists. Data were weighted according to the age-sex-residence distribution data from China's 2010 census population survey to adjust for differential probabilities of selection and differential response, as well as to post-stratify the sample to match the population distribution. Findings: 28 140 respondents (12 537 [44·6%] men and 15 603 [55·4%] women) completed the survey between July 22, 2013, and March 5, 2015. Ethnicity data (Han or non-Han) were collected for only a subsample. Prevalence of any depressive disorders was higher in women than men (lifetime prevalence odds ratio [OR] 1·44 [95% CI 1·20-1·72] and 12-month prevalence OR 1·41 [1·12-1·78]), in unemployed people than employed people (lifetime OR 2·38 [95% CI 1·68-3·38] and 12-month OR 2·80 [95% CI 1·88-4·18]), and in people who were separated, widowed, or divorced compared with those who were married or cohabiting (lifetime OR 1·87 [95% CI 1·39-2·51] and 12-month OR 1·85 [95% CI 1·40-2·46]). Overall, 574 (weighted % 75·9%) of 744 people with 12-month depressive disorders had role impairment of any SDS domain: 439 (83·6%) of 534 respondents with major depressive disorder, 207 (79·8%) of 254 respondents with dysthymic disorder, and 122 (59·9%) of 189 respondents with depressive disorder not otherwise specified. Only an estimated 84 (weighted % 9·5%) of 1007 participants with 12-month depressive disorders were treated in any treatment sector: 38 (3·6%) in speciality mental health, 20 (1·5%) in general medical, two (0·3%) in human services, and 21 (2·7%) in complementary and alternative medicine. Only 12 (0·5%) of 1007 participants with depressive disorders were treated adequately. Interpretation: Depressive disorders in China were more prevalent in women than men, unemployed people than employed, and those who were separated, widowed, or divorced than people who were married or cohabiting. Most people with depressive disorders reported social impairment. Treatment rates were very low, and few people received adequate treatment. National programmes are needed to remove barriers to availability, accessibility, and acceptability of care for depression in China. Funding: National Health Commission and Ministry of Science and Technology of People's Republic of China. Translation: For the Chinese translation of the abstract see Supplementary Materials section.

The lancet. Psychiatry · 591 citationsread the source →

Associations between adolescent sleep difficulties and active versus passive screen time across 38 countries.

Background: High screen use has been adversely linked with mental wellbeing; however, little is known about how active versus passive screen time are associated with sleep-onset difficulties among adolescents. Methods: We analysed data from 38 European and North American countries that participated in the 2014 Health Behaviour in School-aged Children (HBSC) survey. Difficulties in falling sleep were assessed using a self-reported item with a 5-point Likert scale, and then dichotomised. Participants reported h/day of discretional time spent watching television, electronic gaming, and computer use. Results: Of the 195,668 participants (Mage 13.59 [1.62] years; 51 % girls), about 25 % of girls reported sleep-onset difficulties, while the rate was 18 % in boys. Adolescents who played electronic games >4 h/day (≤1 h/day as reference) had 30 % higher odds in boys (OR 1.30; 95 % CI: 1.23-1.38) and 38 % higher odds in girls (OR 1.38; 95 % CI: 1.31-1.45) of reporting sleep difficulties. High computer use (>4 h/day) increased the odds of sleep difficulties by 41 % in boys (OR 1.41, 95 % CI: 1.33-1.49) and 61 % in girls (OR 1.61, 95 % CI: 1.53-1.69). Similarly, high television time (>4 h/day) had increased the odds of sleep difficulties by 15 % in boys (OR 1.15, 95 % CI: 1.08-1.22) and 19 % in girls (OR 1.19, 95 % CI: 1.12-1.25). Limitations: Cross-sectional analyses cannot establish causality of the associations. Conclusions: Higher levels of recreational screen use of any type were associated with sleep-onset difficulties among adolescents with adverse effects being more prevalent in active than passive screen time. Prospective research with objective measures is warranted to understand causality of these relationships.

Journal of affective disorders · 13 citationsread the source →

Combat sports and wellbeing: advancing health and inclusion in athletes and practitioners. An opinion paper

Historically, combat sports have been predominantly conceptualized within the framework of elite competition, emphasizing physical aptitude, technical proficiency, and strategic execution (1-3). Despite their traditional and peculiar constitutions and developments, disciplines such as judo, karate, taekwondo, wrestling, fencing, boxing, and mixed martial arts have commonly been associated with high-performance athletes striving for competitive excellence on national and international stages (1, 4-6). However, contemporary discourse increasingly recognizes their expansive role in contributing to physical and psychological well-being, and social inclusion of the practitioners (7, 8). This paradigmatic shift underscores the capacity of combat sports to function as inclusive and accessible modalities for fostering multidimensional health benefits across diverse populations, including individuals with disabilities and other marginalized groups (9-13).The interdisciplinary exploration of physical activity and health highlights the intricate interrelationship between structured sports engagement and holistic well-being (14). Whilst conventional team and individual sports have long been acknowledged for their physiological and psychosocial benefits, combat sports exhibit distinct characteristics that might amplify these advantages (15, 16). Within combat sports, the synergistic interplay of rigorous physical conditioning, the cognitive engagement, adherence to rules, competition dynamics, respect, externalizing emotions regulation, are intertwined with pedagogical and philosophical values, thus presenting a unique framework for enhancing psychological resilience, cognitive adaptability, and emotional control. Consequently, the systematic practice of combat sports has been increasingly examined as a way of promoting mental health, stress modulation, and social cohesion (17, 18).The inclusive nature of many combat sports programmes further accentuates their relevance in dismantling stereotypes, facilitating integration, and fostering equity and social integration (19-21). In fact, they demonstrated significant adaptability to accommodate individuals with disabilities (e.g., physical impairments, developmental, emotional, intellectual disorders), thereby ensuring equitable access and fostering empowerment (9, 22). Adapted judo, para-taekwondo, and other modified combat disciplines provide individuals with disabilities a structured platform to engage in physical activity, cultivate self-efficacy, and develop meaningful social connections within a supportive and adaptive environment (23). From a public health perspective, the integration of combat sports within community-based health initiatives offers a compelling opportunity to engage populations that may not traditionally participate in structured physical activity programmes (7, 8, 19). The distinctive accessibility of combat sports, which cater to practitioners of all skill levels (e.g., from novices to elite athletes) sets them apart from many other sports. While their structured progression, adaptability, and emphasis on holistic development make them a viable option for lifelong and intergenerational participation (19, 24, 25), the mentorship and pedagogical frameworks cultivate positive role modeling, discipline, and intrinsic motivation, which are integral for sustaining long-term adherence to health-promoting behaviors (8).Furthermore, the intersection between combat sports and mental health has increasingly emerged as a focal point within academic and clinical research (17) with empirical evidence suggesting an association between participation and enhanced self-regulation and self-efficacy, and reduction in anxiety and depressive symptomatology (8, 26, 27). In necessitating sustained focus, adaptability, and emotional equilibrium, combat sports inherently require cognitive and affective demands, which align closely with established psychological frameworks that underpin mental well-being (28, 29). Moreover, the integration of mindfulness techniques, stress management strategies, and resilience-building paradigms within combat sports training substantiates their potential as a non-pharmacological intervention for addressing various mental health challenges (e.g., autism spectrum and oppositional defiant disorders) (30, 31).Despite these advantages, the discourse surrounding combat sports and well-being necessitates a critical examination of inherent risks and potential challenges. Issues related to injury risk, hypercompetitive environments, eating disorders, sexual harassment, and the psychological stressors associated with high-intensity training warrant careful scrutiny (32-36). The implementation of evidence-based injury prevention protocols, the establishment of ethically responsible coaching methodologies, and the promotion of safe training environments are imperative to ensure that the benefits of combat sports are maximized while minimizing adverse outcomes. Against this backdrop, this opinion paper seeks to examine the role of combat sports in advancing health and social inclusion among athletes and practitioners. Through a synthesis of contemporary empirical findings, theoretical paradigms, and applied insights, this paper aims to contribute to the evolving discourse on the potential of combat sports as a catalyst for holistic well-being. By delineating the multidimensional impact of combat sports on physical, psychological, and social health, this paper endeavors to underscore their transformative potential as an instrument for fostering individual and community well-being within different populations. DiscussionWhilst an expanding body of research and an evolution in scholarly discourse is recognizing the combat sports’ broader implications for holistic well-being (30, 37), a rigorous evaluation of the investigation methodologies, the validity of hypotheses, and the translational potential of recent findings is necessary to contextualize their significance within the sports and public health sciences, considering their strengths, weaknesses, opportunities, and threats (Figure 1).----------------------------------------ADD FIGURE 1 ABOUT HERE----------------------------------------Empirical evidence robustly shows the positive impact of combat sports on physical fitness, motor coordination, and cardiovascular health (3, 38). These benefits are attributed to the high-intensity, intermittent nature of combat sports training, which enhances aerobic and anaerobic endurance, muscular strength, and neuromuscular control (39). However, concerns regarding injury risk, particularly in striking and contact-intensive disciplines such as boxing, taekwondo, and mixed martial arts, necessitate continued research into injury mitigation strategies, particularly those targeting concussion and repetitive head trauma (6, 35, 40, 41). Moreover, many combat sports have developed styles with reduced or simulated contact to minimize injury risk. For example, the French "boxe éducative" emphasizing technique and control, penalizing any violent behaviors (42) and the value and application of kata (i.e., forms; prearranged, pattern practices) to learning and adopting judo technique in a safe way educating the athlete culturally, to enrich her/him as a person (43).Beyond physical health, recent studies highlight the psychological benefits of combat sports, including reductions in anxiety and depression and improvements in self-efficacy, emotional regulation, resilience, and stress management (27, 44-47). Therefore, combat sports-based interventions for individuals with mental health conditions have yielded promising outcomes (23). Despite these encouraging findings, variability in study designs, participant demographics, and intervention protocols limits their external validity, underscoring the need for further rigorously controlled investigations. Furthermore, some authors claimed that combat sport athletes might present symptoms of low energy availability and high anxiety levels associated with competition- and injury-related psychological stressors, deficits in executive functions and neuropsychological impairments associated with occurrence of concussions, disordered eating and eating disorders associated with weight-loss, and might suffer offensive, frightening, hostile, degrading, humiliating experiences, or sexual harassment, which urge safeguarding actions (32-36).The role of combat sports in fostering social inclusion has gained empirical support, particularly in programmes aimed at individuals with disabilities and marginalized communities (25, 48). For instance, a recent systematic review shows that judo interventions adapted for intellectual disabilities help improve social integration and self-perception and enhance participants' quality of life (49). The development of para-combat sports demonstrates enhanced physical and motor abilities while providing psychosocial benefits to various populations with different disabilities, promoting social integration, self-perception, and community belonging (50, 51). However, longitudinal research is needed to assess the long-term retention rates and sustainability of these benefits. Furthermore, there is a need of studies focused on the most appropriate adapted rules to achieve a fairer competition for ensuring a sense of success in individuals with physical, emotional, mental, hearing or visual impairments participating in adapted sports competitions at local, national, and international levels. Methodological approaches in combat sports research encompass experimental, longitudinal, qualitative, and systematic review designs. While randomized controlled trials remain the gold standard for establishing causality, their application in combat sports research is constrained by ethical concerns, logistical challenges, and the inherently dynamic nature of training environments (52, 53). Consequently, many studies rely on observational designs, which, despite their value in identifying associations, are susceptible to confounding variables and biases (24, 54).Qualitative methodologies have provided critical insights into the lived experiences of combat sports practitioners, offering perspectives on psychological and social dimensions that are often overlooked in quantitative studies (28). Ethnographic research has been particularly instrumental in elucidating the role of combat sports in shaping identity, discipline, and personal development (55). However, limitations in reproducibility and generalizability highlight the need for mixed-methods approaches to generate a more comprehensive understanding of combat sports' impact (25, 56).Additionally, the incorporation of biometric and neurocognitive assessments, such as heart rate variability analysis, functional MRI, and salivary cortisol measurements, has advanced our understanding of the physiological and psychological mechanisms underlying combat sports participation (47, 57, 58). Despite their objective precision, these techniques often face challenges related to cost, accessibility, and limited sample sizes, necessitating the development of scalable and cost-effective methodologies for broader research application. Finally, recent studies show that virtual reality (VR) technology and digital platforms are increasingly becoming part of combat sports training methods. Due to COVID-19 restrictions, martial arts schools and organizations implemented hybrid or online training models, which allowed athletes to stay engaged. VR boxing programmes provide users with virtual sparring simulations to enhance their motor skills without needing physical interaction. Initial results indicate that VR training enhances response behavior in karate athletes (59). Digital adaptations offer great potential, especially for people with limited mobility or remote locations. However, further studies are necessary to prove their enduring effects on physical health and psychological and social aspects (59-61).Strengths and Weaknesses of Scientific HypothesesThe hypothesis that combat sports confer multidimensional health benefits is strongly supported by empirical evidence spanning physiological, psychological, and social domains (8, 62-64). The integration of physical exertion, cognitive engagement, and structured discipline inherent in combat sports aligns with established theories of exercise psychology, neuroplasticity, and social identity formation (65, 66). This multidimensional perspective provides a robust theoretical foundation for advocating combat sports as a health-promoting activity. Nevertheless, several limitations warrant consideration. The heterogeneity of disciplines, which vary highly in intensity, contact level, and training methodologies, is often inadequately addressed in research, leading to overgeneralized conclusions (17, 39). Often underexamined, individual differences in personality, motivation, and previous trauma history may strongly moderate the psychological outcomes of combat sports participation (35, 67, 68).Additionally, a research focus is needed on concerns regarding the potential for adverse psychological effects (e.g., anxiety, depression, disordered eating behaviors, burnout, and decreased self-esteem), particularly in competitive environments where performance pressure, extreme weight-cutting practices, and aggressive coaching styles are prevalent (69, 70). Indeed, a balanced perspective that considers both benefits and risks is essential for the development of evidence-based recommendations (10, 71).Future DirectionsTo enhance the field, future research should prioritize well-structured longitudinal studies that assess the long-term impact of combat sports participation on physical, psychological, and social health. Standardization of outcome measures, intervention protocols, and participant demographics would facilitate cross-study comparisons and strengthen the reliability of findings (72, 73). Moreover, interdisciplinary collaborations incorporating sports science, psychology, and sociology could provide a more holistic perspective on combat sports' broader implications on practitioners (74).From a policy perspective, to yield valuable insights into combat sports’ practical applications research should investigate their efficacy within public health, educational, and rehabilitation initiatives, particularly for underserved and vulnerable populations (23, 75, 76).Furthermore, while safety remains a primary concern, advancements in protective equipment, training methodologies, education for athletes, coaches, referees and tournament directors, and regulatory frameworks should be continually evaluated to optimize benefits while mitigating risks (40, 41, 58, 77, 78). Ethical considerations, particularly concerning athlete well-being and inclusive participation, should remain a central focus in both research and practical implementation (17, 34, 36).Therefore, key research challenges to be addressed are: 1. Injury risk and safety: a need for injury prevention strategies, especially for concussions and head trauma in striking sports. 2. Psychological wellbeing: risks of stress, anxiety, burnout, and negative self-perception in competitive environments. 3. Inclusion and accessibility: a need for more research on long-term social and psychological benefits for marginalized groups and individuals with disabilities. 4. Methodological limitations: lack of standardized protocols, variability in study designs, and limited reproducibility of findings. 5. Ethical and regulatory issues: concerns over coaching practices, extreme weight-cutting, and athlete wellbeing in high-pressure environments. 6. Technological innovations: more research required on the effectiveness of VR and digital training tools in combat sports. 7. Public health and policy: exploration of combat sports' role in health initiatives, rehabilitation, and educational programs. ConclusionThe evolving discourse on combat sports highlights their potential as a multidimensional tool for well-being promotion. While a substantial body of evidence supports their benefits, a critical examination of methodological limitations, scientific hypotheses, and practical applications is essential for further refine our understanding and enhance their effectiveness. Finally, this article makes a significant contribution not only to the field of martial arts but also to public health and sports psychology. Its interdisciplinary approach calls for scientific collaboration and methodological rigor, reinforces the need for evidence-based policies and can serve as a valuable guide for researchers and policymakers looking to integrate combat sports into strategies for promoting health and social inclusion.

Frontiers in Psychology · 12 citationsread the source →

Psychosexual health in gynecological cancer

The literature surrounding psychosexual health and cancer patients has primarily considered the functional aspects of the disease and its treatment at the major expense of the emotional sequelae. Sexual health is defined by WHO as: "a state of physical, emotional, mental, and social well-being in relation to sexuality; it is not merely the absence of disease, dysfunction or infirmity. Sexual health requires a positive and respectful approach to sexuality and sexual relationships, as well as the possibility of having pleasurable and safe sexual experiences, free of coercion, discrimination and violence" [1]. A principle goal of WHO is to assist its member states in achieving the highest attainable standard of health care for all, including sexual and reproductive health [2]. Global statistics show that the world's female population is carrying an overwhelming burden of need in this area. Over 200 million women cannot access modern contraception, and millions of women suffer rape, domestic violence, and sexual abuse, not only in the context of wars and criminal activities, but also in their own homes [2]. Although the physical sequelae of these disasters can be treated, such as treatment for sexually transmitted infections, the emotional impact can frequently be hidden, ignored, or may not reveal its impact until many years after the event. Any illness or traumatic life event, past or present, can lead to sexual problems in the lifetime of a woman, and gynecological cancer is no exception. It is the root cause or trigger for sexual difficulties in at least 50% of women affected [3]. In 2012, the estimated number of women living with gynecological cancers was over three million, which means that potentially 1.5 million gynecological cancer survivors could be affected by an associated sexual difficulty [4]. Within the context of gynecological cancer, many of these problems can be alleviated if recognized and acknowledged early in the cancer journey, therefore contributing dramatic improvements to a woman's overall well-being. It is now estimated that half of the population of either sex will develop cancer at some time in their life. Globally, 40% − 45% of women will have a sexual problem at some stage, with the prevalence increasing with age [5]. Between 10% and 90% of women with any cancer will have sexual problems [6] and over 50% of women with gynecological cancer will have either temporary or persistent sexual difficulties [3]. As diagnosis and treatments improve, the number of women surviving cancer will increase, and survivorship issues including quality of life have become increasingly important. Sexuality is a key component of most subjective measurable quality of life indicators [7]. Sexual function and enjoyment are important components of survivorship and should not be ignored. The most common sexual problems can be divided into two groups: problems of function and/or problems of desire. There is, however, a complex interplay of organic disorders with emotional and psychosocial issues, and these divisions are merely artificial. Formal definitions of female sexual dysfunction have been adopted, including the US classifications in the Diagnostic and Statistical Manual of Mental Disorders [8], although having a sexual difficulty does not constitute having a mental health disorder. Basson et al. [9] published a useful classification of the problems. Such classifications are useful for research purposes, but may often be less helpful when treating women. The predominant functional female sexual problem is pain on sexual intercourse, or dyspareunia. Deep dyspareunia describes intracoital pelvic pain, and superficial dyspareunia is pain on vaginal entry. Either could signify organic disease, and should be appropriately investigated. If no pathology is demonstrated, and the pain persists, then an emotional cause must be considered and pursued. Vaginismus, or involuntary spasm of the pubococcygeal and related musculature, can prevent sexual intercourse taking place. Good history taking can clarify whether there has been any penetration of the vagina, not only penile, but by fingers, sex toys, or tampons. If not, this is diagnostic of primary vaginismus, and apart from close inspection of the vulva and offer of gentle digital vaginal examination to determine the extent of the vaginismus, no further clinical investigation is warranted. Women with gynecological cancer are more likely to have secondary vaginismus caused by pain experienced from the disease or its treatment, and fear of the pain occurring during sex [10]. Loss of libido or loss of sexual interest on the other hand is a problem of desire. There are no physiological markers for loss of desire when its origins are psychogenic, with psychosocial contributions, past and present relationships, traumas, and emotional factors all inhibiting the woman's wish to be sexual. One of the key ways to determine the origins of the sexual difficulty is to ask about the sexual and emotional relationship between the woman and her partner before the cancer diagnosis. It should not be assumed that problems are all due to the cancer, as long-standing relationship problems may be disclosed, and need to be incorporated into any counselling. The exception to this is the woman who suddenly becomes menopausal following cancer treatment, who had no problems with sex or desire prior to her cancer therapy. Appropriate standard therapy for her menopausal symptoms should be considered; however, the impact of a cancer diagnosis will be life changing, and drug treatment of hormonal deprivation symptoms may not be sufficient without some psychological or counselling support, or may be contraindicated as in the case of breast and endometrial cancer [11]. A diagnosis of gynecological cancer is overwhelming. While the instinctive professional response from clinicians is to ensure long-term survival, sexual issues are important for quality of life and should be considered in the decision-making process [12]. Sexual dysfunction is one of the most common and distressing consequences of cancer treatment [13]. Many treatments are shown to have sexual impacts, both positive and negative, and should be discussed fully with the woman pre-treatment so that she can make an autonomous decision about her care. Early offer of discussion of sexual issues in the cancer journey can lead to better sexual outcomes. Cervical cancer is the most common gynecological cancer worldwide. Cervical cancer survivors are at risk of sexual pain disorders, no matter which modality of treatment is used. A small study of patients who underwent radical vaginal trachelectomy for early stage cervical cancer showed sexual dysfunction, including loss of libido, for up to one year following treatment; however, by 12 months, sexual activity had reached that of healthy women [14]. Following radical hysterectomy for locally advanced cervical cancer, there was no significant difference in sexual activity and enjoyment between women with benign or malignant disease; however, the cancer group had worse problems than healthy controls with body image and vaginal functioning [15]. In women with advanced cervical cancer given chemoradiotherapy, pain during intercourse was in fact reduced after treatment [16]. This may have been a result of the resolution of bleeding, discharge, and pelvic pain. However, the anxiety surrounding cancer remains for many women. Women surviving up to 15 years following cervical cancer treatment showed poorer quality of life than healthy controls, and those who had received radiotherapy were significantly more affected by sexual dysfunction than those who had surgery alone [17]. Despite this however, orgasm may be unimpaired following radiation [18]. Many additional needs were expressed by women with cervical cancer; however, sexuality and intimacy came to the fore as a predominant issue for survivorship [19]. It has been known for some time that the physical and emotional impact of ovarian cancer can be devastating, leading to sexual as well as global quality of life issues [20]. One study has shown a prevalence of 63% for sexual difficulties among women with a diagnosis of ovarian cancer [3]. The effects of chemotherapy and surgery, combined with the anxiety about survival can have a dramatic negative effect on the woman's libido, and even women who undertake risk-reducing salpingo-oophorectomy can suffer sexual dysfunction [21]. Many of these women are totally unprepared for the devastating effects of sudden menopause, with hot flushes, vaginal dryness, and loss of libido replacing a previously healthy sex life. This could be helped by more realistic counselling before the procedure, and increased postoperative emotional support. One study has shown that women who had surgery for endometrial cancer had no differences in their own sexual experience postoperatively, but compared with healthy controls, they had more sexual difficulties overall [22]. Women with Lynch syndrome who opt for preventive surgery tend to be happy overall with the surgery, but are often unprepared for the physical adverse effects of menopause [23]. In contrast, Moldovan et al. [24] has reported that, despite sometimes debilitating menopausal symptoms, there were no significant sexual difficulties associated with the procedure. Vulvectomy is a common treatment for vulvar malignancy. This is increasingly affecting younger women, who are HIV positive. Women with vulvar cancer can have many years of difficulties with sex due to often distressing vulvar symptoms and bleeding. Following treatment they still suffer severe dyspareunia and body image distortion due to the effects of treatment. Although a recent study showed no differences in psychosocial and sexual functioning before and after vulvectomy, it was acknowledged that women with vulvar malignancy have a high risk for sexual problems compared with healthy controls [25]. Factors associated with postoperative sexual difficulties are increased age, poor overall physical and mental health well-being, and extent of the surgical excision [25]. This often elderly group of patients is usually neglected from the psychosexual point of view. The majority of the literature related to sexuality and cancer stems from high-resource countries. Although most of these studies encompass all women, there is a lack of good published evidence on the treatment of the sexual sequelae of cancer in relation to ethnic minority groups, within a majority culture [26]. Furthermore, data from low- and middle-income countries are scant. Much of the literature focuses on sexual distress and activity in relation to HIV and AIDS which, of course, is a global priority; however, this focus on infection transmission should not take away from the emotional needs of the woman who suffers from gynecological cancer. Sexuality research around the globe must be perceived and researched in terms of cultural, spiritual, ethnic, and religious contexts. Sexual problems in women with gynecological cancer may be associated with adverse effects of surgical, hormonal, and chemical treatments, as well as by the cancer itself. Fortunately, emotional, sexual, and quality of life outcomes improve as less morbid, more minimally invasive surgical treatments for gynecological cancers develop [12]. Chemotherapy-induced ovarian failure in cancer patients is associated with all the possible symptoms of a sudden menopause, combined with the emotional impact not only of the cancer, but loss of physical well-being and fertility all at the same time. Vaginal dryness can be a major problem to those women who wish to have sex [27], and appropriate vaginal moisturizers and lubricants can help. The issue of vaginal estrogen is still debated, but should be discussed with the patient, weighing up the risk − benefit ratio for each individual. Vaginal estrogen will, in most cases, alleviate the dryness, but there may be concerns about using hormones, especially in relation to breast cancer where the evidence is unclear. The scientific data, however, support the safety of low dose vaginal estrogen therapy [28]. It is not well understood that following a few weeks of vaginal estrogen, the vagina thickens and cornifies and estrogen is not absorbed as a result. Newer treatments such as selective estrogen receptor modulators have been used in place of vaginal estrogen in women without cancer [29], and may prove good alternatives in the future [30]. There are non-hormonal vaginal moisturizers and lubricants to make sexual intercourse more comfortable. Unfortunately, some commercial sexual lubricants can be hyperosmolar and could cause epithelial disruption, facilitating HIV transmission [31]. Simple lubricants such as olive oil or liquid glycerin have been used successfully in interventions to alleviate pain on intercourse due to vaginal dryness, combining their use with physiotherapy and psychosexual counselling. Treatments with pelvic external beam radiotherapy and/or with brachytherapy may cause vaginal shortening, tightening, and lack of pliability. The use of vaginal dilators to overcome these complications is widespread, despite lack of conclusive evidence, either for or against, either with or without a coating of estrogen cream [32]. Unsurprisingly, the intrusion of inserting a plastic (or sometimes glass) tube into a tender vagina after treatment is a task that may carry a deep psychological and emotional impact [33], and will have resultant poor compliance. Radiation oncologists agree that information about dilator use should be given before treatment [34], and that sufficient patient information and support are essential to improve compliance. Sensitivity to emotions and women's views and personal values in relation to sexuality are essential supports to encouraging dilator use [35]. Any of the above problems cannot fail to have an emotional impact on the woman and on her partner. Many sexual difficulties are automatically blamed on the organic disruption caused by cancer and its treatments; however, once any clearly indicated treatments have been given, in a sizable proportion of cases, the sexual difficulty will remain unresolved. Many sexual difficulties are psychogenic, and no amount of skilled clinical treatments will help if not linked closely to appropriate counselling, psychological, or psychosexual therapy. This form of intervention will enable the woman to expose and reflect on her sexual difficulties, in the context of her life and relationship not only since the cancer, but beforehand. This is often a time when past problems, such as childhood abuse, or problems with her current partner will surface. Some partners are disgusted by the physical impacts of cancer, and the relationship will suffer. On the other hand, some partners become more supportive and the cancer leads to stronger relationships [36]. Classic psychosexual therapy, using brief, focused psychotherapeutic techniques is the mainstay of treatment. It can be used with an individual or a couple, of any sexual orientation or cultural or religious background. This is a way of listening reflectively to the patient, so that they can gain their own insights into their sexual problem. The issue of genital examination is considered if relevant, as it enables the woman to connect with her genital area, and may trigger deep-seated thoughts or anxieties that the woman had blocked emotionally. This, of course, is a technique used only by clinicians who are qualified to examine the patient [37]. Clinical psychologists and counsellors trained in psychosexual work also treat women with sexual problems. Globally, because the availability of trained personnel differs, many simple innovative treatment interventions have been tried. A brief intervention using a well-accepted treatment, cognitive behavioral therapy (CBT), combined with sexual health education had positive results on patients who had risk-reducing salpingo-oophorectomy [21]. Psychosexual interventions work [38], and like all psychodynamic interventions only require a trained counsellor and a means of allowing access to the patient. The internet has enabled access to health care for many people around the world who are not able to travel long and difficult land journeys to direct provision of health care. An online intervention with a professional moderator has proven acceptable to gynecological cancer patients with a sexual difficulty [39], and another internet-based sexual difficulties intervention with counselling sessions proved more successful in improving sexuality issues than without a counsellor; however, there was no difference between the two groups in relation to emotional distress and quality of life [40]. Elsewhere, telephone interventions are being used, also with some success; however, it is clear that the knowledge, skills, and training of the health professional providing the intervention are relevant to the patient outcome. Multidisciplinary care should form the backbone of treatment of sexual difficulties in women with gynecological cancer, incorporating physical, psychoeducational, and psychosexual input. Team discussions, including clinicians, psychosexual therapists, and physiotherapists are well within the capabilities of many cancer centers, remembering that the patient and her partner are the focal point and should always be consulted. It is impossible to diagnose and treat a sexual problem if one does not acknowledge that it exists. Many studies in the past have identified lack of willingness of doctors and nurses to discuss sex, but sadly recent research has shown that not much has changed. For instance, in a cohort sample of 1154 US obstetrician − gynecologists, 60% did not ask patients about sexual problems [41]. Too often clinicians make value judgements about their patients including whether sexuality is an important part of their lives. Such assumptions may include biases about age, appearance, sexual preferences, and marital status of people who have sex. People with cancer and their partners have unmet sexual information and support needs [42], often due to the unwillingness of healthcare professionals to discuss sexual issues, even though they recognize it may be important to the patient. There are many barriers to talking about sex, affecting both the patient and the clinician, such as cultural background, and age and gender discrepancies between doctor and patient. There may be simple barriers, such as lack of privacy in a consultation, as often cancer patients are accompanied by family or close friends. Patients often state that they feel it is trivial to take up the doctor's time with non-life-threatening issues such as sex. Clinicians often cite lack of training as a reason that they are uncomfortable talking about sex and poor provision of this training has been noted [13]. Different models of communication skills training have been used and those undertaking the training have shown greater empathy and were more inclined to use open questions [43]. This technique of speaking to the patient in an open rather than interrogative manner can easily facilitate discussion of intimate issues. An even greater challenge in communication is the recognition that individuals are sexual beings up to the end of life. To some women in the palliative phase, sexual touch and closeness to their partner is of vital importance. Sadly this is rarely recognized and addressed by palliative care physicians [44]. It is important to remember that a minority of the female population identifies as lesbian, and that about 8% of the population is bisexual. While this should make no difference to the quality of sexual health care they receive, lesbians and bisexuals find it difficult to disclose their sexuality to clinicians, often inhibited by their cultural or religious background, and fears of facing discrimination [45]. If the clinician asks the patient at the outset if they have a sexual partner, and whether the partner is male or female, it will greatly enhance the quality of the doctor − patient interaction. Lesbian partners in particular can be very supportive during the cancer journey, and should be given the opportunity to be present if the patient wishes. Despite the recognized need for treatment of sexual problems in menopause and gynecological cancer, there is poor provision of specialist training to ensure that this important area of service provision is met [46]. Undergraduate teaching is important, but it is only by recognizing psychosexual medicine in formal gynecology or oncology training, as a compulsory requirement of the course, that this situation will begin to be addressed. Innovative online programs [47] can make a major impact on global training opportunities and give trainees around the world an opportunity to gain some skills and insight into treating sexual difficulties in a nonjudgmental way. Owing to the global prevalence of sexual problems associated with gynecological cancer, it should be within every gynecologist's or oncologist's duty of care to the patient to be aware of and have some understanding of how to diagnose and facilitate treatment for sexual problems in a nonjudgmental manner. This is true holistic medicine, recognizing not only the cancer, but the woman behind the symptoms, and requires awareness of the emotional, social, and relationship aspects of the patient's life. The ability of any person to enjoy a sexual life free of coercion, shame, disease, or pain in a consensual manner is a fundamental element of the human rights of women, and should be an unequivocally accepted as part of her gynecological cancer care. To make a difference, even in the absence of expensive and sophisticated cancer treatments, just acknowledging, listening, and offering support to the woman with sexual difficulties related to cancer will ultimately have a major benefit to her quality of life. The author has no conflict of interest. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

International Journal of Gynecology & Obstetrics · 17 citationsread the source →

Pathophysiology of the risk factors associated with osteoporosis and their correlation to the T-score value in patients with osteopenia and osteoporosis in the United Arab Emirates

INTRODUCTION Osteoporosis is a bone disorder, characterized by loss of bone strength because of an imbalance between the bone resorption and the mechanisms of bone formation, leading to increased fragility and fractures. Pathophysiological mechanisms underlying this disorder include an inadequate formation response during the remodeling process of bone formation, which is an essential factor in osteoporosis pathogenesis. This inadequacy is due to the activation of large numbers of osteoclasts as a response to initiation of hematopoietic precursor cells with failure of normal interaction with the osteoblastic lineage. This will lead to excessive bone resorption that may result in complete loss of trabecular structure and loss of template for new bone formation. The time required for osteoblastic replacement is longer than the resorption phase of bone remodeling by osteoclasts. Therefore, any increase in bone remodeling will lead to damaged architecture and loss of bone mass.[1] Recently, it has been estimated that more than 200 million people worldwide have osteoporosis. On the basis of a statistics from the International Osteoporosis Foundation in 2017, one in five men and one in three women over the age of 50 years will experience fractures during their lifetime because of osteoporosis. Furthermore, it has been found that an osteoporotic fracture occurs every 3s, with the most common fractures occurring at the hip, spine, and wrist.[23] Osteoporotic fractures may be the first manifestation of the disease, which is why it is called a silent disease. Risk factors of osteoporosis, decreased bone mineral density (BMD), and increased fragility fractures may be modifiable or non-modifiable. Among the modifiable factors are low body mass index (BMI), vitamin D deficiency, low calcium intake, excessive caffeine and alcohol consumption, smoking, sedentary life and low physical activity, endocrine disorders (such as estrogen deficiency and insulin-dependent diabetes mellitus or hyperparathyroidism), some drugs (such as corticosteroids), and previous history of fragility fractures. The non-modifiable factors include female gender, family history, race, and early menopause.[45] According to the World Health Organization (WHO) diagnostic criteria, osteoporosis is diagnosed by BMD at the hip or spine, which is below the young normal mean reference population by 2.5 standard deviations (SDs) or more. This is called the T-score, and osteopenia is diagnosed by BMD less than or equal to 1 SD.[6] The guidelines for osteoporosis screening vary greatly in various publications. In general, most organizations recommend that all adults older than 50 years of age with a history of fracture must receive BMD screening.[7] Dual-energy X-ray absorptiometry (DXA) at the hip or spine is the best test for measuring central BMD. An association is present between the T-score values in DXA in patients with osteoporosis or osteopenia and the risk of fractures. A fracture risk assessment tool (FRAX) was designed. It is estimated that for every 1 SD decline in spine BMD, the risk of having a spine fracture increases 2.3 times and the risk of having a hip fracture increases 2.6 times.[89] As the most common bone disease in humans, the prevalence of osteoporosis is steadily increasing due to a growing elderly population, and thus represents a major public health concern with reduced bone strength and a higher risk of fractures.[68] The prevalence of osteoporosis is steadily escalating due to increased life expectancy as a result of developed health services. According to the 2016 WHO report, in the United Arab Emirates (UAE), life expectancy at birth for men was 76 years and for women it was 79 years.[10] The UAE population projection showed that in 2011, 7% of the population were 50 years of age or over and less than 1% were 70 years of age or over. By 2050, it is estimated that 12% of the population will be 50 years or over and 2% will be 70 years or over.[11] MATERIALS AND METHODS Study design The study was performed in accordance with the International Conference on Harmonisation Good Clinical Practice guidelines. Ethical approval number UG-H-18-11-7-10 was obtained from the Research Ethics Committee of the college. The study was conducted on a population sample of national and nonnational people in the UAE. Both men and women were recruited in the study. Data were collected from the patients in six governmental and private hospitals. Research tools A total of 200 male and female participants between the age of 25 and 80 years were recruited in the study. Eighty percent of the sample were women and 20% were men. After obtaining the required consent, each participant was asked to fill a structured questionnaire consisting of 25 questions, which was used as the primary tool for data collection. The questions were formulated both in Arabic and English, it required 3–4min to be completed. BMD of the participants was assessed in the International Radiology Centre and correlated with their data in the questionnaires. DXA scan was used for the measurement of BMD. Data collection and data analysis After ensuring strict confidentiality, data were collected between March 20, 2016 and May 20, 2016. The following information was obtained: Demographic data (gender, age, race, BMI, and occupation) Family history of osteoporosis or osteoporotic fractures Social history and lifestyle, physical activity, and exposure to the sun Dietary habits such as calcium, caffeine, and soft drinks intake Medical history of diseases and medicines. For female participants, number of pregnancies, lactation, and age at menopause were included The following criteria were used to evaluate osteoporosis: Normal BMD: if T-score between +2.5 and –1 Osteopenia: if T-score between –1 and –2.5 Osteoporosis: if T-score below –2.5 The filled questionnaires were coded and data were analyzed statistically using the Statistical Package for the Social Sciences (SPSS) software (version 24; IBM Corporation, Newyork, USA). Spearman’s correlation test was carried out to assess the association between different variables in the study. A P value of less than 0.05 was considered significant. RESULTS Sociodemographic data The sociodemographic background of the study participants is listed in Table 1. A total of 200 participants were included in the study. The control group and the osteoporotic group consisted of 100 participants each, 20% of them were men, whereas 80% of the respondents were women. Table 1: Background demographic data of the respondentsBody mass index The patients with osteoporosis have significantly lower BMI than the control group (P < 0.05). Results showed that 72% of them have a BMI less than 25 kg/m2 (P < 0.05) [Table 2] [Figure 1].Table 2: Body mass index of the respondentsFigure 1: Body mass index (kg/m2) of the respondentsSmoking behavior Regarding smoking behavior, a significant value was evident between smoking and osteoporosis (P < 0.01) as 54% of the patients with osteoporosis were current smokers, whereas 72% of the controls had never smoked before [Table 3] [Figure 2].Table 3: Smoking behavior and intake of milk, coffee, and soft drinks by the respondentsFigure 2: Intake of milk and caffeine and smoking behavior by the respondentsDietary calcium intake The intake of milk and dairy products by the participants was used to assess the dietary calcium intake. The patients with osteoporosis have a significant low calcium intake (P < 0.01), whereas non-osteoporotic control significantly consume more milk and dairy products (P < 0.01). A positive correlation was found between the intake of milk and dairy products and the T-score value of the participants (P < 0.05) [Table 3] [Figures 2 and 3].Figure 3: Correlation between milk intake and T-score in patients with osteoporosisCaffeine consumption Caffeine intake was evaluated in this study by the amount of coffee, tea, or soft drinks consumed by the participants each day. The results showed that the patients with osteoporosis significantly consume more caffeine (P < 0.01). A negative correlation is present between the amount of caffeine intake and T-score value of the participants (P < 0.05) [Table 3] [Figures 2, 4, and 5].Figure 4: Correlation between tea/coffee intake and T-score in patients with osteoporosisFigure 5: Correlation between soft drinks intake and T-score in patients with osteoporosisExercise behavior and exposure to the sun Results showed a significant positive correlation between the duration of exercise and the T-score value of the participants (P < 0.05) [Table 4] [Figure 6].Table 4: Exercise behavior and exposure to sun of the respondentsFigure 6: Correlation between exercise duration and T-score in patients with osteoporosisRegarding the exposure to the sun, the results showed that 96% of the patients with osteoporosis were exposed to the sun for less than 15min, three to four times a week or not exposed at all, whereas most of the normal controls (72%) exposed their bodies to the sun for 16–30min/day, three to four times a week [Table 4] [Figure 7].Figure 7: Sun exposure behavior of the respondentsDiseases and medications Results of the study revealed that 46% of the patients with osteoporosis were diabetic, 42% of them were treated by antidiabetics, 18% had arthritis and 38% had been treated previously by corticosteroids [Table 5].Table 5: Distribution of patients with osteoporosis by their diseases and medicationsNumber of pregnancies and breastfeeding Female participants constituted 80% of the study sample, 75% of the females with osteoporosis were menopausal, 75% of them had three or more pregnancies, and 82.5% of them breastfed their children, whereas these values for the control group participants are 30%, 28%, and 33%, respectively. Results showed a significant positive correlation between the age at menopause and the T-score value of females with osteoporosis (P < 0.05) [Table 6] [Figure 8]. The distribution of patients according to the joint affected by Osteoporosis or Osteopenia is shown in [Figure 9] and [Table 7].Table 6: Distribution of female patients with osteoporosis by number of pregnancies and breastfeedingFigure 8: Correlation between age at menopause and T-score in female patients with osteoporosisFigure 9: Distribution of patients having osteopenia or osteoporosis in wrists, hips, or spineTable 7: Distribution of patients having osteoporosis and/or osteopenia in hips, wrists, and spineDISCUSSION To maintain normal bone structure, a remodeling process that consists of osteoclasts, removing old bone, and osteoblasts, synthesizing new bone, occurs. Hematopoietic progenitors produce osteoclasts, whereas mesenchymal stem cells called marrow stromal fibroblasts produce osteoblasts. This process is controlled by certain circulating hormones, growth factors, and locally produced cytokines through their effects on apoptosis of osteoblasts and osteoclasts. Estrogen deficiency or glucocorticoid excess leads to bone loss because of changes in the production of bone cells. This is caused by the prolongation of the life span of osteoclasts and the shortening of the life span of osteoblasts. On the contrary, drugs that aim to treat or prevent osteoporosis prevent apoptosis of osteoblasts and/or stimulate the apoptosis of osteoclasts.[12] The pathogenesis of osteoporosis is the consequence of various hormonal, genetic, dietary, lifestyle, and physical factors. Genetic factors mainly affect the BMD and bone formation, whereas low levels of estrogen increase parathyroid hormone, and local cytokines are mainly responsible for bone remodeling imbalance.[13] Age and gender In this study, 76% of the patients with osteoporosis were women at or above 50 years of age. Osteoporosis is usually considered a disease of the elderly with low BMD. In a recent study, most of the patients with osteoporosis were in the age groups of 45–49 and 50–54 years.[14] Previous studies showed that women were at an increased risk of developing osteoporosis because of their faulty behavior of physical inactivity, sun-avoidance behavior, low intake of dairy products, and poor diets.[151617] Body mass index The results of this study showed a significant number of patients of osteoporosis with BMI <25 kg/m2, where P < 0.05. Women that have low BMI are at a higher risk of developing osteoporosis. It is reported that one unit change in BMI has a larger effect on the risk of developing osteoporosis than most other modifiable risk factors. To help reduce the risk of osteoporosis, patients should be advised to maintain a weight within the normal range.[1516] The risk of osteoporotic fractures increases in adults who have low BMI of less than 20 kg/m2.[18] On the contrary, patients who are obese (BMI >30 kg/m2) are also at a high risk of developing osteoporosis and fractures because of the risk of repeated falls and the weakness of the skeletal muscles due to loss of its mass as a result of aging.[19] Exercise and physical activity The results of this study showed a significant correlation between the exercise time and the T-score value. Previous studies concluded that physical activity and exercises stimulate skeletal growth and bone strength.[45] Estrogen Estrogen deficiency has a critical effect on the pathogenesis of osteoporosis. The results of this study showed a significant positive correlation between the age at menopause and the T-score value of the female patients. Estrogen has a crucial role in bone formation and physiology. It stimulates the production of T cell cytokines, affects the osteoblastic cell by altering its production of receptor activator of nuclear factor-Kappa B ligand (RANKL) or Osteoprotegerin (OPG), inhibits the differentiation of osteoclasts by direct action, and stimulates the formation of bone performed by osteoblasts and osteocytes, which allows them to enhance their ability to respond to mechanical forces.[2021] Estrogen produces its effect through a specific cell surface receptor called the estrogen receptor alpha (ERα). This receptor binds and then transports estrogen into the nucleus of the cell where certain genes are then activated by the receptor–hormone complex. ERα receptors and estrogen receptor–related receptor alpha (ERRα) are found on the surface of osteoblasts. ERRα may play a supporting role in the regulation of bone cells.[22] Previous studies also suggest that sex hormone–binding globulin may play a significant role in regulating bone cells as well because it facilitates entry of estrogen into cells.[23] Because of the natural drop of estrogen level in postmenopausal women, they are at the highest risk of developing osteoporosis. A previous study showed that it is an increase in bone resorption that might be the driving force for bone loss during estrogen deficiency in postmenopausal women not impaired bone formation as was previously thought.[1] However, other studies indicated that both markers of bone resorption and formation also increased, leading to accelerated bone remodeling at menopause.[2425] Calcium intake and vitamin D Calcium and vitamin D are two pivotal contributors of bone formation and mineralization. The results of this study showed that the patients with osteoporosis have a significant low calcium intake, whereas controls significantly consume more milk and dairy products (P < 0.01). This significant result showed the importance of calcium intake. Results also established a positive correlation between calcium intake and the T-score value of the participants. Vitamin D plays an important role in maintaining calcium homeostasis and bone integrity as it is essential for intestinal calcium absorption.[26] It is estimated that over one billion people around the world have vitamin D deficiency.[2728] Sun exposure is considered as the source of vitamin D, the present results showed a significant value (P < 0.01) as 74% of the patients with osteoporosis exposed their bodies to the sun for 5min or less, three to four times per week, whereas 72% of controls exposed their bodies to the sun for 15–30min, 3 to 4 times a week. A previous study conducted in the UAE showed that 58.2% of the UAE nationals were vitamin D deficient compared to 45% of the patients from other nationalities.[29] In spite of living in sunny areas, such as UAE, Saudi Arabia, and India, young populations have a high prevalence of vitamin D deficiency because of insufficient knowledge and practice of vitamin D and its health implications.[3031] Decreased blood calcium level will lead to secondary hyperparathyroidism. This decrease may result from impaired intestinal calcium absorption due to vitamin D deficiency, aging, or other diseases. Calcitriol, the active form of vitamin D, stimulates the intestinal absorption of calcium and phosphorus. It has an inhibitory effect on the synthesis of parathyroid hormone as well. Therefore, calcitriol deficiency will lead to secondary hyperparathyroidism as well.[32] There is a clear evidence that the risk of having an osteoporotic fracture increases when vitamin D levels are below 50 nmol.[3334] However, a recent study showed that pathological macrophages produced by vitamin D receptor signaling play an important role in the development of myelofibrosis.[35] Smoking The results of this study showed that nicotine has a significant effect on the incidence of osteoporosis (P < 0.01). Smoking has been identified as a modifiable risk factor for low BMD and increased osteoporotic fracture risk.[3637] Smoking behavior should be evaluated when assessing the fracture risk and FRAX.[1638] The role of smoking in decreasing BMD is complicated; smoking is shown to be associated with other risk factors for osteoporosis such as decreased physical activity, low BMI, and poor diet.[38] Nicotine has both direct and indirect effects on BMD. The direct effect is on bone cell proliferation and is described to be biphasic, small doses have a stimulatory effect, whereas toxic large doses have an antiproliferative effect on the proliferation of osteoblasts.[39] This effect on osteoblasts is receptor mediated by the nicotinic acetylcholine receptors, where nicotine in low doses upregulates gene expression of alkaline phosphatase, type 1 collagen, and osteocalcin.[40] Nicotine produces an increased level of tumor necrosis factor α (TNFα) secretion that reduces bone formation by osteoblasts and increases bone resorption by osteoclasts. TNFα has a powerful osteoclastogenic effect through its stimulating effect on RANKL production and by intensifying osteoclasts production.[41] It is strongly supported that RANK/RANKL/OPG systems have a role in regulating bone resorption and the formation of osteoclasts.[42] The main predisposing factor for chronic obstructive pulmonary disease (COPD) has been found to be smoking. The most important factor in managing COPD continues to be the termination of smoking.[43] It has been shown in numerous studies that smokers with COPD have elevated levels of pro-inflammatory cytokines in the form of interleukin-6. In addition, TNFα levels are much higher in COPD smokers than in asymptomatic smokers. This indicates that COPD affects local and systemic inflammatory responses, which in turn affects bone remodeling.[4445] Nicotine has an indirect effect on BMD, which is caused by releasing calcitropic hormones and glucocorticoids, which leads to an increase in bone resorption.[43] Furthermore, smoking has been linked to an increase in the level of cortisol[4446] as well as a decrease in the level of estradiol.[47] Nicotine also harms intestinal calcium absorption, which might lessen the effectiveness of dietary calcium supplements.[48] Also, toxic carcinogenic metabolites of nicotine have also been found to increase osteoclast formation in rats.[49] Moreover, one hip fracture in eight postmenopausal women with osteoporosis is attributable to smoking. This correlation could not be explained by early menopause, low BMI, lower levels of exercise, or by the actions of nicotine on estrogen. This indicates that there is an independent negative effect of nicotine on BMD, which means that smokers lose bone at a faster rate than nonsmokers.[50] CONCLUSION Prevalence of osteoporosis is high in the UAE and is expected to grow due to increased life expectancy and faulty lifestyle of inadequate dietary habits, sun exposure, exercise behavior, and smoking. More intervention should be directed toward changing the modifiable risk factors in the patients with osteoporosis, and more studies should be directed toward osteoporosis in the UAE. Limitations of the study To make the study a polycentric research, it would require greater number of participants from all the emirates of the UAE. Financial support and sponsorship This work is self-funded by the authors. Conflicts of interest There are no conflicts of interest.

Journal of Pharmacy And Bioallied Sciences · 11 citationsread the source →

Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.

Background: Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout. Methods: The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function. Findings: Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, -1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, -1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function. Interpretation: Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI. Funding: Bill & Melinda Gates Foundation.

Lancet (London, England) · 4695 citationsread the source →

The impact of end-stage kidney disease (ESKD) on close persons: a literature review

Kidney disease is defined as end-stage when a patient's glomerular filtration rate has fallen to <15 ml/min/ 1.73 m2 [1]. Mortality associated with end-stage kidney disease (ESKD) is high [2]. The incidence of treated ESKD is rising in the western world, with a corresponding increase in the incidence of diabetes and cardiovascular disease, especially in ethnic minority groups. Survival on dialysis has been shown to be poorer in the older age group, especially in patients with increased comorbidity and in those whose functional status at the start of dialysis is poor [3]. Whilst renal transplant rates vary between different countries [4], the liberalization in the acceptance of older people into renal replacement therapy (RRT) programmes, together with changes in population demographics and the fact that kidney transplantation is less suitable for this group of older patients, means that dialysis may be the only treatment option available for an increasing number of patients aged 65 years and over [5]. Recent health policy changes in the OECD countries [6,7] acknowledge that end of life care may be more appropriate for some of these people, and maximum conservative management programmes (where residual renal function is supported, haemoglobin levels maintained and symptoms relieved) have been introduced into many renal units, particularly in the United Kingdom [6]. The onset of ESKD and subsequent recommendation of dialysis as a treatment option involves a change in lifestyle for both patients and close persons [8]. Even before end-stage disease is reached, as renal function deteriorates, patients frequently require additional support, and it is often family members who provide this [9]. In the UK it is estimated that 9 out of 10 carers of patients with either physical or neurological disabilities will be close relatives. In particular when home haemodialysis is undertaken, family members have been involved in supporting patients [10,11]. Studies have shown that good family support is associated with successful adaptation to dialysis and compliance with dietary restrictions [12,13]. Conversely, one of the main factors associated with patients discontinuing dialysis is patients’ perception that they have become a ‘burden’ to close family members [14]. There is therefore a need for health professionals to be aware of the important contribution that close persons make to the care of renal patients, to communicate effectively with them and to provide bereavement support for this group when appropriate [15]. The literature on close persons of patients with renal disease has identified two main areas of impact. Firstly, both haemodialysis and peritoneal dialysis may have a disruptive influence on family members’ social lives [16] and the structure of the week may be geared towards dialysis sessions. Secondly, some patients become frail and lose functional independence, leaving family members to provide greater physical support. Family members may have health and social care needs of their own that need to be addressed [16,17]. Qyinan [18] reported that close persons commonly felt overwhelmed and stressed, although this review was limited to an evidence base of four articles and considered home dialysis only. Campbell [19] used findings from the general carer literature to illustrate demands of ageing partners with ESKD. In other chronic illnesses such as stroke [20] or in palliative care for cancer and mental health [21], interventions aimed at providing family members with training to support patients with their rehabilitation, or to address unmet needs as a result of the patient's illness, have been developed and evaluated. Results have been mixed. In the case of stroke, carers in the intervention group experienced less depression and anxiety and better quality of life [20], whilst in the palliative care study, no statistically significant differences were found between the intervention and control group on carers’ psychological outcomes [21]. However, before such interventions can be developed in ESKD, it is important to understand better the emotional and physical needs of close persons. This review aims to identify all studies involving close persons caring for ESKD patients, to describe the main findings and critique the methodology. Specific attention has been paid to (a) studies exploring the impact of ESKD on close persons, in particular for those close persons where the patients are either withdrawing from dialysis or being provided with end of life care and (b) studies looking at the provision of health care for close persons. A literature search for relevant articles was conducted in five databases: Medline (1950–2006), Embase (1991–2006), CINAHL (1982–2006), PsycINFO (1970–2006) and AMED (1985–2006), employing the following key words: carers, caregivers, end-stage kidney disease, end-stage renal disease, haemodialysis, peritoneal dialysis and renal replacement therapy. These keywords were used both in word search options and exploded as thesaurus terms to obtain the maximum number of articles. The abstracts for each article were read to check for inclusion into the main review, using the following criteria: Published in peer-reviewed journals. Research studies with an introduction, a methodology and results section and a conclusion. Involve close persons, defined as either a family member or the person identified by the patient as an informal carer. By an informal carer, we mean a person who provides the majority of a patient's physical and emotional care needs and who is neither a volunteer nor in the employment of statutory services. Use a sample of close persons caring for adult ESKD patients (over 18 years). Non-English language articles were considered if the English translation of the abstract met the above criteria. Using these criteria, 334 articles were identified from the five databases (139 in Medline, 121 in Embase, 80 in CINAHL, 8 in AMED and 34 in PsycINFO). J.L. went through the abstracts of each of the 382 articles, of which 37 initially met the inclusion criteria. One was later excluded on closer inspection, as it was specifically a validation study of a fatigue severity scale. Of the remaining 36 studies, 16 exclusively looked at family members, 12 specifically at the patient-family dyad and 3 at the family-health professional dyad. Whilst the latter two types of studies did not concentrate solely on family concerns, we decided to include them in the analysis, because these findings further contribute to the limited number of studies in this field. Thirty-six studies were included in the review. Both J.L. and G.S. first went through the remaining 36 studies independently and extracted the following information for each study: the number of carers in the study sample, the RRT population they were caring for, authors’ definition of a carer, demographic details of the sample, patients’ dialysis history, caring history, study design, outcome measures used and main findings. J.L. and G.S. then met together to discuss these findings and obtain an initial consensus before meeting with A.B. and L.J. to obtain a final consensus. We undertook an exploration of the aims of these studies, their study design, the sample of participants and the outcome measures highlighted in the quantitative studies. The three main themes explored were (a) the impact of caring for a patient with ESKD on dialysis on close persons, in particular quality of life, psychological morbidity, close person responsibilities—which authors often referred to as ‘burden’ or ‘carer burden’—and their life situation; (b) the coping strategies employed by these close persons and (c) factors that influence psychological morbidity. No studies of health provision for close persons of patients with ESKD were identified. Four studies looking at end of life issues explored the following themes for close persons: (a) their perceptions of patients’ terminal symptoms; (b) their reasons for why patients decided to stop dialysis; (c) the long-term impact of patient death following dialysis cessation and (d) their perceptions of advance directives. End of life care may be provided by the renal multi-disciplinary team alone, or it may involve referral for specialist palliative care advice. Such advice is likely to include symptom control, attention to spiritual and psychological issues for patients and, where possible, involvement of their families in decision-making. Whilst most studies were interested in the direct impact on close persons only, one triangulated close person data with patient data. The majority of studies reviewed used a cross-sectional design; there was only one longitudinal study. Whilst most were quantitative (24/36), there were some qualitative studies (11/36) and one used a mixed methods approach. The total sample was predominantly female, with mean ages ranging from 41 to 68 years (analysis possible in only 18 studies). Sample sizes also tended to be small, with a median sample of 55 participants for the quantitative and 15 participants for the qualitative studies. Most of the sample was recruited in studies where associated patients were undergoing haemodialysis or peritoneal dialysis. Three studies also involved kidney transplant patients. Only five studies looked at close persons dealing with end of life issues or with patients withdrawing from dialysis. Many studies did not focus on close persons in their potential role as ‘informal carers’. Thirteen studies actively sought close persons who also considered themselves to be informal carers, of which eight provided full definitions of what they meant by this term. All studies included spouses as part of their sample, of which eight specifically concentrated on this group alone. Adult children were included in seven of these studies and parents in five. A wide variety of outcome measures were used to rate health-related quality of life, anxiety, depression, coping strategies and patient disease severity. Some studies used standardized outcome measures; others used simple self-rated tools. The most commonly used standardized measures were the Zarit Burden Interview [22] to evaluate the sense of carer responsibility (3/8), the Beck Depression Scale [23] to evaluate depression (2/5), SF-36 [24] to evaluate health-related quality of life (3/8), Jalowiec Coping Scale [25] to evaluate close persons’ use of coping strategies (3/3) and End-Stage Renal Disease Severity Index [26] to evaluate patients’ disease severity (2/4). A breakdown of the country of origin for each study showed that over half originated from either the USA (11/36) or Canada (7/36), with five originating from Australia and only seven from the European Union, of which only one was conducted in the UK. The remaining six studies came from the following countries: Japan (2/36), Brazil (2/36), China (1/36) and Turkey (1/36). The 36 studies have shown mixed results. They have mainly explored the following areas associated with caring for an ESKD patient: the impact on close persons and their social life and the factors affecting close persons’ psychological health. There have been very few studies looking at palliative care issues and these have primarily concentrated on dealing with end of life issues rather than the provision of supportive care in the pre-terminal phase. In only one study, close persons rated their quality of life as excellent and reported few pressures resulting from their carer responsibilities [27], whilst in all others, ESKD and dialysis were shown to increase the close person's sense of responsibility and lead to a poorer quality of life when compared with age-matched controls [28]. Close persons found living with an ESKD patient on dialysis stressful [29] and experienced increased fatigue [30]. The dominating effect of caring for an ESKD patient often led close persons to neglect their own health. For those who took time to have a break from their carer responsibilities, there were health benefits [31]. Other issues that close persons reported included isolation through the loss of social activity [30–36], life restrictions [36–38], increased workload, negative economic consequences [39,40], changed relationship with the patient [30,34] and sexual problems for spouses [41]. Impact on family life (quantitative and mixed methods studies) CAPD = Continuous Ambulatory Peritoneal Dialysis; CBI = Caregivers Burden Interview; FES = Family Environment Scale; HD = Haemodialysis; IIRS = Illness Intrusiveness Ratings Scale; MAES = Marital Attitudes Evaluation Scale; NGQ = Norris & Groves Questionnaire; PAF = Physicians’ Assessment Form; PAIS = Psychosocial Adjustment to Illness Scale; SF-36 = Short-Form 36; SwQoL = Swedish Health-Related Quality of Life Survey; VAS = Visual Analogue Scale; ZBI = Zarit Burden Interview. Impact on family life (quantitative and mixed methods studies) CAPD = Continuous Ambulatory Peritoneal Dialysis; CBI = Caregivers Burden Interview; FES = Family Environment Scale; HD = Haemodialysis; IIRS = Illness Intrusiveness Ratings Scale; MAES = Marital Attitudes Evaluation Scale; NGQ = Norris & Groves Questionnaire; PAF = Physicians’ Assessment Form; PAIS = Psychosocial Adjustment to Illness Scale; SF-36 = Short-Form 36; SwQoL = Swedish Health-Related Quality of Life Survey; VAS = Visual Analogue Scale; ZBI = Zarit Burden Interview. Impact on family life (qualitative studies) CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis; PD = peritoneal dialysis. Impact on family life (qualitative studies) CAPD = continuous ambulatory peritoneal dialysis; HD = haemodialysis; PD = peritoneal dialysis. The treatment modality may also have an impact on family members. Studies have highlighted that spouses of transplant patients were more assertive, self-sufficient and able to handle the physical, social and existential aspects of the illness better than dialysis spouses [33,42]. Despite these pressures, close persons recognized that they play a positive role in promoting patients’ well-being [11,43]. They recognized that health care professionals were important in providing support to discuss their problems [39] and would like to have more information about the care being provided to patients [44]. However, they also reported poor communication with professionals, felt that their needs were not always addressed [30,39,45] and felt themselves uneducated and poorly equipped to deal with the regimented lifestyle associated with the dialysis regimen [14]. Whilst some studies have shown that close persons display few signs of psychological distress [40,46–49], others have identified the following: Caring and psychological health ABS = Affect Balance Scale; BDI = Beck Depression Inventory; BI = Barthel Index; CAPD = Continuous Ambulatory Peritoneal Dialysis; CAS = Clinical Anxiety Scale; CBI = Caregivers Burden Interview; CBS = Caregiver Burden Scale; CES-D = Center for Epidemiologic Studies Depression Scale; CID = Cognitive Index of Depression; DAS = Adjustment Scale; = = Anxiety and Scale; = Questionnaire; = Depression Questionnaire; = Questionnaire; = End-Stage Renal Disease Severity Index; = End-Stage Renal Disease Severity = Family Questionnaire; = Scale; = = Index; HD = haemodialysis; = Scale; = Impact on Family Scale; = Jalowiec Coping Scale; = Scale; = of control of = Marital Adjustment = Marital Questionnaire; = Scale of = Psychosocial Adjustment to Illness PD = peritoneal dialysis; = Scale; = for and Family Scale; = Quality of Life Index; = Scale; = Inventory; SF-36 = Short-Form 36; = = Anxiety Inventory; = with Life Scale; = ZBI = Zarit Burden Interview. Caring and psychological health ABS = Affect Balance Scale; BDI = Beck Depression Inventory; BI = Barthel Index; CAPD = Continuous Ambulatory Peritoneal Dialysis; CAS = Clinical Anxiety Scale; CBI = Caregivers Burden Interview; CBS = Caregiver Burden Scale; CES-D = Center for Epidemiologic Studies Depression Scale; CID = Cognitive Index of Depression; DAS = Adjustment Scale; = = Anxiety and Scale; = Questionnaire; = Depression Questionnaire; = Questionnaire; = End-Stage Renal Disease Severity Index; = End-Stage Renal Disease Severity = Family Questionnaire; = Scale; = = Index; HD = haemodialysis; = Scale; = Impact on Family Scale; = Jalowiec Coping Scale; = Scale; = of control of = Marital Adjustment = Marital Questionnaire; = Scale of = Psychosocial Adjustment to Illness PD = peritoneal dialysis; = Scale; = for and Family Scale; = Quality of Life Index; = Scale; = Inventory; SF-36 = Short-Form 36; = = Anxiety Inventory; = with Life Scale; = ZBI = Zarit Burden Interview. A negative between close persons’ psychological health and their sense of carer responsibility their use of coping strategies strategies that the symptoms of the of the the close person's age and the social and changes as a result of ESKD A positive between good mental health and the following a of of dialysis the of dialysis patients are on of social support and sense of carer responsibility The sense of carer responsibilities are if patients are in of living have less or comorbidity This was further in studies in patients home haemodialysis or transplant where close persons not anxiety or depression felt less by their carer responsibility and a quality of life to the age-matched population were found between levels of responsibility and other outcomes such as quality of life and The use of coping was found to have a negative with a positive with the number of years on dialysis Close persons were more likely to have negative towards patients if they no of the dialysis and a high of involvement with the caring whilst living in a We identified five studies that explored end of life only one specifically on close persons. This study the long-term impact of death on families when dialysis was found that most families felt that patients a good death as at and with close people and most family members showed only levels of However, carers and those with levels of caring responsibility for the did End of life care HD = End of life care HD = The remaining four studies on patient outcomes such as reasons for withdrawing from dialysis the quality of death the of close persons in ESKD patients’ to and care and use of advance as a in advance by patients, which the of treatment to be by health care a patient is to provide to that person's of These studies found that close persons that whilst most patients a many patients were to be in and from fatigue care family members in that patients’ were and most recognized the of living which they felt were health care professional Close persons were poorly for caring for a dialysis and patients did not to be a on their families [14]. They were also poor at both patients’ and for or dialysis No studies were identified for carers of patients with supportive care those on maximum conservative management The main of most studies included in this review is the of and of the demographic over half of the studies demographic details of close persons’ ages and or details of their relationship to patients of other relevant demographic such as employment status or social is and only seven studies the time that close persons as Whilst all studies the of dialysis half reported the of time a patient has been on with very few patients’ functional although carer studies in other that this has an impact on carers’ quality of life In only 18 9 qualitative and mixed methods study details of their sample of the quantitative studies included in the used cross-sectional and were predominantly Such studies are in exploring between are limited as they not to be only five studies provide the full details of sample it is therefore not possible to rates or the sample The sample sizes were with a median of 55 and details of were reported in only one study. the of the used to the different outcomes it to between the different studies. We identified that most studies poor of their methods and a of of their data Most used of family members with five studies using only one details of their studies with their studies with their one a of their their approach. One study no details of their the studies were poorly that the was and authors were as to to use qualitative data with the and of the qualitative data demographic of data and poor use of supporting This study reviewed the literature exploring the of close persons of patients with ESKD, from which can be the quality of and for the of in this Firstly, studies exploring end of life issues are with only four identified. these four studies are they that health are the time for informal carers to discuss patients’ about end of life care and, long-term distress of close persons resulting from the patients’ However, about such end of life issues close persons, and we studies in this Secondly, definitions of close persons were there were some differences identified between the different groups. the literature the that most close persons are to patients, the in to patients who were and those with family and relationship were not not all close persons to on the role of the informal carer, and the of this role can be a as illness review did not identify differences between informal carers and family carers in the outcome measures used included both the of differences may in their with ‘informal carers’ a more members’ may be as being more this needs further issues that need to be addressed the use of methodology were identified in the Most quantitative studies were and with no intervention studies being identified. Studies of demographic details and rates and all were cross-sectional with sample sizes that used standardized Whilst the use of standardized measures the of the the findings from cross-sectional studies are limited in that they can only between We the use of longitudinal methods in that would that between key be explored in more This would also into the long-term of close persons. In those studies using qualitative most used with poor and of demographic and social and Many authors used the ‘burden’ or ‘carer such terms may influence of the relationship between close person and was not they were by close persons to use the ‘burden’ or it was a by the authors to describe the responsibilities of Such and the of study findings the half of the studies originated from either the USA (11/36) or Canada This it to the results of these studies their to in the of health care provision in other there is evidence that the psychological health of close persons them to to care which in can the mental health of patients, we to identify studies in review that looked specifically at health close persons of patients with ESKD. review has identified in the literature that need to be is therefore to the relationship between health and close persons in to We would like to acknowledge for this review and for support in this of

Clinical Kidney Journal · editorial or comment · 83 citationsread the source →

Atypical Antipsychotics: CATIE Study, Drug-Induced Movement Disorder and Resulting Iatrogenic Psychiatric-Like Symptoms, Supersensitivity Rebound Psychosis and Withdrawal Discontinuation Syndromes

Chronic illness can result in chronicity of clinical practice. As we have moved away from prescribing classical antipsychotics and tricyclic antidepressants, issues remain with the use of atypical antipsychotics and second-generation antidepressants that need to be addressed, namely, iatrogenic discontinuation syndromes and supersensitivity psychiatric symptoms. An optimal maintenance drug treatment consists of regular attempts to reduce the dose by finding a minimal therapeutic dose, regularly asking the question of when to reduce or withdraw treatment and for which patients, and moreover, why it is difficult to decrease a given drug treatment. Recently, Falloon [1] proposed that maintenance pharmacotherapy in schizophrenia will depend on finally finding minimally effective doses through ‘extensive training in stress management’. In the long-term treatment of major depression, Fava [2] has hypothesized that antidepressants can aggravate the course of depressive illness. Lambert [3] recently suggested that ‘antipsychotic-switching syndromes’, which include discontinuation syndromes, are a ‘major barrier’ to adjusting antipsychotic treatment. In this paper, we propose that to achieve optimal maintenance treatment with antipsychotics, and to reduce or withdraw antipsychotics effectively, we must distinguish syndromes associated with discontinuing antipsychotics, such as supersensitivity psychosis, from true relapse. While the prevalence and incidence of drug-induced movement disorder(s) (DIMD) has continuously decreased with atypical antipsychotics, DIMD persist as do psychiatric and psychiatric-like symptoms associated with DIMD, and these must also be identified and evaluated. Persistent DIMD have been found to be a predictor of the later emergence of tardive dyskinesia (TD) and supersensitivity psychosis [4]. At present, we need to determine the relative risk of iatrogenic discontinuation syndromes, DIMD and DIMD psychiatric symptoms resulting from atypical antipsychotics. Although atypical antipsychotics are now most commonly prescribed, a debate has emerged on the differences between classical and atypical antipsychotics following the results of the Clinical Antipsychotic Trials of Intervention Effectiveness (CATIE) study [5]. The question that comes to the forefront is why recent studies are no longer finding well-established differences between these two generations in terms of efficacy and DIMD. Reasons to explain why recent schizophrenia studies have found reduced drug and placebo differences were examined at the International Society for CNS Clinical Trials and Methodology Annual Mid-Year Conference [6]. While the fact must be considered that patients included in recent studies have less severe illness with symptoms that are better controlled than in past studies (likely due to earlier treatment), the issue that psychiatric symptoms specific to schizophrenia are not being adequately measured nor differentiated from psychiatric and psychiatric-like symptoms associated with DIMD is crucial to answering this question. For example, it is hard to believe that in a recent review of psychomotor slowing in schizophrenia, the authors, when evaluating its effect on measurement and treatment research to improve cognition in schizophrenia (MATRICS), nearly completely ignored the influence of akinesia and DIMD on neuropsychological tests in schizophrenia and the importance of accurate DIMD measurements [7]. As we pursue this ongoing discussion, we recommend the discontinuation of all classical antipsychotics due to their neurotoxic association with a high prevalence of DIMD and increases in basal ganglia volumes [8], and now address how to prescribe atypical antipsychotics most effectively, by taking into account DIMD-associated psychiatric symptoms and iatrogenic discontinuation syndromes. The first widely prescribed atypical antipsychotic, risperidone, was first approved in Canada in 1993 following the publication of the Canadian Multicenter Risperidone Study, which reported clear advantages of risperidone over haloperidol and the placebo, and significantly less appearance of DIMD with risperidone than haloperidol [9]. DIMD includes the 4 types of movement disorders induced by antipsychotics: parkinsonism, dystonia, dyskinesia and akathisia [10]. These findings were confirmed by the American Risperidone Study [11] and several other studies reporting greater efficacy of risperidone over classical antipsychotics in terms of cost-efficiency [12] and the clinical management of patients with schizophrenia [13,14,15,16,17]. However, the CATIE study [5] challenged these results. The CATIE study found that of the 4 atypical antipsychotics studied, olanzapine was the only atypical to be more efficacious than the classical antipsychotic perphenazine, and to be highly superior to risperidone for discontinuation of treatment, due to lack of efficacy [5]. Olanzapine is known to produce less DIMD compared to risperidone, therefore one would expect psychiatric symptoms caused by DIMD to be less frequent with olanzapine than risperidone. The expected higher rate of DIMD-induced emergent psychiatric symptoms associated with risperidone would explain the CATIE results, showing risperidone to be significantly less efficacious than olanzapine [5], despite risperidone being known to be at least as efficacious as olanzapine for true schizophrenic symptoms. Furthermore, the rating scales used to measure DIMD did not find the well-established differences between the 5 antipsychotics for DIMD rates [5]. Thus, we propose that DIMD and DIMD-induced psychiatric symptoms were confounded with true schizophrenic symptoms in the CATIE study. DIMD-associated psychiatric symptoms could be classified into 3 types: (1) emergent psychiatric symptoms caused by DIMD, such as akinesia inducing depression, akathisia inducing anxiety; (2) iatrogenic psychiatric-like symptoms resulting from confounding DIMD with psychiatric symptoms, such as akinesia confounded with psychomotor retardation, akathisia with agitation; (3) supersensitivity psychosis symptoms associated with DIMD. In the CATIE study, quetiapine (mean dose = 543.4 mg/day), which shares a low rate of DIMD with olanzapine, was also found to be significantly less efficacious compared to olanzapine, but in contrast to risperidone, this lack of efficacy could be due to psychiatric symptoms related to supersensitivity psychosis explained by quetiapine’s loose binding properties at the D2 receptor [18]. Patients taking quetiapine had a completion rate of 18% out of 329 patients, whereas in our 3-year prospective study of quetiapine monotherapy with a lower mean dose of 487 mg/day (thus less likely to develop therapeutic tolerance), the completion rate was 21.7% out of 23 patients; 6 of 7 patients who relapsed, after a minimum 3 months of stabilized quetiapine treatment, met the criteria for supersensitivity psychosis [19]. Without distinguishing these DIMD-associated psychiatric symptoms from symptoms due to the original illness, the major impact of atypical antipsychotics is on the reduction of DIMD and TD [10, 20,] and their beneficial effects on psychosis are masked by DIMD emergent psychiatric symptoms, including supersensitivity psychosis. We will review 4 multicenter trials, which include a total of 14,497 patients, to illustrate how psychiatric and schizophrenic symptoms are confounded with DIMD-associated psychiatric symptoms.TD epidemiology has changed significantly since the introduction of atypical antipsychotics, with a constant decline in its prevalence [10]. TD, classified as a DIMD, is a hyperkinetic, involuntary and purposeless movement disorder [10, 20]. Considered as the most significant side effect of classical antipsychotics, TD has been associated with antipsychotics and gastrointestinal neuroleptics, and usually occurs after several years of treatment. Persistent TD can also occur after short-term exposure to classical antipsychotics and gastrointestinal neuroleptics even at low doses and for as few as 2 months [8,21,22,23], while reversible and withdrawal dyskinesias share properties with levodopa-induced dyskinesia [24]. We conducted several epidemiological studies of TD [4,25,26,27] and in 1975, using the National Institute of Mental Health (NIMH) psychopharmacology criteria, we found a 31% prevalence of TD in 261 outpatients with schizophrenia [25]. We also evaluated these patients according to the Schooler and Kane research diagnostic criteria and found a 22% prevalence of TD. This variability of findings related to defining criteria complicates comparisons across studies [10]. In a 5-year follow-up study of 169 of the same patients [4, 25], 45% met the research diagnostic criteria for TD. In 1975, 131 of the 261 patients did not meet the research diagnostic for TD, and in 1980 treatment-emergent TD was found in 46 of the patients who did not have it in 1975, for a 5-year cumulative incidence rate of 35% and a mean annual incidence rate of 8.4%. When corrected for remissions, the mean annual incidence rate decreased to 2.9%. This incidence rate, which includes both patients who developed and remitted from TD over time, is similar to results found by other studies during the same time period [28, 29]. The cumulative incidence of treatment-emergent TD in the study by Kane et al. [29] was 12% after 4 years and 40% after 8 years of neuroleptic exposure, which is similar to our finding of an annual incidence rate (corrected for remissions) of 3% for classical antipsychotics. In a study carried out in 130 lithium-treated affective disorder patients previously, but less, exposed to antipsychotics, we found a TD prevalence of 9.2% [26], which was a quarter of the incidence reported in our previous studies on patients with schizophrenia who had greater exposure to antipsychotics. In this time period of classical antipsychotics, 2 meta-analyses (including mostly patients with schizophrenia) reported mean TD prevalences of 23% [30] and 20% [31]. In view of the fact that 58% of patients treated with classical antipsychotics will develop treatment-emergent TD after 10–15 years of treatment [4], and the known beneficial neuroprotective effects of atypical antipsychotics on TD [32] and on increased basal ganglia volumes induced by classical antipsychotics [8], we recommend the discontinuation of all classical antipsychotics due to their neurotoxic effects. In the time period of both classical and atypical antipsychotics, the following multicenter studies (n = 3,753) evaluated the incidence and prevalence of TD, using the same definitions, Extrapyramidal Symptom Rating Scale [20] and training videotapes as in the previous time period. In the first study, an annual TD incidence of 0.68% was reported prospectively in 725 patients with schizophrenia, treated with the long-acting injectable atypical antipsychotic risperidone [27, 33]. Treatment-emergent TD was found in 12 of 587 patients without dyskinesia at the baseline [33]; however, expert case assessment determined 7 cases (1.19%) of withdrawal dyskinesia (3 cases resolved, 4 cases unchanged), 1 case (0.17%) of reversible dyskinesia and 4 cases (0.68%) of persistent treatment-emergent TD. Of the patients with baseline dyskinesia, 28.4% improved, no longer met TD criteria and maintained this response [33]. This annual treatment-emergent TD incidence of 0.68% with atypical antipsychotics is only 22% of the annual incidence of 3% reported with classical antipsychotics [4]. In the second study, the Schizophrenia International Suicide Prevention Trial (67 centers in 11 countries) [34], 980 patients with schizophrenia, or schizoaffective disorders, taking an atypical alone (25.6%), a classical alone (31.5%) or both a classical and an atypical antipsychotic (42.9%) were included from March 19, 1998, to February 14, 1999, and TD was found at the baseline in 115 (12%) patients [27, 35]. Thus, after 10 years in the time period of both classical and atypical antipsychotics, the overall prevalence of TD decreased by at least twofold compared to our previous 1979–1988 studies with classical antipsychotics [4, 25], using the same definitions, Extrapyramidal Symptom Rating Scale and training videotapes. In the third study (baseline data from three Ris-Consta multicenter studies) [27, 36] carried out 1 year later, 2,048 patients were included from March 21, 1999, to December 15, 2000, and TD was found at the baseline in 209 patients (10.2%), using the same methodology. This study showed a further decrease in the prevalence of TD after an additional year of atypical use. This changing epidemiology of TD with atypical antipsychotics is confirmed by Correll et al. [37] in a systematic review of 1-year prospective studies with atypical antipsychotics, and by Jeste et al. [38] in a 1-year study of elderly patients treated with risperidone. In conclusion, following the introduction of atypical antipsychotics, the prevalence and incidence of TD have significantly decreased. However, the risk for TD still exists with both atypical and classical antipsychotics, and there is a need for continued surveillance of emerging cases of TD in patients taking antipsychotics [39], especially as the current debate continues on the differences in efficacy between these two generations of antipsychotics following results from studies such as the CATIE [5, 39]. Furthermore, Kane [39] has pointed out that newly trained clinicians using mostly atypical antipsychotics may not have had the same exposure to TD as previously trained clinicians.A high prevalence of all 4 types of DIMD (parkinsonism, dystonia, dyskinesia and akathisia) remains. In the Schizophrenia International Suicide Prevention Trial (n = 980), a prevalence of 57.5% of DIMD (n = 551 patients) was found [27, 35]. In the Ris-Consta studies (n = 2,048) [27, 36], 970 patients (47.4%) had DIMD at the baseline, which consisted of 778 patients with parkinsonism (38.0%), 285 patients with akathisia (14%) and 209 patients with TD (10.2%). Thus, nearly 1 patient out of 2 had a definite DIMD in this time period of classical and atypical antipsychotics. In addition, DIMD have been consistently associated with significant psychiatric symptoms as measured by the positive and negative syndrome scale (PANSS) [40, 41]. In the InterSept study (n = 980), which included patients with schizophrenia and schizoaffective disorder who were at risk of suicide, suicidality was associated at baseline with DIMD, parkinsonism, TD and akathisia, and depression was associated with TD and akathisia [27, 35]. Based on these results, we recommend routinely assessing DIMD in patients with schizophrenia with suicidal and depressive symptoms. In the Ris-Consta studies (n = 2,048), baseline DIMD were also significantly associated with the PANSS total score, positive, negative and anxiety/depression symptoms [27, 36]. Greater anxiety and depression were seen in patients with severer DIMD, akathisia and parkinsonism. Higher PANSS negative symptom rating was associated with parkinsonism and higher PANSS total scores were associated with akathisia. In this time period, these last two studies (n = 3,028) show that DIMD persists with atypical antipsychotics, and that patients with DIMD have significantly higher PANSS scores compared to patients without DIMD.These results are in agreement with findings from 2 other multicenter studies: the American CATIE study [5] and the European Schizophrenia Outpatient Health Outcomes (SOHO) study [42]. In the CATIE baseline data, patients with TD (n = 212) were found to have significantly more psychopathology than patients without TD (n = 1,098) as measured by the PANSS total score and PANSS general psychopathology subscale [43]. In the 3-year prospective SOHO study, emergent cases of TD were associated with greater overall psychopathology. An increase in clinical global impression overall symptom severity was longitudinally associated with cases of TD in patients without TD at the baseline (n = The SOHO and the CATIE studies have also examined other for TD. the CATIE and SOHO studies found that other DIMD were associated with TD the CATIE study showed that patients with TD had more parkinsonism akathisia while the SOHO study found that baseline symptoms TD our findings in a prospective study of TD [4]. In to reporting that the incidence of TD was lower in patients taking atypical compared to classical antipsychotics after 6 months the SOHO study showed that the incidence of TD was associated with the incidence of of drug-induced in is crucial to that there is a of DIMD with atypical antipsychotics, which are not and confounded with psychiatric symptoms rating scales used routinely in clinical to DIMD do not DIMD from psychiatric symptoms from the 4 multicenter (n = 14,497 patients) into this the CATIE the [27, the Ris-Consta [27, 36] and the SOHO studies have all confirmed the association of DIMD with psychiatric symptoms. most of the studies included in this measure psychiatric symptoms according to the we propose the following of PANSS psychiatric symptoms associated with emergent psychiatric symptoms caused by DIMD, such as depression and suicidality example, akinesia is known to produce depression, psychomotor and suicidal while akathisia psychomotor and suicidal and TD is also associated with suicidal iatrogenic psychiatric-like symptoms resulting from confounding and DIMD with psychiatric symptoms, such as confounding and with and retardation, akathisia with anxiety and and and dyskinesias with and schizophrenic psychiatric schizophrenic symptoms associated with DIMD caused by supersensitivity psychosis, which we are now to first reported drug-induced associated with TD a in and increased receptor after long-term treatment with classical antipsychotics, and we this supersensitivity psychosis. We that TD and supersensitivity psychosis with the decrease or withdrawal of an antipsychotic, given risk not and at the same The debate continues on how to most withdraw antipsychotic [1] and and psychiatric syndromes associated with types of syndromes have been with the discontinuation of (1) withdrawal syndromes and major (2) syndromes anxiety and which have been reported with and (3) supersensitivity syndromes such as TD and supersensitivity psychosis These discontinuation syndromes all produce psychiatric symptoms that can be confounded with true of the original illness. In a recent review of the on psychosis the importance of between antipsychotic withdrawal effects related to the course of the original illness and drug-induced effects such as supersensitivity psychosis. due to the discontinuation of a drug can be differentiated from the course of original illness and more long-term maintenance treatment could be reduced and in patients The long-term maintenance with second-generation antidepressants and of a major depressive disorder is of the in and during long-term maintenance treatment. The has also recently been to produce a persistent disorder following withdrawal to be related to supersensitivity When discontinuing antipsychotics and antidepressants, the of supersensitivity syndromes and other iatrogenic discontinuation syndromes must be to high doses or of outpatients and with schizophrenia treated with a classical antipsychotic treatment also included 1 but no antidepressants, no and no showed a prevalence of 22% for supersensitivity psychosis The prevalence of TD using Schooler and Kane criteria, was that found for supersensitivity psychosis. cases of supersensitivity psychosis increased the prevalence of supersensitivity psychosis to psychosis was associated with a higher maintenance dose of classical antipsychotics, high and schizophrenia with a The higher antipsychotic dose and higher associated with supersensitivity psychosis to the of supersensitivity and these results that lower doses of antipsychotics could the appearance of supersensitivity psychosis. In this study, there was no found between TD and supersensitivity psychosis, due to TD being associated with schizophrenia and supersensitivity psychosis with higher antipsychotic dose was not to be a risk for TD, whereas increased was associated with TD but not associated with supersensitivity psychosis. is that most patients in this study were treated with which has a high for the D2 which could to both a high incidence of supersensitivity psychosis and DIMD as the drug is known to produce a high incidence of symptoms psychosis, in its masked and withdrawal is known to occur 6 following the decrease or withdrawal of an antipsychotic or 3 months for a long-acting injectable We have proposed that TD and supersensitivity psychosis can result from the of in the caused by following in D2 with high for The of supersensitivity psychosis and TD share can both occur after long-term use of antipsychotics and can and difficult to with of the antipsychotic stress both TD and supersensitivity psychosis and both can be by and by and TD was to be the predictor of supersensitivity psychosis in our and follow-up study of supersensitivity psychosis [4, TD and supersensitivity psychosis may or may not occur in the same time but TD is associated with supersensitivity psychosis when it occurs during withdrawal of antipsychotics These two supersensitivity syndromes have been difficult to study due to the fact that antipsychotics can their appearance further with supersensitivity psychosis is that symptoms the original illness and true however, supersensitivity psychosis can be as it more after of the antipsychotic than true occurs with high doses of antipsychotics and not with antipsychotic treatment and therapeutic to antipsychotic treatment after drug response time, as therapeutic there is further of supersensitivity and further syndromes, TD, can (1) or (2) persistent or (3) reversible or symptoms can persist for several months or years and can still be reversible or When persistent and supersensitivity symptoms symptoms, being severer than the original symptoms, but these supersensitivity symptoms persist in contrast to symptoms and may include symptoms atypical antipsychotics, it has been proposed that supersensitivity psychosis occurs more with antipsychotics with from the D2 receptor The 2 atypical antipsychotics most associated with supersensitivity psychosis are quetiapine and which both have loose binding properties at the D2 receptor An additional which and severe in the withdrawal of is its effect as an receptor Thus, for the withdrawal would be by the receptor following of at this drug in the of the a and psychosis results cases of supersensitivity psychosis have also been reported with olanzapine psychosis was found to be associated with quetiapine in our 3-year study of quetiapine in 23 outpatients with schizophrenia and schizoaffective disorder who had previously been treated with classical antipsychotics risperidone, and had symptoms and of side effects [19]. As in our of the CATIE study, 7 patients after a minimum of 3 months of stabilized treatment and 6 of these patients met the criteria for supersensitivity psychosis [19]. the 11 of patients with baseline TD relapsed, the that TD to supersensitivity psychosis and have been to be efficacious in of patients with supersensitivity psychosis We also recommend the use of in supersensitivity and anxiety disorder induced by the discontinuation of the An can be used in with an antipsychotic or an in to more decrease or withdraw these and find the minimal therapeutic dose for patients who still need long-term treatment. a minimal therapeutic dose with an has an additional for a drug olanzapine, as the dose will significant side In in the of Mental Health psychiatric 35% of patients with a of schizophrenia and For severe cases of schizophrenia, the use of or is in to drug to antipsychotic While is less than or it is superior to for anxiety and the of optimal minimal maintenance drug treatment. proposed the beneficial results of treatment in schizophrenia is their effect We have also related their beneficial effects to an of a We recommend treatment as a first for from treatment, can also be prescribed as with as it has a In a and that and had than other in addition, emerging that may improve DIMD has also been to be effective as an to antipsychotic monotherapy in patients with schizophrenia who treatment We that of cases of schizophrenia can be related to supersensitivity psychosis. In patients for maintenance treatment is a minimal therapeutic dose can be with the use of an that will patients from antipsychotic or conclusion, DIMD-induced psychiatric symptoms and supersensitivity syndromes will to to results such as found in the CATIE study which show that olanzapine is the only atypical antipsychotic more efficacious than a classical The proposed for psychiatric and psychiatric-like symptoms associated with DIMD may to the of all classical antipsychotics and the use of higher doses and longer than of atypical antipsychotics. research is in to develop to distinguish between true and iatrogenic discontinuation syndromes and to to more withdraw antipsychotics and antidepressants by and supersensitivity syndromes, for the antipsychotics and quetiapine and for the may to further of DIMD, TD and supersensitivity psychosis as we to more differences in the of As most of antipsychotics and second-generation antidepressants are not routinely or for more differences in drug will also to prescribe minimal therapeutic doses of antipsychotics and antidepressants for greater efficacy and better in the maintenance has and the last 3 years from and

Psychotherapy and Psychosomatics · editorial or comment · 168 citationsread the source →

PATHOPHYSIOLOGY OF DEPRESSION: DO WE HAVE ANY SOLID EVIDENCE OF INTEREST TO CLINICIANS?

Major depressive disorder (MDD) is a common and costly disorder which is usually associated with severe and persistent symptoms leading to important social role impairment and increased mortality 1,2. It is one of the most important causes of disability worldwide 3. The high rate of inadequate treatment of the disorder remains a serious concern 1. This review is aimed at summarizing the solid evidence on the etiology and pathophysiology of MDD that is likely relevant for clinical psychiatry. Neurobiological findings are regarded as solid when they are consistent and convergent, i.e., they have been confirmed by several studies using the same method and fit into results from studies using different methodological approaches. Family, twin, and adoption studies provide very solid and consistent evidence that MDD is a familial disorder and that this familiality is mostly or entirely due to genetic factors 4. This important finding suggests that parental social behavior and other familial environmental risk factors are not as important in the pathogenesis of MDD as previously assumed and should not be the major focus of the treatment of the disorder. The above-mentioned studies consistently show that the influence of genetic factors is around 30–40% 4. Non-genetic factors, explaining the remaining 60–70% of the variance in susceptibility to MDD, are individual-specific environmental effects (including measurement error effects and gene-environment interactions). These effects are mostly adverse events in childhood and ongoing or recent stress due to interpersonal adversities, including childhood sexual abuse, other lifetime trauma, low social support, marital problems, and divorce 5,6. These results suggest that there is a huge potential in the prevention of MDD by means of psychosocial interventions (e.g., in schools, at workplace). In addition, these results mirror the clinical practice of empirically validated psychotherapies to treat depression 7,8,9, including interpersonal, psychodynamic and cognitive behavioral psychotherapies and cognitive behavioural analysis system of psychotherapy, which all focus directly or indirectly on interpersonal difficulties and skills. This does not exclude the fact that unidentified non-genetic, non-psychosocial risk factors may also play important roles in some patients (e.g., climatic change, medical conditions). Stress sensitivity in depression is partly gender-specific. While men and women are, in general, equally sensitive to the depressogenic effects of stressful life events, their responses vary depending upon the type of stressor. Specifically, men are more likely to have depressive episodes following divorce, separation, and work difficulties, whereas women are more sensitive to events in their proximal social network, such as difficulty getting along with an individual, serious illness, or death 10. These findings point to the importance of gender-sensitive psychosocial approaches in the prevention and treatment of MDD. In contrast to the very solid evidence from epidemiological studies on broad risk factor domains, there is no solid evidence for specific genes and specific gene-by-environment interactions in the pathogenesis of MDD. Genome-wide association studies have indicated that many genes with small effects are involved in complex diseases, increasing the difficulty in identifying such genes 11. While there has been progress in the search for risk genes for several complex diseases despite this methodological problem 12, psychiatric conditions have turned out to be very resistant to robust gene identification. For example, based on a community-based prospective study, it has been proposed that a specific genetic variation in the promoter region of the serotonin transporter (a target of antidepressant drugs) interacts with stressful life events in the pathogenesis of depression 13. Although there is high clinical and neurobiological plausibility of this interaction, a recent meta-analysis yielded no evidence that the serotonin transporter gene alone or in interaction with psychological stress was associated with the risk of depression 14. The limited success of genetic studies of depression has been related to use of current classification schemas including ICD-10 and DSM-IV. These diagnostic manuals are based on clusters of symptoms and characteristics of clinical course that do not necessarily describe homogenous disorders but instead reflect common final pathways of different pathophysiolgical processes 15,16. The clinician should be aware that family history will continue to be the most solid source of information to estimate the genetic risk of MDD. Corticotropin-releasing hormone (CRH) is released from the hypothalamus in response to the perception of psychological stress by cortical brain regions. This hormone induces the secretion of pituitary corticotropin, which stimulates the adrenal gland to release cortisol into the plasma. The physiologic response to stress is partly gender-specific: women show generally greater stress responsiveness than men, which is consistent with the greater incidence of major depression in women 17. Moreover, men show greater cortisol responses to achievement challenges, whereas women show greater cortisol responses to social rejection challenges 18. Although MDD is considered as a stress disorder, most subjects treated for MDD have no evidence of dysfunctions of the hypothalamic-pituitary-adrenal axis (HPA) 19. However, some subjects with MDD do show abnormalities of that axis and of the extrahypothalamic CRH system 20. Altered stress hormone secretion appeared to be most prominent in depressed subjects with a history of childhood trauma 21. Elevated cortisol may act as a mediator between major depression and its physical long-term consequences such as coronary heart disease, type II diabetes, and osteoporosis 22. The importance of HPA axis dysfunction for the efficacy of antidepressants is a matter of debate 23. This axis is regulated through a dual system of mineralocorticoid (MR) and glucocorticoid (GR) receptors. Decreased limbic GR receptor function 24,25 and increased functional activity of the MR system 26 suggest an imbalance in the MR/GR ratio in stress-related conditions such as MDD. Epigenetic regulation of the glucocorticoid receptors has been associated with childhood abuse 27. Such environmental programming of gene expression may represent one possible mechanism that links early life stress to abnormal HPA axis function and increased risk of MDD in adults. While the CRH stimulation test (dex/CRH test) 28 is a sensitive measure of the HPA axis dysfunction in depression, the specificity of this test for MDD is low. However, non-suppression in the dex/CRH test has consistently predicted increased risk for depressive relapse during clinical remission 23. Additionally, the measurement of waking salivary cortisol concentration has been shown to be a simple and sensitive test for HPA axis hyperactivity in depression 29. Hypercortisolemia is almost exclusively found in subjects with severe and psychotic depression, in whom glucocorticoid antagonists may have some therapeutic effect 30. There is convergent evidence for CRH to play a major role in the pathogenesis of certain types of depression. Levels of CRH in the cerebrospinal fluid are elevated in some depressed subjects 31. Post-mortem studies reported an increased number of CRH secreting neurons in limbic brain regions in depression 32, likely reflecting a compensatory response to increased CRH concentrations 33. In addition, CRH produces a number of physiological and behavioral alterations that resemble the symptoms of major depression, including decreased appetite, disrupted sleep, decreased libido, and psychomotor alterations 34. There is also preliminary evidence that CRH1 receptor antagonists reduce symptoms of depression and anxiety 35. “Sickness behavior” as a result of an activation of the inflammatory response system shares many symptoms with depression, including fatigue, anhedonia, psychomotor retardation, and cognitive impairment. Sickness is mediated by pro-inflammatory cytokines such as interleukin-1α, tumor necrosis factor-α, and interleukin-6, which activate the HPA axis and impair the central serotonin system 36. The prevalence of depression as an unwanted effect of recombinant interferons is around 30% 37. In animals, blocking pro-inflammatory cytokine-mediated signaling produces antidepressant-like effects 38. Clinical data suggest that cytokines may play a role in the pathophysiology of a subgroup of depressed subjects, particularly those with comorbid physical conditions 36. The antidepressant enhancing effect of acetylsalicylic acid 39 points to the possible clinical relevance of psychoneuroimmunology in clinical depression research. Taken together, the laboratory tests with the highest potential to be clinically useful in the care of depressed individuals are based on abnormalities of the neuroendocrine and neuroimmune systems. Despite the large amount of basic science data suggesting that the HPA axis is importantly involved in the pathophysiology of depression, the effect of pharmacological modulation of this neuroendocrine system as antidepressant therapy has been disappointing. The link between childhood trauma and a permanently altered physiologic stress system points to the use of specific psychotherapies in the treatment of depressed patients with a history of early life trauma 40. Most of the serotonergic, noradrenergic and dopaminergic neurons are located in midbrain and brainstem nuclei and project to large areas of the entire brain. This anatomy suggests that monoaminergic systems are involved in the regulation of a broad range of brain functions, including mood, attention, reward processing, sleep, appetite, and cognition. Almost every compound that inhibits monoamine reuptake, leading to an increased concentration of monoamines in the synaptic cleft, has been proven to be a clinically effective antidepressant 19. Inhibiting the enzyme monoamine oxidase, which induces an increased availability of monoamines in presynaptic neurons, also has antidepressant effects. These observations led to the pharmacologically most relevant theory of depression, referred to as the monoamine-deficiency hypothesis. The monoamine-deficiency theory posits that the underlying pathophysiological basis of depression is a depletion of the neurotransmitters serotonin, norepinephrine or dopamine in the central nervous system. Serotonin is the most extensively studied neurotransmitter in depression. The most direct evidence for an abnormally reduced function of central serotonergic system comes from studies using tryptophan depletion, which reduces central serotonin synthesis. Such a reduction leads to the development of depressive symptoms in subjects at increased risk of depression (subjects with MDD in full remission, healthy subjects with a family history of depression) 41,42, possibly mediated by increased brain metabolism in the ventromedial prefrontal cortex and subcortical brain regions 42. Experimentally reduced central serotonin has been associated with mood congruent memory bias, altered reward-related behaviors, and disruption of inhibitory affective processing 16, all of which add to the clinical plausibility of the serotonin deficiency hypothesis. There is also evidence for abnormalities of serotonin receptors in depression, with the most solid evidence pointing to the serotonin-1A receptor, which regulates serotonin function. Decreased availability of this receptor has been found in multiple brain areas of patients with MDD 43, although this abnormality is not highly specific for MDD and has been found in patients with panic disorder 44 and temporal lobe epilepsy 45, possibly contributing to the considerable comorbidity among these conditions. However, there is no explanation for the mechanism of serotonin loss in depressed patients, and studies of serotonin metabolites in plasma, urine and cerebrospinal fluid, as well as post-mortem research on the serotonergic system in depression, have yielded inconsistent results. There is preliminary evidence that an increased availability of the brain monoamine oxidase, which metabolizes serotonin, may cause serotonin deficiency 46. In addition, loss-of-function mutations in the gene coding for the brain-specific enzyme tryptophan hydroxylase-2 may explain the loss of serotonin production as a rare risk factor for depression 47. Dysfunction of the central noradrenergic system has been hypothesized to play a role in the pathophysiology of MDD, based upon evidence of decreased norepinephrine metabolism, increased activity of tyrosine hydroxylase, and decreased density of norepinephrine transporter in the locus coeruleus in depressed patients 48. In addition, decreased neuronal counts in the locus coeruleus, increased alpha-2 adrenergic receptor density, and decreased alpha-1 adrenergic receptor density have been found in the brains of depressed suicide victims post-mortem 49. Since there is no method to selectively deplete central norepinephrine and no imaging tool to study the central norepinephrine system, solid evidence for abnormalities of this system in depression is lacking. While the classical theories of the neurobiology of depression mainly focused on serotonin and norepinephrine, there is increasing interest in the role of dopamine 50. Dopamine reuptake inhibitors (e.g., nomifensine) and dopamine receptor agonists (e.g., pramipexole) had antidepressant effects in placebo-controlled studies of MDD 51. In the cerebrospinal fluid and jugular vein plasma, levels of dopamine metabolites were consistently reduced in depression, suggesting decreased dopamine turnover 52. Striatal dopamine transporter binding and dopamine uptake were reduced in MDD, consistent with a reduction in dopamine neurotransmission 53. Degeneration of dopamine projections to the striatum in Parkinson's disease was associated with a major depressive syndrome in about one half of cases, which usually preceded the appearance of motor signs 54. Experimentally reduced dopaminergic transmission into the accumbens has been associated with anhedonic symptoms and performance deficits on a reward processing task in subjects at increased risk of depression 55,56. These findings are consistent with the clinical observation that depressed patients have a blunted reaction to positive reinforcers and an abnormal response to negative feedback 57. Almost all established antidepressants target the monoamine systems 58. However, full and partial resistance to these drugs and their delayed onset of action suggest that dysfunctions of monoaminergic neurotransmitter systems found in MDD represent the downstream effects of other, more primary abnormalities. Despite this limitation, the monoamine-deficiency hypothesis has proved to be the most clinically relevant neurobiological theory of depression. New findings on the role of dopamine in depression emphasize the scientific potential of this theory, and promising reports of antidepressant effects of drugs that modulate the dopaminergic system (e.g., pramipexole, modafinil) in difficult-to-treat depression underline its clinical relevance 51,59. Although many historical attempts to localize mental functions have failed, they have considerably contributed to a modern neuroscientific understanding of mental disorders 60. The development of neuroimaging techniques has opened up the potential to investigate structural and functional abnormalities in living depressed patients. Unfortunately, the diversity of imaging techniques used, the relatively small and heterogeneous study samples studied, and the limited overlap of results across imaging paradigms 61 make it difficult to reliably identify neuronal regions or networks with consistently abnormal structure or function in MDD. Functional imaging studies have provided the most limited overlap of findings. This may be due to methodological limitations and/or the complexity of neurocircuitry involved in MDD. A recent meta-analytic study found the best evidence for abnormal brain activity in MDD in lateral frontal and temporal cortices, insula, and cerebellum. In these brain regions activity was decreased at rest, they showed a relative lack of activation during induction of negative emotions, and an increase in activity following treatment with serotonin reuptake inhibitors. Opposite changes may exist in ventromedial frontal areas, striatum and possibly other subcortical brain regions 61. More solid evidence has been provided by structural imaging and post-mortem studies. A recent meta-analytic study on brain volume abnormalities in MDD revealed relatively large volume reductions in the ventromedial prefrontal cortex, particularly in the left anterior cingulate and in the orbitofrontal cortex. Moderate volume reductions were found in the lateral prefrontal cortex, hippocampus and striatum 62. Post-mortem studies consistently identified a reduction in glia cell density in dorsal, orbital and subgenual prefrontal cortices, as well as in the amygdala 63,64. Overall, functional, structural and post-mortem studies suggest that structural and functional abnormalities in the left subgenual cingulate cortex are the most solid neuroanatomical finding in MDD. Volume reduction in this region was found early in illness and in young adults at high familial risk for MDD 65, suggesting a primary neurobiological abnormality associated with the etiology of the illness. Humans with lesions that include the subgenual prefrontal cortex showed abnormal autonomic responses to social stimuli 66, and rats with left-sided lesions in this region had increased sympathetic arousal and corticosterone responses to restraint stress 67. Most importantly, chronic deep brain stimulation to reduce the potentially elevated activity in the subgenual cingulated cortex produced clinical benefits in patients with treatment-resistant depression 68. In summary, despite the considerable heterogeneity of findings from neuroimaging studies, there is convergent evidence for the presence of abnormalities in the subgenual prefrontal cortex in some patients with MDD. Neuroanatomical research in depression is of great clinical interest, since novel antidepressant treatments such as deep brain stimulation can target specific brain regions. In addition, there are promising leads for neuroimaging findings to predict the likelihood of responses to specific treatments 69. Risk factors for depressive episodes change during the course of the illness. The first depressive episode is usually “reactive”, i.e., triggered by important psychosocial stressors, while subsequent episodes become increasingly “endogenous”, i.e., triggered by minor stressors or occurring spontaneously 70. There is consistent evidence that the volume loss of the hippocampus and other brain regions is related to the duration of depression 71, suggesting that untreated depression leads to hippocampal volume loss, possibly resulting in increased stress sensitivity 72 and increased risk of recurrence 73. Glucocorticoid neurotoxicity, glutamatergic toxicity, decreased neurotrophic factors, and decreased neurogenesis have been proposed as possible mechanisms explaining brain volume loss in depression. There is no solid evidence on of these since there are no imaging to directly and neurotrophic processes in neurotrophic factor has considerable Specifically, studies have shown between and in hippocampal as well as expression of following antidepressant treatment The clinician should be aware of the potentially effect of depression and treat depressed patients as early and as A of studies consistently showed reductions in acid concentrations in the prefrontal and cortex in depression This may reflect stress since psychological stress to presynaptic of prefrontal neurotransmission low concentration may reflect reduction in the density and of In addition, chronic stress may reduce receptor possibly through changes in evidence of the hypothesis of depression the lack of effects of drugs on depressive symptoms and prefrontal concentration in subjects with MDD of evidence suggest a dysfunction of the neurotransmitter system in a of the receptor produced and large antidepressant effects in patients with treatment-resistant MDD inhibitors of release (e.g., antidepressant abnormal levels were found in depressed subjects as by and there is evidence for abnormal signaling in post-mortem Since is the major neurotransmitter involved in almost every brain the of the specific role of in depression (e.g., there are promising leads that the receptor is involved in MDD and are diagnostic for MDD, suggesting regulation in depressed patients. In addition, some depressive symptoms may show psychomotor of of positive and negative and a subgroup of patients with MDD may have a disorder In healthy young subjects, changes in the of the had specific effects on subsequent mood In depressed patients, of can have antidepressant on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of on these abnormalities have been hypothesized to be associated with MDD The association between of the and in cortisol in some subjects with and the effect of antidepressants on of and to the of this hypothesis Despite of the many promising the and genetic of this hypothesis are It remains to be antidepressant effects of such as directly to of The and of the neurobiological of depression are in 1. The many theories of depression and the relatively low response rate of all antidepressant treatments a hypothesis of and suggest that depression is a clinically and heterogeneous disorder. This research on of the response to therapeutic interventions using such as neuroimaging and neuroendocrine tests in with for with to stress sensitivity and antidepressant The of of therapeutic will for the development of that has the potential to interventions and to up pathways in the of novel therapeutic approaches.

World Psychiatry · editorial or comment · 607 citationsread the source →

Understanding nutrition, depression and mental illnesses

INTRODUCTION Few people are aware of the connection between nutrition and depression while they easily understand the connection between nutritional deficiencies and physical illness. Depression is more typically thought of as strictly biochemical-based or emotionally-rooted. On the contrary, nutrition can play a key role in the onset as well as severity and duration of depression. Many of the easily noticeable food patterns that precede depression are the same as those that occur during depression. These may include poor appetite, skipping meals, and a dominant desire for sweet foods.[1] Nutritional neuroscience is an emerging discipline shedding light on the fact that nutritional factors are intertwined with human cognition, behavior, and emotions. The most common mental disorders that are currently prevalent in numerous countries are depression, bipolar disorder, schizophrenia, and obsessive-compulsive disorder (OCD).[2] The dietary intake pattern of the general population in many Asian and American countries reflects that they are often deficient in many nutrients, especially essential vitamins, minerals, and omega-3 fatty acids.[3] A notable feature of the diets of patients suffering from mental disorders is the severity of deficiency in these nutrients.[3] Studies have indicated that daily supplements of vital nutrients are often effective in reducing patients' symptoms.[4] Supplements containing amino acids have also been found to reduce symptoms, as they are converted to neurotransmitters which in turn alleviate depression and other mental health problems.[4] On the basis of accumulating scientific evidence, an effective therapeutic intervention is emerging, namely nutritional supplement/treatment. These may be appropriate for controlling and to some extent, preventing depression, bipolar disorder, schizophrenia, eating disorders and anxiety disorders, attention deficit disorder/attention deficit hyperactivity disorder (ADD/ADHD), autism, and addiction.[4] Most prescription drugs, including the common antidepressants lead to side effects.[4] This usually causes the patients to skip taking their medications. Such noncompliance is a common occurrence encountered by psychiatrists. An important point to remember here is that, such noncompliant patients who have mental disorders are at a higher risk for committing suicide or being institutionalized. In some cases, chronic use or higher doses may lead to drug toxicity, which may become life threatening to the patient.[4] An alternate and effective way for psychiatrists to overcome this noncompliance is to familiarize themselves about alternative or complementary nutritional therapies. Although further research needs to be carried out to determine the best recommended doses of most nutritional supplements in the cases of certain nutrients, psychiatrists can recommend doses of dietary supplements based on previous and current efficacious studies and then adjust the doses based on the results obtained by closely observing the changes in the patient.[4] When we take a close look at the diet of depressed people, an interesting observation is that their nutrition is far from adequate. They make poor food choices and selecting foods that might actually contribute to depression. Recent evidence suggests a link between low levels of serotonin and suicide.[5] It is implicated that lower levels of this neurotransmitter can, in part, lead to an overall insensitivity to future consequences, triggering risky, impulsive and aggressive behaviors which may culminate in suicide, the ultimate act of inwardly directed impulsive aggression. Depression is a disorder associated with major symptoms such as increased sadness and anxiety, loss of appetite, depressed mood, and a loss of interest in pleasurable activities. If there is no timely therapeutic intervention, this disorder can lead to varied consequences. Patients who are suffering from depression exhibit suicidal tendency to a larger degree and hence are usually treated with antidepressants and/or psychotherapy.[6] Deficiencies in neurotransmitters such as serotonin, dopamine, noradrenaline, and γ-aminobutyric acid (GABA) are often associated with depression.[6–11] As reported in several studies, the amino acids tryptophan, tyrosine, phenylalanine, and methionine are often helpful in treating many mood disorders including depression.[12–17] When consumed alone on an empty stomach, tryptophan, a precursor of serotonin, is usually converted to serotonin. Hence, tryptophan can induce sleep and tranquility. This implies restoring serotonin levels lead to diminished depression precipitated by serotonin deficiencies.[8] Tyrosine and sometimes its precursor phenylalanine are converted into dopamine and norepinephrine.[18] Dietary supplements containing phenyl alanine and/or tyrosine cause alertness and arousal. Methionine combines with adenosine triphosphate (ATP) to produce S-adenosylmethionine (SAM), which facilitates the production of neurotransmitters in the brain.[19–22] The need of the present paradigm is, more studies shedding light on the daily supplemental doses of these neurochemicals that should be consumed to achieve antidepressant effects. Researchers attribute the decline in the consumption of omega-3 fatty acids from fish and other sources in most populations to an increasing trend in the incidence of major depression.[23] The two omega-3 fatty acids, eicosapentaenoic acid (EPA) which the body converts into docosahexanoic acid (DHA), found in fish oil, have been found to elicit antidepressant effects in human. Many of the proposed mechanisms of this conversion involve neurotransmitters. For instance, antidepressant effects may be due to bioconversion of EPA to leukotrienes, prostaglandins, and other chemicals required by the brain. Others hypothesize that both EPA and DHA influence neuronal signal transduction by activating peroxisomal proliferator-activated receptors (PPARs), inhibiting G-proteins and protein kinase C, in addition to calcium, sodium, and potassium ion channels. Whichever may be the case, epidemiological data and clinical studies have clearly shown that omega-3 fatty acids can effectively treat depression.[24] In depressed patients, daily consumption of dietary supplements of omega-3 fatty acid that contain 1.5-2 g of EPA has been shown to stimulate mood elevation. Nevertheless, doses of omega-3 higher than 3 g do not show better effects than placebos and may be contraindicative in cases, such as those taking anticlotting drugs.[25] In addition to omega–3 fatty acids, vitamin B (e.g., folate) and magnesium deficiencies have been linked to depression.[26–28] Randomized, controlled trials that involve folate and vitamin B12 suggest that patients treated with 0.8 mg of folic acid/day or 0.4 mg of vitamin B12/day will exhibit decreased depression symptoms.[27] In addition, the results of several case studies where patients were treated with 125-300 mg of magnesium (as glycinate or taurinate) with each meal and at bedtime led to rapid recovery from major depression in < 7 days for most of the patients. Previous research has revealed the link between nutritional deficiencies and some mental disorders.[232529–32] The most common nutritional deficiencies seen in patients with mental disorders are of omega–3 fatty acids, B vitamins, minerals, and amino acids that are precursors to neurotransmitters.[20232427283033] Accumulating evidence from demographic studies indicates a link between high fish consumption and low incidence of mental disorders; this lower incidence rate being the direct result of omega–3 fatty acid intake.[233132] One to two grams of omega-3 fatty acids taken daily is the generally accepted dose for healthy individuals, but for patients with mental disorders, up to 9.6 g has been shown to be safe and effective.[34–36] Majority of Asian diets are usually also lacking in fruits and vegetables, which further lead to mineral and vitamin deficiencies. The significance of various nutrients in mental health, with special relevance to depression has been discussed below. CARBOHYDRATES Carbohydrates are naturally occurring polysaccharides and play an important role in structure and function of an organism. In higher organisms (human), they have been found to affect mood and behavior. Eating a meal which is rich in carbohydrates triggers the release of insulin in the body. Insulin helps let blood sugar into cells where it can be used for energy and simultaneously it triggers the entry of tryptophan to brain. Tryptophan in the brain affects the neurotransmitters levels. Consumption of diets low in carbohydrate tends to precipitate depression, since the production of brain chemicals serotonin and tryptophan that promote the feeling of well being, is triggered by carbohydrate rich foods. It is suggested that low glycemic index (GI) foods such as some fruits and vegetables, whole grains, pasta, etc. are more likely to provide a moderate but lasting effect on brain chemistry, mood, and energy level than the high GI foods - primarily sweets - that tend to provide immediate but temporary relief. PROTEINS Proteins are made up of amino acids and are important building blocks of life. As many as 12 amino acids are manufactured in the body itself and remaining 8 (essential amino acids) have to be supplied through diet. A high quality protein diet contains all essential amino acids. Foods rich in high quality protein include meats, milk and other dairy products, and eggs. Plant proteins such as beans, peas, and grains may be low in one or two essential amino acids. Protein intake and in turn the individual amino acids can affect the brain functioning and mental health. Many of the neurotransmitters in the brain are made from amino acids. The neurotransmitter dopamine is made from the amino acid tyrosine and the neurotransmitter serotonin is made from the tryptophan.[5] If there is a lack of any of these two amino acids, there will not be enough synthesis of the respective neurotransmitters, which is associated with low mood and aggression in the patients. The excessive buildup of amino acids may also lead to brain damage and mental retardation. For example, excessive buildup of phenylalanine in the individuals with disease called phenylketonuria can cause brain damage and mental retardation. ESSENTIAL FATTY ACIDS Omega-3 fatty acids The brain is one of the organs with the highest level of lipids (fats). Brain lipids, composed of fatty acids, are structural constituents of membranes. It has been estimated that gray matter contains 50% fatty acids that are polyunsaturated in nature (about 33% belong to the omega-3 family), and hence are supplied through diet. In one of the first experimental demonstrations of the effect of dietary substances (nutrients) on the structure and function of the brain, the omega-3 fatty acids (specially alpha-linolenic acid, ALA) were the member to take part. An important trend has been observed from the findings of some recent studies that lowering plasma cholesterol by diet and medications increases depression. Among the significant factors involved are the quantity and ratio of omega-6 and omega-3 polyunsaturated fatty acids (PUFA) that affect serum lipids and alter the biochemical and biophysical properties of cell membranes. It has been hypothesized that sufficient long chain PUFAs, especially DHA, may decrease the development of depression.[37] The structural and functional components of membrane in cells of brain which is a lipid-rich organ, include polar phospholipids, spingolipids, and cholesterol. The glycerophospholipids in brain consist of high proportion of PUFA derived from the essential fatty acids (EFAs), linoleic acid and α-linolenic acid. The main PUFA in the brain are DHA, derived from the omega-3 fatty acid α-linolenic acid, arachidonic acid (AA) and docosa tetraenoic acid, both derived from omega-6 fatty acid linoleic acid. Experimental studies have revealed that diets lacking omega-3 PUFA lead to considerable disturbance in neural function.[38] Studies by Marszalek and Lodish indicate that despite their abundance in the nervous system, DHA and AA cannot be synthesized by mammals de novo and hence they or their precursors have to be supplied through the diet and transported to the brain. During late gestation and the early postnatal period, neurodevelopment occurs at significantly rapid rates which make the supply of adequate quantity of PUFAs, particularly DHA, imperative to ensure neurite outgrowth in addition to appropriate development of brain and retina.[39] Bruinsma and Taren of University of Arizona College of Public Health, Tucson, USA explored the involvement of dieting-related psychological factors as potential confounders.[40] They discussed studies that have both supported and contested the proposition that lowering plasma cholesterol by diet and medications contributes to depression. Research findings point out that an imbalance in the ratio of the EFAs, namely the omega-6 and omega-3 fatty acids, and/or a deficiency in omega-3 fatty acids, may be responsible for the heightened depressive symptoms associated with low plasma cholesterol. These relationships may explain the inconsistency in the results of trials on cholesterol-lowering interventions and depression. On similar lines, dieting behaviors have been associated with alterations in moods.[41] Dietary omega-3 fatty acids play a role in the prevention of some disorders including depression. Their deficiency can accelerate cerebral aging by preventing the renewal of membranes. However, the respective roles of the vascular component on one hand (where the omega-3s are active) and the cerebral parenchyma itself on the other, have not yet been clearly resolved. The role of omega–3 in certain diseases such as dyslexia and autism is suggested. It was omega–3 fatty acids that participated in the first coherent experimental demonstration of the effect of dietary substances (nutrients) on the structure and function of the brain. Experiments were first of all carried out on x-vivo cultured brain cells (1), then on in vivo brain cells (2), finally on physicochemical, biochemical, physiological, neurosensory, and behavioral parameters (3). These findings indicated that the nature of polyunsaturated fatty acids (in particular omega–3) present in formula milks for infants (both premature and term) determines the visual, cerebral, and intellectual abilities.[16] VITAMINS B-complex vitamins Nutrition and depression are intricately and undeniably linked, as suggested by the mounting evidence by researchers in neuropsychiatry. According to a study reported in Neuropsychobiology,[42] supplementation of nine vitamins, 10 times in excess of normal recommended dietary allowance (RDA) for 1 year improved mood in both men and women. The interesting part was that these changes in mood after a year occurred even though the blood status of nine vitamins reached a plateau after 3 months. This mood improvement was particularly associated with improved vitamin B2 and B6 status. In women, baseline vitamin B1 status was linked with poor mood and an improvement in the same after 3 months was associated with improved mood. Thiamine is known to modulate cognitive performance particularly in the geriatric population.[43] Vitamin B12 (Cynocobalamin) Clinical trials have indicated that Vitamin B12 delays the onset of signs of dementia (and blood abnormalities), if it is administered in a precise clinical timing window, before the onset of the first symptoms. Supplementation with cobalamin enhances cerebral and cognitive functions in the elderly; it frequently promotes the functioning of factors related to the frontal lobe, in addition to the language function of people with cognitive disorders. Adolescents who have a borderline level of vitamin B12 deficiency develop signs of cognitive changes.[43] Folate It has been observed that patients with depression have blood folate levels, which are, on an average, 25% lower than healthy controls.[44] Low levels of folate have also been identified as a strong predisposing factor of poor outcome with antidepressant therapy. A controlled study has been reported to have shown that 500 mcg of folic acid enhanced the effectiveness of antidepressant medication.[45] Folate's critical role in brain metabolic pathways has been well recognized by various researchers who have noted that depressive symptoms are the most common neuropsychiatric manifestation of folate deficiency.[46] It is not clear yet whether poor nutrition, as a symptom of depression, causes folate deficiency or primary folate deficiency produces depression and its symptoms. MINERALS Calcium A recent study showed that selective serotonin uptake inhibitors (SSRIs) inhibit absorption of calcium into bones. In addition to this, the SSRIs can also lower blood pressure in people, resulting in falls which may lead to broken bones. Indiscriminate prescription of SSRIs by doctors and ingestion by patients at risk of depression or other mental health problems may put them at increased risk of fractures. Compounded by the fact that they may be aging and already taking other medications, may also predispose them to osteoporosis.[47] Chromium Many studies on the association of chromium in humans depression have been recorded[4849] which indicate the significance of this micronutrient in mental health. Iodine Iodine plays an important role in mental health. The iodine provided by the thyroid hormone ensures the energy metabolism of the cerebral cells. During pregnancy, the dietary reduction of iodine induces severe cerebral dysfunction, eventually leading to cretinism. Iron Iron is necessary for oxygenation and to produce energy in the cerebral parenchyma (through cytochrome oxidase), and for the synthesis of neurotransmitters and myelin. Iron deficiency is found in children with attention-deficit/hyperactivity Iron in the are critical during the development of the and in with the in the with its associated deficiency is associated with disturbance in the development of cognitive Research findings out that as many as men are This in and more with of more depression than during other times in their These indicate the of in the of depression since its deficiency is known to cause and depression. Iron deficiency is for instance, with depression, and rapid a was first and by in while an of the mineral The role of has been well known in a into its its for bipolar disorder with and The therapeutic use of also its as an in depression, disorder, disorder, eating disorders, and in certain of adequate has to be taken while the mood in the can be used in patients with and The use of during and in and geriatric population needs observation about its In a of the of identified at studies, which indicate that low intake is associated with mood studies with with other populations that mood and in the of studies have shown that levels are lower in those with clinical intervention research that can influence the effectiveness of antidepressant also the brain cells the potential damage by studies have revealed the potential of the for physical development and mental development may be due to deficiency of When children and with poor nutritional status are to alterations of mental and behavioral they can be by dietary but to certain It has been observed that, of diet and meal pattern can have or immediate or effects. Dietary deficiencies of and nutrients vitamins, and such as during aging may precipitate brain which may be due to for of diet and depression which is a of to a factor that is often linked to increased and premature of aging may play an important role in this, by reducing food intake or reducing food intake in to such factors as in and poor use of prescription drugs, and and occurring in the in both and due to to They suggest changes associated with mental disorders such as dementia and depression, and and as to the of depression, people are the alternative and complementary are by the for and as a of and health and that are not currently to be a part of health need to be aware that it is likely that a of their patients with bipolar disorder might use these interventions to be and safe or to research in and brain indicates the of pathways that can provide a of the association between nutritional nervous system, and function an psychological health status. These findings may lead to of the therapeutic of dietary intervention health and health depression and other psychological disorders.

Indian Journal of Psychiatry · editorial or comment · 409 citationsread the source →

Taking a Spiritual History Allows Clinicians to Understand Patients More Fully

Journal of Palliative MedicineVol. 3, No. 1 Innovations in End-of-Life CareTaking a Spiritual History Allows Clinicians to Understand Patients More FullyDr. Christina Puchalski and Anna L. RomerDr. Christina Puchalski and Anna L. RomerPublished Online:19 Apr 2005https://doi.org/10.1089/jpm.2000.3.129AboutSectionsPDF/EPUB ToolsPermissionsDownload CitationsTrack CitationsAdd to favorites Back To Publication ShareShare onFacebookTwitterLinked InRedditEmail FiguresReferencesRelatedDetailsCited byVerbalizing spiritual needs in palliative care: a qualitative interview study on verbal and non-verbal communication in two Danish hospices4 January 2022 | BMC Palliative Care, Vol. 21, No. 1Implementation of an Educational Toolkit to Increase Nurse Competence in Spirituality and Spiritual Care of Oncology Patients8 November 2022 | Journal of Holistic Nursing, Vol. 5Posicionamento sobre a Saúde Cardiovascular nas Mulheres – 2022Arquivos Brasileiros de Cardiologia, Vol. 119, No. 5Experiences of German health care professionals with spiritual history taking in primary care: a mixed-methods process evaluation of the HoPES3 intervention15 October 2022 | Family Practice, Vol. 29Religious and spiritual journeys of LGBT older adults in rural Southern Appalachia25 October 2021 | Journal of Religion, Spirituality & Aging, Vol. 34, No. 4The CASH assessment tool: A window into existential suffering19 May 2021 | Journal of Health Care Chaplaincy, Vol. 28, No. 4Integrating religion/spirituality into professional social work practice27 July 2022 | Journal of Religion & Spirituality in Social Work: Social Thought, Vol. 41, No. 4The Concept of Spirituality in the Health Sector: Contributions from the Study of Religion27 September 2022 | International Journal of Latin American Religions, Vol. 12Systematic review: The relationship between religion, spirituality and mental health in adolescents who identify as transgender13 September 2022 | Journal of Gay & Lesbian Mental Health, Vol. 26„Des Lebens Ruf an uns wird niemals enden“ – Sinnzentrierte Interventionen im Überblick30 August 2022 | Zeitschrift für Palliativmedizin, Vol. 23, No. 05Case discussion: The critically ill older adult in spiritual distressGeriatric Nursing, Vol. 47Australian Patient Preferences for the Introduction of Spirituality into their Healthcare Journey: A Mixed Methods Study3 August 2022 | Journal of Religion and Health, Vol. 27Religion, Spirituality, and Ethics in Psychiatric Practice30 March 2022 | Journal of Nervous & Mental Disease, Vol. 210, No. 8Spiritual distress in dialysis: A case report21 July 2022 | Progress in Palliative Care, Vol. 211Interprofessional communication training to address spiritual aspects of cancer care19 July 2022 | Journal of Health Care Chaplaincy, Vol. 29Spirituality in Serious Illness and HealthJAMA, Vol. 328, No. 2What is the role of spiritual care specialists in teaching generalist spiritual care? 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Kamal3 February 2022 | Journal of Palliative Medicine, Vol. 25, No. 2Moving Beyond Spiritual Assessments: A Dynamic, Augustinian Approach to Spiritual Care of the Dying24 January 2022 | Journal of Pastoral Theology, Vol. 29Integrating Spiritual Care in the Frame1 January 2022Evaluation of a Spiritual History with Elderly Multi-Morbid Patients in General Practice—A Mixed-Methods Study within the Project HoPES34 January 2022 | International Journal of Environmental Research and Public Health, Vol. 19, No. 1Invited Commentary: Religious Service Attendance and Implications for Clinical Care, Community Participation, and Public Health11 May 2021 | American Journal of Epidemiology, Vol. 191, No. 1Use of the Classic Hallucinogen Psilocybin for Treatment of Existential Distress Associated with Cancer1 January 2022Religiousness and Spirituality in Coping with Cancer1 January 2022Spirituality/Religiosity as a Therapeutic Resource in Clinical Practice: Conception of Undergraduate Medical Students of the Paulista School of Medicine (Escola Paulista de Medicina) - Federal University of São Paulo (Universidade Federal de São Paulo)24 December 2021 | Frontiers in Psychology, Vol. 12Patient desire for spiritual assessment is unmet in urban and rural primary care settings31 March 2021 | BMC Health Services Research, Vol. 21, No. 1Australian perspectives on spiritual care training in healthcare: A Delphi study13 July 2021 | Palliative and Supportive Care, Vol. 19, No. 6Defining Spirituality in Healthcare: A Systematic Review and Conceptual Framework18 November 2021 | Frontiers in Psychology, Vol. 12Assessing the Impact of Provider Training and Perceived Barriers on the Provision of Spiritual Care: a Mixed Methods Study12 November 2021 | Journal of Cancer Education, Vol. 5Development of an Instrument to Assess Spirituality: Reliability and Validation of the Attitudes Related to Spirituality Scale (ARES)4 November 2021 | Frontiers in Psychology, Vol. 12Association between Spirituality, Religiosity, Spiritual Pain, Symptom Distress, and Quality of Life among Latin American Patients with Advanced Cancer: A Multicenter Study Marvin O. Delgado-Guay, Alejandra Palma, Eva Duarte, Mónica Grez, Laura Tupper, Diane D. Liu, and Eduardo Bruera27 October 2021 | Journal of Palliative Medicine, Vol. 24, No. 11Spirituality and Vicarious Trauma Among Trauma Clinicians: A Qualitative Study19 October 2021 | Journal of Trauma Nursing, Vol. 28, No. 6Abordando o Sofrimento Existencial na Pessoa com Cancro20 February 2022 | Revista Portuguesa de Psiquiatria e Saúde MentalQuestioning Capacity in an Elderly Jamaican Man with Terminal Cancer Exhibiting Near-Death Awareness: A Case Report and Review of Literature Cynthia X. Pan, Kelly Thomson, Bruno A. Costa, and Jane Morris13 August 2021 | Journal of Palliative Medicine, Vol. 24, No. 9Posicionamento sobre Hipertensão Arterial e Espiritualidade – 20211 September 2021 | Arquivos Brasileiros de Cardiologia, Vol. 117, No. 3The Content, Teaching Methods and Effectiveness of Spiritual Care Training for Healthcare Professionals: A Mixed-Methods Systematic ReviewJournal of Pain and Symptom Management, Vol. 62, No. 3Religiosity and spirituality in psychiatry residency programs: why, what, and how to teach?1 August 2021 | Brazilian Journal of Psychiatry, Vol. 43, No. 4Editorial: children’s life, religiosity and spirituality matter: perspectives of special groups and their related adults16 July 2021 | International Journal of Children's Spirituality, Vol. 26, No. 3Development and protocol for a nurse-led telephonic palliative care programNursing Outlook, Vol. 69, No. 4Psychological Distress Among a Tunisian Community Sample During the COVID-19 Pandemic: Correlations with Religious Coping27 March 2021 | Journal of Religion and Health, Vol. 60, No. 3Optimism and social support as contributing factors to spirituality in Cancer patients3 January 2021 | Supportive Care in Cancer, Vol. 29, No. 6A mixed‐methods approach to comparing perceptions of cancer patients' and cancer care providers' religious and spiritual beliefs, behaviours, and attitudes23 December 2020 | European Journal of Cancer Care, Vol. 30, No. 3Spirituality and religion in residents and inter-relationships with clinical practice and residency training: a scoping review28 May 2021 | BMJ Open, Vol. 11, No. 5Using Simulation to Prepare Students for Medical Mission TripsJournal of Christian Nursing, Vol. 38, No. 2Implementation of a Meaning-Centered Psychotherapy training (MCPT) program for oncology clinicians: a qualitative analysis of facilitators and barriers9 October 2019 | Translational Behavioral Medicine, Vol. 11, No. 1Medical student reflections: Chaplain shadowing as a model for compassionate care training27 September 2020 | Medical Teacher, Vol. 43, No. 1Competence 3: Spiritual Care, Assessment and Planning19 May 2021Psychospirituelle Ressourcen in einer VUCA-Welt: Implikationen für Beratung und Coaching26 May 2021Application and Implementation of the Spiritual Needs Questionnaire in Spiritual Care Processes29 May 2021Spiritual Care in Health Care: Guideline, Models, Spiritual Assessment and the Use of the ©FICA Spiritual History Tool29 May 2021Relevance of Addressing Spiritual Needs for Clinical Support in Palliative Medicine29 May 2021Addressing Spiritual Needs in Faith Community Nursing29 May 2021Sentidos de vida e morte: reflexões de pacientes em cuidados paliativos1 January 2021 | Psicologia USP, Vol. 32Spiritual Care Competencies for Advanced Practice Nurses16 October 2021Introduction to Spirituality16 October 2021Global APN Case Study in Spirituality-Stories of Hope from Australia16 October 2021Four aspects of spiritual care: a phenomenological action research study on practicing and improving spiritual care at two Danish hospices22 October 2021 | Palliative Care and Social Practice, Vol. 15A Holistic Approach to Meeting Physical, Social and Psychological Needs23 December 2020Effectiveness of spiritual care training for rehabilitation professionals: An exploratory controlled trialNeuroRehabilitation, Vol. 47, No. 4Spiritual Well-Being in People Living with Persistent Non-Cancer and Cancer-Related Pain9 December 2020 | Pain Medicine, Vol. 196Testing of a (Spiritual) Self-Assessment Tool ((S)SAT) in a Community Hospital Setting23 November 2020 | Journal of Pastoral Care & Counseling: Advancing theory and professional practice through scholarly and reflective publications, Vol. 74, No. 4Genetic counseling graduate training to address religion and spirituality in clinical practice: A qualitative exploration of programs in North America30 May 2020 | Journal of Genetic Counseling, Vol. 29, No. 6The relationship between caregivers’ perceptions of end-of-life care in long-term care and a good resident death15 May 2020 | Palliative and Supportive Care, Vol. 18, No. 6“Give them the door but don’t push them through it”: Family Attitudes Toward Physician-Led Spiritual Care in Pediatric Palliative Medicine12 February 2020 | Journal of Religion and Health, Vol. 59, No. 6Exploring spirituality with older people: (1) rich experiences11 August 2019 | Journal of Religion, Spirituality & Aging, Vol. 32, No. 4Cultural Competency9 September 2020The Urgency of Spiritual Care: COVID-19 and the Critical Need for Whole-Person PalliationJournal of Pain and Symptom Management, Vol. 60, No. 3Spirituality in Recovery From Substance Use DisordersJournal of Psychosocial Nursing and Mental Health Services, Vol. 58, No. 9A Narrative Approach to Spirituality and Spiritual Care in Health Care3 October 2019 | Journal of Religion and Health, Vol. 59, No. 3Neural underpinning of a personal relationship with God and sense of control: A lesion-mapping study25 April 2020 | Cognitive, Affective, & Behavioral Neuroscience, Vol. 20, No. 3Patterns of Religiosity, Death Anxiety, and Hope in a Population of Community-Dwelling Palliative Care Patients in New Zealand—What Gives Hope If Religion Can’t?9 December 2019 | American Journal of Hospice and Palliative Medicine®, Vol. 37, No. 5Pain Management in Patients with Serious IllnessMedical Clinics of North America, Vol. 104, No. 3Varieties of Religious (Non)AffiliationJournal of Nervous & Mental Disease, Vol. 208, No. 5Cuidados paliativos31 August 2020 | PAJAR - Pan American Journal of Aging Research, Vol. 8, No. 1The Invisibility of Spiritual Nursing Care in Clinical Practice28 November 2019 | Journal of Holistic Nursing, Vol. 38, No. 1Spirituality in heart failure: a review of the literature from 2014 to 2019 to identify spiritual care needs and spiritual interventionsCurrent Opinion in Supportive & Palliative Care, Vol. 14, No. 1Plädoyer für einen (berufs-) alltagstauglichen Begriff von Spiritualität9 July 2021 | Spiritual Care, Vol. 0, No. 0Spirituality and mental health17 February 2020 | Journal for the Study of Spirituality, Vol. 10, No. 1Positive Interventions in Substance Use Disorders25 January 2020Spirituality/religion and painA Mother’s Love – Support Despite Disagreeing with Goals of Care10 June 2020Charting Spiritual Care: Psychiatric and Psychotherapeutic Aspects11 August 2020Spirituality5 September 2020CE: Assessing and Managing Spiritual Distress in Cancer SurvivorshipAJN, American Journal of Nursing, Vol. 120, No. 1Health Care Professionals' Reflections on Their Learning as Spiritual Generalists and Integration Into Practice28 October 2020 | Journal of Continuing Education in the Health Professions, Vol. 40, No. 4End-of-Life, Grief, and Bereavement: Strategies to Provide Comfort?3 October 2020Our transformational leader might be replaced, we are extremely stressed out!Management Research Review, Vol. 43, No. 5Navigating the Murky Waters of Hope, Fear, and Spiritual SufferingSurgical Clinics of North America, Vol. 99, No. 5Spirituality and Religion-Relevance and Assessment in the Clinical SettingCurrent Psychiatry Research and Reviews, Vol. 15, No. 2Religion, Belief, and Spirituality in Health Care2 August 2019Faith-Health Collaboration to Improve Community and Population Health12 August 2019 | NAM PerspectivesBrazilian Physicians’ Beliefs and Attitudes Toward Patients’ Spirituality: Implications for Clinical Practice29 September 2018 | Journal of Religion and Health, Vol. 58, No. 4Recent Advances in Cognitive Behavioral Therapy For Digestive Disorders and the Role of Applied Positive Psychology Across the Spectrum of GI CareJournal of Clinical Gastroenterology, Vol. 53, No. 7Preferences, use of and satisfaction with mental health services among a sample of Puerto Rican cancer patients18 July 2019 | PLOS ONE, Vol. 14, No. 7Spirituality as agency and restoration in existential recovery11 April 2018 | Journal of Spirituality in Mental Health, Vol. 21, No. 3Meaning-Centered Interventions for Patients With Advanced or Terminal Cancer18 July 2018 | Cancer Nursing, Vol. 42, No. 4Spiritual and Religious Coping of Medical Decision Makers for Hospitalized Older Adult Patients Saneta M. Maiko, Steven Ivy, Beth Newton Watson, Kianna Montz, and Alexia M. Torke27 March 2019 | Journal of Palliative Medicine, Vol. 22, No. 4Time to follow the evidence – Spiritual care in health careEthics, Medicine and Public Health, Vol. 9How and When Is Role Modeling Effective? The Influence of Mentee Professional Identity on Mentoring Dynamics and Personal Learning Outcomes18 April 2019 | Group & Organization Management, Vol. 44, No. 2Teenagers and Cannabis Use: Why It's a Problem and What Can Be Done About ItJournal of Psychosocial Nursing and Mental Health Services, Vol. 57, No. 3Haken und Ösen: Spiritualität in der klinischen PalliativversorgungWege zum Menschen, Vol. 71, No. 2Approaching Spirituality Using the Patient-Centered Clinical Method27 January 2018 | Journal of Religion and Health, Vol. 58, No. 1Medical Students’ (Dis)comfort with Assessing Religious and Spiritual Needs in a Standardized Patient Encounter10 October 2018 | Journal of Religion and Health, Vol. 58, No. 1Spirituality and Religiosity of Pharmacy Students1 February 2019 | American Journal of Pharmaceutical Education, Vol. 83, No. 1Interprofessional spiritual care in oncology: a literature review16 February 2019 | ESMO Open, Vol. 4, No. 1Physical, Psychological/Psychiatric, Social, and Spiritual Problems and Symptoms13 April 2019Spiritual Assessment in Healthcare: An Overview of Comprehensive, Sensitive Approaches to Spiritual Assessment for Use Within the Interdisciplinary Healthcare Team18 May 2019The Role of the Nurse in Providing Spiritual Care: A Case Study Approach to Exploring Specific Care Provision by Healthcare Workers in the Context of an Interdisciplinary Healthcare Team18 May 2019Teaching and Learning About Spirituality in Healthcare Practice Settings18 May 2019Religion and Spirituality Among Medical Students5 June 2019Spiritual Care: The Role of Health Care Chaplaincy4 September 2019End-of-life milieu of critically sick children admitted to a pediatric hospital: A comparative study of survivors versus nonsurvivorsIndian Journal of Palliative Care, Vol. 25, No. 4Incorporating and Teaching Spirituality into Medical Education: An Overview of the Field and Possible Educational Strategies4 September 2019Religion, Spirituality, and Stress6 March 2019Toward Comprehensive Medicine: Listening to Spiritual and Religious Needs of Patients26 April 2019 | Gerontology and Geriatric Medicine, Vol. 5Din ve Psikoloji Arasındaki Uçurum Gerçekten Ne Kadar Derin? Psikoterapilerdeki Dini İzler15 December 2018 | Cumhuriyet İlahiyat Dergisi, Vol. 22, No. 3Women's Perceptions of Using Short Films to Integrate Spirituality in TherapyJournal of Systemic Therapies, Vol. 37, No. 4Content Validation of Advanced Illness Criteria of a Palliative Care Screening Tool Lauren C. DiLello, Karen Mulvihill, Jennifer Delli Carpini, Riddhi Shah, Julia Hermanowski, and Damanjeet Chaubey29 October 2018 | Journal of Palliative Medicine, Vol. 21, No. 11Understanding, assessing, and in the spiritual of medical and October 2018 | Theology, Vol. 11, No. and of in Living with October 2018 | Journal of & Social Services, Vol. No. for the spirituality as October 2018 | Revista de Vol. 71, No. An of an aged psychiatry March 2018 | Psychiatry, Vol. 26, No. de de vida de de Vol. 25, No. support and with in Care in the Care A Narrative June | Journal of Care Medicine, Vol. No. Care in Cancer: in the of of Clinical Oncology Educational Vol. 3, No. religion/spirituality in clinical practice: A among social and and October | Journal of Clinical Psychology, Vol. 74, No. Spirituality in Care December | Journal of Religion and Health, Vol. 57, No. of to spiritual care at the of a phenomenological exploration from the of palliative care February 2018 | Journal for the Study of Spirituality, Vol. 8, No. Existential Distress in Pediatric Cancer December and Patient Spiritual in the through October of Spirituality in November Psychological/Psychiatric, Social, and Spiritual Problems and July and End-of-Life Care in Cancer in Oncology Nursing, Vol. No. Care in Hospice and Palliative Journal of Hospice and Palliative Care, Vol. 20, No. and Spirituality: Literature review and Journal of Counseling, Vol. 18, No. of the tool existential communication between and cancer August | European Journal of General Practice, Vol. 23, No. Education and of Christian Nursing, Vol. 34, No. Care Interventions in to and Therapy C. and D. September | Journal of Palliative Medicine, Vol. 20, No. in Patients with A Qualitative September | Journal of Research in Nursing and Vol. 14, No. theory on the and in an exploratory case study September | Vol. 69, No. of the of Spirituality and Palliative Care Research and of Pain and Symptom Management, Vol. No. of a spiritual care training program for staff on November | Palliative and Supportive Care, Vol. 15, No. 4Spiritual distress and spiritual care in advanced heart July | Reviews, Vol. and Spiritual Patient Simulation in Nursing, Vol. No. Vol. 42, No. 4The impact of a spiritual in patients with and and their support December | Vol. 26, No. 3The Importance of a Spiritual History in Healthcare Vol. No. About Substance Use DisordersJournal of Psychosocial Nursing and Mental Health Services, Vol. No. and Spiritual Beliefs of April | Journal of Religion and Health, Vol. No. Care Perceptions of and With of Hospice & Palliative Nursing, Vol. 19, No. in Substance Use What to Know to Practice30 November | in Mental Health Nursing, Vol. 38, No. End-of-Life Care to Religious and Vol. No. of Social Education, Vol. 53, No. Nursing Care and of Christian Nursing, Vol. 34, No. 1The of taking a religious and spiritual July | Psychiatry, Vol. 24, No. religion and spirituality in Vol. No. the role of religious in the at the of of Vol. No. care spiritual March | Supportive Care in Cancer, Vol. 24, No. Spiritual Care and the Role of An Review of Literature and April | Journal of Religion and Health, Vol. No. of the Spiritual Needs of of with Is in the June | Journal of Palliative Medicine, Vol. 19, No. Impact of a Tool for Comprehensive Assessment of Palliative Care on Assessment at and of Pain and Symptom Management, Vol. No. from Healthcare Students to Understand Spiritual Assessment in Clinical Practice29 October | Journal of Religion and Health, Vol. No. Spirituality in January | Journal of Religion and Health, Vol. No. 3Development and of to Assess Nurse Provision of Spiritual August 2014 | Journal of Holistic Nursing, Vol. 34, No. and Validation of the Practice Assessment September 2014 | Research on Social Practice, Vol. 26, No. and the Medical A of July | Journal of Health Care Chaplaincy, Vol. 22, No. history taking in palliative care: A controlled September | Palliative Medicine, Vol. 30, No. Is Is Using A and the Life With American in Spiritual March | Journal of in Mental Health, Vol. 11, No. and spiritual in September | International Journal of and Mental Health, Vol. No. 1The of Hospital to and Patients’ Spiritual A May | Journal for the Study of Spirituality, Vol. No. 1The and to March End-of-Life Spiritual March in Holistic Patient Journal of Nursing, Vol. No. of spiritual assessment for older September 2014 | and Vol. No. und der der Care, Vol. No. Spirituality and A for Holistic January | Journal of Religion and Health, Vol. No. and Belief, in Care spiritual history tool by C. M. Puchalski as an for an interdisciplinary in January | Journal for of and Social Vol. 21, No. the of Spiritual A Pain and Palliative Care Service Quality of Pain and Symptom Management, Vol. No. of Spiritual Assessment in September | Vol. No. the of Christian Nursing, Vol. 32, No. 4Spiritual care: is the assessment tool for palliative Journal of Palliative Nursing, Vol. 21, No. und Spiritualität in der September | Vol. 60, No. of September of spirituality assessment in palliative care patients in November 2014 | Progress in Palliative Care, Vol. 23, No. 4The for Spiritual A Mixed-Methods July | Oncology Nursing Vol. 42, No. 4The Integration of Religion and Spirituality in Social Practice: A May | Social Vol. 60, No. 3The and Educational of a Spiritual Life Review for Patients with and June 2014 | Journal of Cancer Education, Vol. 30, No. in Geriatric Palliative in Geriatric Medicine, Vol. No. An for Spiritual Well-Being May | Journal of Religion & Spirituality in Social Work: Social Thought, Vol. 34, No. Spiritual Assessment March | Journal of Health Care Chaplaincy, Vol. 21, No. American on Mental Health, and Help April | and Vol. 60, No. of Christian Nursing, Vol. 32, No. the Spiritual Needs and of Oncology Patients in Nursing Practice, Vol. 29, No. Care Training to Healthcare Professionals: A Systematic April | Journal of Pastoral Care & Counseling: Advancing theory and professional practice through scholarly and reflective publications, Vol. 69, No. analysis of spiritual

Journal of Palliative Medicine · 741 citationsread the source →

A social neuroscience perspective on clinical empathy

Clinical empathy is an important element of quality health care. Empathic communication is associated with improved patient satisfaction, increased adherence to treatment, and fewer malpractice complaints 1. Patients' perceptions of their physicians' empathy are positively related to more favorable health outcomes 2-4. In addition to improving patient outcomes, clinical empathy is associated with increased overall well-being for the physician 5. High levels of practitioner empathy have been associated with decreased burnout, personal distress, depression and anxiety, along with increased life satisfaction and psychological well-being 6, 7. Despite increasing appreciation of the value of empathy, medical educators continue to struggle with how best to educate students and residents on empathy maintenance. There have been several promising creative approaches that have shown demonstrable short-term success 8. However, there is a lack of evidence for enduring success, that is, for interventions during medical education that will enable physicians to sustain empathy throughout their careers. A more comprehensive and precise understanding of the subcomponents of empathy and how they are influenced by stress and anxiety is needed in order to design targeted interventions. Empathy is difficult to define, and an operational definition remains elusive. In medicine, empathy has often been conceptualized as consisting of two primary features: cognitive empathy, defined as the ability to recognize and understand another's experience, to communicate and confirm that understanding with the other person, and to take effective action to then act appropriately in a helpful manner 9, and affective empathy, defined as emotional resonance with the patient 10. Cognitive empathy has been singled out as beneficial in the clinical relationship, while affective empathy has been viewed as interfering with the physician's ability to make effective diagnoses and facilitate better outcomes. This has resulted in the teaching and practice of “detached concern”, a process where physicians establish a certain emotional distance from their patients in order to maintain objectivity and limit exposure to the negative emotions routinely experienced by those patients 11. However, recent research has demonstrated that the underlying rationale for implementing a “detached concern” approach is no longer tenable. First, affective engagement contributes to empathy, improving cognitive accuracy as well as affective understanding 12. Second, patients respond differently to emotionally engaged physicians. Patients who perceive their physicians as emotionally attuned or genuinely concerned disclose more, are more adherent to treatment, and show greater agency in addressing serious health problems such as cancer 11. Furthermore, there is now convincing empirical evidence that cognitive and affective aspects interact in the experience of empathy 13. Finally, the primary motivation behind the “detached concern” approach, that emotional connection will necessarily lead individuals into emotional turmoil, is not supported by the literature 14. Despite the clear importance of empathy in clinical settings, many physicians experience difficulty empathizing with their patients. For instance, a study which coded interviews between physicians and lung cancer patients found that, out of 384 empathic opportunities – defined as patients' statements including an explicit description of emotion or patients' statements or clues that indicated an underlying emotion – physicians responded empathically to only 39 (10%), most often reacting with little emotional support and shifting to biomedical questions and statements 15. Using patient-physician interaction videos where students are taught to identify and code these types of empathic opportunities, as well as what would be appropriate empathic responses, could help them more effectively address those opportunities. Additionally, sustaining empathy during distressing moments begins with doctors learning to take their own emotional temperatures, so that they can notice when they are anxious and take a deep breath or count to ten before responding to the patient. Both implementing mindfulness skills 16 and learning to return focus on the patient by becoming curious about what the patient is most concerned about at that moment can help physicians maintain empathy 11. Intensive training in mindful communication has been shown to reduce psychological distress and burnout, and increase empathy 17. The vast majority of individuals have the capacity for empathy, and research suggests that medical students start school with similar or higher levels of empathy compared to an age-matched control group 18. However, empathy significantly declines over the course of medical school 10. The precise underlying causes of this decline are not well understood, and multiple factors likely play a role. The decrease has been attributed to a curriculum that promotes the objectification of the patient 19, increasing workload, mistreatment by supervisors, and lack of emotional support 6, 20. High levels of burnout, personal distress, depression and anxiety have also been found to contribute to the erosion of empathy in medical school 7, 20. Notably, the decline in empathy is not consistent across students. A longitudinal study of 446 medical students found two distinct groups, with 70% showing a significant decline on the Jefferson Scale of Physician Empathy, and 30% seeming to have protective factors that neutralize the erosion of empathy 10. This study demonstrated that individuals in patient oriented specialties showed less decline in empathy than those in technology oriented specialties, and suggested that students with individual traits that protect against empathy erosion self-select into the more patient focused specialties 10. This could be the case, or it could be that training for patient focused areas places more emphasis on skills such as listening to the patient and how to counteract objectification of the patient, important to maintaining empathy in a patient-physician interaction. Additionally, greater perceived social support from faculty and greater satisfaction with the learning quality of the environment have been associated with increased resilience to burnout, and high levels of stress and fatigue have been associated with decreased resilience to burnout 21. As increased burnout has previously been associated with decreased empathy in medical students 22, it is possible that these protective factors might also contribute to maintaining empathy. Empathy is a natural socio-emotional competency that has evolved with the mammalian brain to form and maintain social bonds, and which encompasses different components 13. Affective sharing, the first element of empathy to appear during ontogeny, refers to the unconscious sharing of the affective state of another, which can be assessed by measures of concordance of skin conductance (an index of autonomic arousal) between two individuals 23. Empathic understanding entails the conscious awareness of the emotional state of another person. Empathic concern refers to a motivation to care for someone in need. Successful emotion regulation enables the control of emotion, drive and motivation in the service of adaptive behavior. Even though these components are intertwined and not independent of one another, it is helpful to consider them separately, as each contributes to various aspects of the experience of empathy, and could be the target of specific interventions to promote clinical empathy in medical students 24. Recent work in social neuroscience using functional neuroimaging demonstrates that the affective, cognitive and regulatory components of empathy involve interacting neural circuits 25. Empathic arousal is mediated by strong bidirectional connections between the brainstem, amygdala and sensory cortices, as well as connections with the hypothalamus, insula and somatosensory cortex 13, 24. The cognitive aspects of empathy, such as emotion understanding and emotion regulation, are closely related to processes involved in perspective taking, self-regulation, and executive attention subserved by the medial prefrontal cortex, dorsolateral prefrontal cortex and temporo-parietal junction. Finally, the ability to feel concern and care for others has deep evolutionary roots that likely evolved in the context of parental care 26. Its neural underpinnings are found in subcortical neural systems similar to those known to regulate maternal behavior, especially the hypothalamus and orbitofrontal cortex 27. These components differently contribute to the experience of clinical empathy. Affective sharing may act as a gain antecedent to empathic understanding, while cognitive components are important for representing the mental states of self and other, necessary to make decisions in a medical context 24. Importantly, the type of emotion regulation an individual employs largely determines whether cognitive resources are drained or primed 28. Specifically, research shows that a detached perspective can quickly dampen emotional reactions or filter out emotional information. This can be adaptive to a surgeon while operating on his anesthetized patient, but maladaptive when the same physician interacts with his patient after the surgery 28. This example illustrates the flexibility of emotion regulation in clinical settings, depending on both the physician's goals and the patient's needs. The perception of pain in others acts as an empathic signal, alerting individuals that another person is at risk, attracting their attention and motivating social behaviors. The neural response to the pain and distress of others, a situation familiar to physicians, has been used in social neuroscience research as a window into the neurobiological underpinnings of empathy. Several regions involved in the experience of physical pain, including the anterior cingulate cortex, insula, periaqueductal gray, orbitofrontal cortex and amygdala, are activated by the perception or even the imagination of another individual in pain 29. Importantly, the pattern of neural response is highly flexible and can be modulated by a number of contextual, cognitive, social and interpersonal factors 25. In the context of medicine, two neuroimaging experiments examined the neurophysiological response to the perception of pain in physicians 30, 31. Physicians as well as matched non-physician controls underwent functional magnetic resonance imaging while watching videos of needles being inserted into another person's body parts (face, hands and feet), as well as videos of the same areas being touched by a cotton bud 30. Physicians showed significantly less activation in brain areas involved in empathy for pain (anterior cingulate cortex, insula) than did non-physicians. In addition, physicians showed significantly greater activation in areas involved in executive control, self-regulation, and mental states understanding. These findings suggest less empathic arousal and greater cognitive regulation of an emotional response among the physicians, and indicate that physicians' down-regulation of the pain response dampens their negative arousal to the pain of others. This may have beneficial consequences by freeing up cognitive resources necessary for being of assistance and perhaps even for expressing empathic concern. These results may also inform individual differences in empathic decline and professional distress. Meta-analyses show that clinicians' distress is a key determinant of empathy decline 6. Medical students who are most vulnerable to professional distress, which may lead to emotional exhaustion, detachment and a low sense of accomplishment, may be those who have difficulties regulating their negative emotions. On the other hand, students with overly suppressed pain responses and insufficient negative arousal will also have problems with empathy. Some modicum empathic arousal (or affective sharing) may be necessary to help physicians attune to and empathically understand patients' emotions. A positive emotional reappraisal requires emotional content from the patient to be reinterpreted, molding potentially important information once it is available 28. Empathic disposition varies across individuals, and these differences are likely in part accounted for by interactions between an individual's life history, psychological traits and genetic makeup. Attachment is one construct, first proposed by Bowlby 32, which appears to reside at the interface of all three of these determinants. Attachment theory offers a compelling framework for understanding one's capacity to connect with others and develop supportive relationships as coping resources, and predicts individual differences in empathy 33. Security of attachment correlates with the individual degree of empathy and successful emotion regulation, and is inversely related to pain report and emotional distress 34. Empirical research also indicates that attachment security provides a foundation for empathic concern and caregiving 35. Importantly, these attachment styles are relatively stable across the lifespan. In recent years, a great deal of work has begun to reveal some of the underlying neuroanatomical and neurochemical foundations of attachment-related processes and the variance in such attributes both between and within species 36. Such research has identified a number of neuropeptides that are clearly involved in an array of attachment-related social behaviors, including opioids, vasopressin and oxytocin. Oxytocin, for example, has been demonstrated to play a central role in the initiation of maternal behaviors, social recognition and pair bonding in rodents 37. Studies in humans have demonstrated that oxytocin infusion can modulate a number of attachment-related behaviors, including trust, generosity, empathic concern, and empathic accuracy 38. Oxytocin administration selectively reduces emotional arousal to threatening social images 39 and differentially modulates visual attention toward social signals of positive approach 40. Moreover, it appears that individuals lacking high quality social connections show significantly reduced responses to oxytocin administration 39, which may reflect reduced receptor sensitivity. Research into the influence of genetic variation within the oxytocin receptor has provided converging evidence of the role that oxytocin plays in human social behavior. Polymorphisms within the oxytocin receptor have been shown to be related to affiliative behavior, behavioral and dispositional empathy, and perceived social connectedness 41. Similarly, genetic variation in the oxytocin receptor is related to decreased neuroendocrine and autonomic reactivity to social stress and interacts with perceived social support to dampen physiological reactivity to social-evaluative threat 41. Importantly, this does not suggest that empathy-related behaviors are genetically determined. Particular alleles in the oxytocin receptor system (or vasopressin or opioid systems) previously considered “vulnerability genes” can actually be viewed as “plasticity genes” in that they allow some individuals to be more sensitive to the social environment in general 42. This is consistent with the observation of large individual differences in what can be viewed as a “biological sensitivity to context”, in which people are especially interpersonally adept in socially supportive environments and especially anxious and withdrawn in noxious environments 43. A meta-analysis of studies that evaluated various contextual influences on patient outcomes found that physicians who adopted a reassuring warm and friendly approach were more effective than those employing detached concern 44. Empathic medical care may provide patients with a sense of personal connection and perceived control over their health that results in more effective coping strategies, influencing health outcomes through chronic modulation of physiological stress responses. In fact, a quarter century of research in neuroendocrinology and stress physiology has clearly demonstrated that the perception of social support and stressor controllability can have profound influences on the hormonal, cardiovascular and immunological response to a broad array of physiological responses in both humans and non-human animal models 45. Indeed, perceived controllability over a stressor is associated with prefrontal cortex mediated regulation of limbic (amygdala and hypothalamus) and brainstem (dorsal raphe nucleus) structures associated with neuroendocrine and autonomic nervous system reactivity 45. This provides a direct pathway through which the perception of one's ability to control aspects of his/her disease is capable of regulating physiological processes ranging from glucose metabolism and blood pressure to immunomodulation and neurogenesis 46. Physicians routinely present information to their patients capable of generating substantial physiological stress responses. In many such cases, the physician-patient relationship represents the front line in the battle against disease, as it has the potential to shape the endogenous responses to illness-related stress that, in some cases, can have effects similar to pharmacological interventions 3. Empathic concern, as opposed to detached concern, allows physicians to better understand their patients and modify their approach to fit the individuals they are attempting to treat. Given the past quarter century of work showing that quality emotional connection has comparable influences on health outcomes as obesity and hypertension 47, it is clear that empathic approaches are needed for patient care. The current view of empathy in clinical practice is limited and focused primarily on self-reports of physicians, with little understanding of the mechanisms which contribute to declining empathy during medical school and a lack of empathy generally within the medical field. A better scientific understanding of the connections between the mechanisms involved in interpersonal sensitivity, empathy, and care-giving behavior is needed to help physicians maintain high levels of empathy in clinical practice while limiting burnout and personal distress 48. This understanding should be incorporated into research on the organizational and contextual factors that shape medical professionalization. It is now possible to bring to the study of clinical empathy a risk-vulnerability approach that promises to be both more precise and more comprehensive than previous research. This approach will increase our capacity to design better institutions and educational interventions to support empathy within clinical practice and to protect against its decline. Some interventions to improve empathy and communication between physicians and patients have already shown positive effects on both physicians' professional satisfaction and well-being. There is a need, however, for dedicated research to respond to the vital call for empathy enhancement in medicine with programs using social neuroscience-based knowledge. The writing of this paper was supported by grants from the John Templeton Foundation (The Science of Philanthropy Initiative and Wisdom Research at the University of Chicago) and from National Institutes of Health (R01MH087525; R01MH084934) to J. Decety.

World Psychiatry · 97 citationsread the source →

Problematic Internet use: an overview

The “global village”, a metaphor used to describe how the Internet has shortened distances and facilitated the flow of information, has grown to over one billion users 1. Statistics from across the world highlight its reach and penetrance: 90% of South Korean households connect to high-speed, inexpensive broadband 2; Londoners spend an average of 45 days a year online, more than they spend watching TV 3; and the rate of increase in the number of Internet users in Africa and the Middle East exceeded 1,300% between 2000 and 2009 4. For the majority of Internet users, the World Wide Web represents a tremendous wellspring of opportunity that enhances well-being. For others, however, it can lead to a state that appears to meet the DSM definition of a mental disorder, described as a “clinically significant behavioral or psychological syndrome…that is associated with present distress… or with a significantly increased risk of suffering death, pain, disability, or an important loss of freedom” 5. Scientific understanding of that state has lagged behind media attention 6, in part because of inconsistency in defining the problem 7, disagreement about its very existence 8, and the variable research methodology used in studying it. Still, a body of data by scientists from the East and West (with the East increasingly leading the way) tells a cautionary tale about the Internet's potential to bring about psychological harm. In 1996, the psychologist K. Young became the first to publish a detailed case report of problematic Internet use 9. Her “patient zero” was a non-technologically oriented 43-year-old homemaker with a “content home life and no prior addiction or psychiatric history”, who, within three months of discovering chat rooms, was spending up to 60 hours per week online. She reported feeling excited in front of the computer, and depressed, anxious, and irritable when she would log off. She described having an addiction to the medium “like one would to alcohol”. Within one year of purchasing her home computer, she was ignoring household chores, had quit social activities she used to enjoy, and had become estranged from her two teenage daughters and her husband of 17 years. Based on this and other patients she interviewed, Young proposed the first set of diagnostic criteria for what she termed “Internet addiction”. She modeled them on the DSM-IV definition for substance dependence because of similarities she observed with the states of tolerance (needing more of the substance to achieve the same effect) and withdrawal (psychological and physical discomfort upon reducing or stopping the substance) 9. Others conceptualized problematic Internet use as a behavioral addiction not involving an intoxicant 10, and Young subsequently updated her definition, adapting the DSM-IV criteria for pathological gambling, an impulse control disorder often described as a behavioral addiction, into her Diagnostic Questionnaire 11 (Table 1). The questionnaire, which required at least five of the eight criteria be met for the Internet addiction diagnosis, has not received adequate psychometric testing. Shapira et al 12 proposed five years later a more inclusive diagnostic schema in the general style of the impulse control disorders. They argued that definitions based solely on substance dependence or pathological gambling were too narrow to capture the population of problematic Internet users and could lead to premature conclusions about the new disorder and the patients. They eschewed the “Internet addiction” label for lack of scientific proof for true addiction and favored the less controversial “problematic Internet use”, defining it as: a) maladaptive preoccupation with Internet use, experienced as irresistible use for periods of time longer than intended; b) significant distress or impairment resulting from the behavior; and c) the absence of other Axis I pathology that might explain the behavior, such as mania or hypomania. To date, only two studies have attempted to develop diagnostic criteria empirically by testing them against the diagnosis made on the basis of a systematic psychiatric interview. Ko et al 13 tested a set of criteria in 468 Taiwanese high school students. Starting with 13 candidate criteria, they eliminated those with low diagnostic accuracy, and determined that a cutoff of six out of the nine remaining criteria had the best diagnostic accuracy while maintaining high specificity (97.1%) and acceptable sensitivity (87.5%). The criterion for functional impairment was listed separately as criterion B and was required for the diagnosis (Table 2). In a second study, Ko et al 14 confirmed the diagnostic accuracy of their criteria in an older cohort of 216 Taiwanese college students. However, the relatively small size of both studies and the non-representative nature of the groups studied limit the applicability of the proposed criteria to the general population. Several assessment scales have been proposed to screen for, and help diagnose, problematic Internet use. As a group, these instruments show no consensus on the underlying dimensions that constitute the condition 6,15. In addition to Young's Diagnostic Questionnaire, two are in relatively common use in research and/or clinical settings: Young's Internet Addiction Test 16 and the Chen Internet Addiction Scale 17. Young's Internet Addiction Test 16 consists of 20 “how-often” questions, each rated on a scale of 1 to 5 (1=rarely; 2=occasionally; 3=frequently; 4=often; 5=always.) A score of 80 or above is consistent with problematic use (Table 3). The psychometric properties of the instrument were studied in 86 subjects 18. Six factors were extracted from the questionnaire: salience, excessive use, neglect of work, anticipation, lack of control, and neglect of social life. These factors showed good concurrent validity and internal consistency. Salience explained most of the variance and was also found to be the most reliable as indicated by its Cronbach's alpha. However, the selection bias introduced by online recruitment and the small size of the study limit its value. The Chen Internet Addiction Scale 17 is a self-report instrument composed of 26 items rated on a 4-point Likert scale (adapted in Table 4). It assesses five domains of Internet-related problems: compulsive use, withdrawal, tolerance, interpersonal and health consequences, and time management difficulties. Scores range from 26 to 104. In a study of 454 Taiwanese adolescents who completed the scale and received a structured diagnostic interview, a cutoff of 64 was shown to have high diagnostic accuracy and specificity (88% and 92.6%, respectively) 19. The internal reliability of the scale and subscales in the original study ranged from 0.79 to 0.93 17. Due to the lack of consensus on diagnostic criteria and the dearth of large epidemiological studies, the prevalence of problematic Internet use in the general population has not been established. Overall, prevalence surveys conducted in various countries fall into two main categories, online vs. offline studies, with the former typically yielding higher rates, most likely because of inherent selection bias 20. Only two epidemiological studies exploring the prevalence of problematic Internet use in the general population have been published. One was conducted in the US, the other in Norway 20,21. The US study used random-digit telephone dialing (cellular phone numbers were not included) to interview 2,513 adults taken from all 50 states in a manner proportional to the population in each state 20. More than half of the people reached agreed to be interviewed. Participants’ average age was 48, and 51% fell in the middle class socioeconomic stratum. 68.9% were regular Internet users. The authors’ diagnostic definition, based on published criteria and on similarities with impulse control disorders, substance dependence and obsessive-compulsive disorder, required: a) Internet use that interferes in personal relationships; b) preoccupation with the Internet when offline; c) unsuccessful attempts at quitting or cutting down; and d) staying online longer than intended. This definition yielded a point prevalence of 0.7%. Less stringent definitions yielded higher prevalence rates, and individual features consistent with problematic Internet use were endorsed by as many as 13.7% (respondents who found it hard to stay offline for days in a row). In the second study, Bakken et al 21 mailed Young's Diagnostic Questionnaire to 10,000 inhabitants of Norway, randomly selected from a database of the entire population. 3,399 completed questionnaires were returned (a somewhat lower response rate than the US study). Recipients of the mailed questionnaire also had the option of completing it online. Among respondents, 87% were Internet users. The prevalence of “addicted Internet use” (≥5 questions answered “yes”) was calculated to be 1%, whereas the prevalence of “at risk” Internet use (3–4 questions answered “yes”) was 5.2%. Multivariate analysis showed young age, male gender, higher educational achievement, and financial stress to be positively associated with “problematic Internet use” (defined by the authors to include both “Internet addicts” and “at risk” respondents). Prevalence rates among adolescents have been researched more extensively, perhaps because the so-called “digital natives” grew up incorporating the Internet in many aspects of life and as a result are perceived to be at higher risk. However, even when online-based surveys are excluded, the results can vary widely and are difficult to compare, due to differences in Internet access, recruitment methodology, the exact age bracket studied, and the definitions utilized. Considering only relatively large and offline studies, research from China 22, South Korea 23,24, Greece 25, Norway 26, and Iran 27 has yielded prevalence estimates ranging between 2% and 11%. Problematic Internet use has not been incorporated into large-scale epidemiological studies aimed at estimating the relative prevalence of mental disorders. Still, a review of published studies reveals that the presence of other psychiatric conditions in patients with problematic Internet use is the rule rather than the exception 6. The studies, however, were not designed or statistically powered to detect the nature of the association (cause, effect, or independent). In Bakken's general-population study 21, based on subjects’ self-report, 41.4% of Internet “addicts” reported feelings of depression in the 12-month period prior to the study, compared to 15.8% of non-problematic users. Sleep disturbances, anxious feelings, and alcohol and substance abuse were also more common (38.6% vs. 26.4%, 36.4% vs. 5%, and 13.6% vs. 1.1%, respectively). However, the questions used to assess co-occurring psychological impairment were not based on established criteria for mood, sleep, anxiety, or substance use disorders. Two US case series involved face-to-face interviews of adult patients with problematic Internet use. Black et al 28 assessed 21 subjects with the Diagnostic Interview Schedule and found the lifetime prevalence of mood disorders and major depression to be 33% and 15%, respectively. Further, 38% had a lifetime substance use disorder and 19% had a lifetime diagnosis of anxiety disorder. In a case series that included 20 patients, Shapira et al 29 found a very high (70%) lifetime prevalence for bipolar affective disorder, type I or II, compared with 15% for major depression. Fifty-five percent had a lifetime prevalence of substance abuse, and 45% met criteria for social anxiety disorder. Fifty percent of subjects had a lifetime diagnosis of an impulse control disorder. The authors highlight their observation that patients’ Internet-related symptoms were more impulsive and egosyntonic than compulsive and egodystonic, concluding that problematic Internet use resembles the DSM-IV definition of an impulse control disorder more closely than that of obsessive-compulsive disorder. Our clinical experience supports this conclusion. As a group, surveys conducted among high school and college students show similarly high comorbidity rates with mood and anxiety disorders, but a link between attention-deficit/hyperactivity disorder (ADHD) and problematic Internet use seems more obvious than among adults. One study in 752 South Korean elementary students found that 33% of those with ADHD also met criteria for problematic Internet use 30. Another study in 216 Taiwanese college students showed that 32% subjects with problematic Internet use also had ADHD compared to only 8% of regular Internet users 31. Whether Web-based activities appeal to the short attention span of ADHD sufferers or whether excessive Internet use may cause inattention remains to be elucidated. The clinical evaluation of the patient with problematic Internet use should include a careful assessment of the comorbid conditions frequently present. Those should then be treated according to established treatment guidelines. To the extent that the Internet-related problem may stem from another diagnosis (e.g., a patient with severe social anxiety who starts leading a “virtual” life at the expense of offline interactions), it might improve as the primary condition is addressed. Pharmacotherapeutic and psychotherapeutic interventions specific to problematic Internet use have not yet received adequate testing in large, rigorous studies. Pharmacotherapy often begins with selective serotonin reuptake inhibitors (SSRIs). However, while effective in treating obsessive-compulsive disorder, SSRIs have shown mixed results in impulse control disorders 32,33,34,35–36. In light of the greater similarity between problematic Internet use and impulse control disorders compared to obsessive-compulsive disorder 29, it is unclear whether SSRIs will ultimately prove beneficial, and no double-blind placebo-controlled studies have been published so far. One discontinuation study tested escitalopram, 20 mg/day, in 19 subjects with problematic Internet use 37. During the 10-week open-label phase, subjects showed significant decreases in weekly hours spent online (from a mean of 36.8 hours to 16.5 hours) and improvement in global functioning. At the end of the 10 weeks, subjects were blindly randomized to either continued escitalopram treatment or to placebo. Beyond that, they were followed for 9 weeks. No significant difference was seen between the two groups at the end of the second phase, as gains achieved at week 10 were maintained in both treatment groups. The authors speculate that nine weeks may have not been sufficient for the effect to be lost in the placebo group or for additional gains to be made in the escitalopram group, but do not rule out the possibility that the improvement seen in the open-label phase may have been a placebo response. One case study reported successful treatment with naltrexone 38, a drug that has shown benefit in other impulse control disorders 39,40. The patient was a 31 year old male with compulsive cybersexual behavior who had failed antidepressants, group and individual psychotherapy, Sexual Addicts Anonymous, and pastoral counseling. Naltrexone (150 mg/day), gradually added to a stable dose of sertraline which on its own had been ineffective in treating his problematic Internet use, helped induce a three-year remission. The authors hypothesize that, by blocking the capacity of endogenous opioids to trigger dopamine release in response to reward, naltrexone may block the reinforcing nature of compulsive Internet sexual activity. Another case study reported the successful use of an atypical antipsychotic, quetiapine, 200 mg/day, gradually added to citalopram, in a 23 year old subject with problematic Internet use 41. The improvement was maintained at four-month follow-up. More recently, a study tested methylphenidate in 62 children with ADHD who were Internet video game players 42. Participants’ average age was around 9. After 8 weeks of treatment (average dose 30.5 mg/day), Internet usage decreased significantly and correlated with reduction in ADHD symptoms. The authors cautiously suggest that methylphenidate might be beneficial as a treatment for problematic Internet use, especially when co-occurring with ADHD. Of the psychotherapy approaches used, cognitive behavioral therapy (CBT) has received the most empiric investigation. The largest study enrolled 114 adult subjects and employed CBT interventions including: keeping a daily log of Internet activity, teaching time management skills, and confronting cognitive distortions and rationalizations frequently used by patients to justify continued Internet usage, such as “just a few more minutes won't hurt” 43. Most subjects were able to control their symptoms by the eighth session, and improvement was sustained over a 6-month follow-up. For children and adolescents, family-based interventions that improve communication and teach family monitoring of Internet use can be helpful 44. However, the intensive (and typically very expensive) residential treatment options that have received much media attention have undergone little empiric investigation to warrant a strong recommendation 2,45. The same applies to online treatment websites that encourage the person with problematic Internet use to “click here if you are addicted to the Internet”. For a medium that has so radically changed the way we conduct our lives, the Internet's effects on our psychological health remain understudied. Simply stating that similar fears were raised when the radio, movies and early video games were introduced is not sufficient: the immersive and interactive qualities of the virtual world, and its sheer penetrance, make it potentially more serious. Also deserving of exploration are the more subtle psychological changes that occur in the virtual world, such as online disinhibition and increased risk-taking 46. Those changes are not necessarily evidence of “Internet addiction”, and may not be pathological, but, as important features of the new virtual psychology, should also be studied. As our field continues to debate whether their condition belongs in the next edition of the DSM 47, patients continue to present with symptoms born out of the digital age, and their symptoms are changing as the technology evolves from browsers, to “crackberries”, to “smart phones” that combine texting, talking, video games, and browsing in one device that to many is like a new appendage. Even the “problematic Internet use” designation now seems outdated, which is why some have wisely opted for “pathological use of electronic media”, instead 47. Technology, like media outlets, remains far ahead of scientific investigation. Given the dramatic changes that our society is undergoing as a result of the Internet revolution, it behooves us to try to bridge the gap.

World Psychiatry · 340 citationsread the source →

Neighborhood safety, collective efficacy, and obesity in women with young children.

Objective: To test the hypothesis that mothers of young children would have a higher prevalence of obesity if they lived in neighborhoods that they perceived as unsafe or as having a low level of collective efficacy. Research methods and procedures: Using data from the Fragile Families and Child Wellbeing Study, a cross-sectional analysis was conducted of 2445 women living in 20 large (population > or = 200,000) U.S. cities. BMI was measured on 72% and self-reported on 28%. Perception of neighborhood safety was assessed with the Neighborhood Environment for Children Rating Scales. The collective efficacy measure was adapted from the Project on Human Development in Chicago Neighborhoods. Results: Thirty percent of the women were married, 38% lived below the U.S. poverty threshold, and 66% reported no education beyond high school. Approximately one-half of the women were non-Hispanic black, and one-fourth were Hispanic (any race). After adjustment for sociodemographic factors (household income, education, race/ethnicity, age, and marital status), smoking, depression, and television time, the prevalence of obesity (BMI > or = 30 kg/m2) increased across tertiles of neighborhood safety from safest to least safe (37% vs. 41% vs. 46%, p = 0.004) but did not differ across tertiles of collective efficacy from highest to lowest (41% vs. 40% vs. 42%, p = 0.67). Discussion: In a national sample of women with young children, obesity was more prevalent among those who perceived their neighborhoods to be unsafe.

Obesity (Silver Spring, Md.) · 85 citationsread the source →

Effects of tesamorelin (TH9507), a growth hormone-releasing factor analog, in human immunodeficiency virus-infected patients with excess abdominal fat: a pooled analysis of two multicenter, double-blind placebo-controlled phase 3 trials with safety extension data.

Context: HIV patients treated with antiretroviral therapy (ART) often develop increased visceral adipose tissue (VAT). Objective: Our objective was to perform a pooled analysis of two phase-3 studies of tesamorelin in ART-treated HIV patients with excess abdominal fat. Design and setting: Two multicenter, international studies were conducted; a 26-wk randomized, placebo-controlled primary intervention phase was followed by a 26-wk safety extension. Patients: A total of 806 ART-treated HIV patients with excess abdominal fat were randomized in a 2:1 fashion to receive tesamorelin 2 mg (n = 543) or placebo (n = 263) sc daily. At wk 26, patients initially on tesamorelin were rerandomized to 2 mg tesamorelin (T-T group, n = 246) or placebo (T-P, n = 135) for an additional 26 wk, whereas patients on placebo were switched to tesamorelin (P-T, n = 197). Interventions: Tesamorelin (GHRH(1-44)) at a dose of 2 mg or identical placebo, sc, was given daily. Main outcome measure: We evaluated percent change in VAT by computed tomography scan at wk 26. Results: At wk 26, VAT decreased significantly in tesamorelin-treated patients (-24 +/- 41 vs. 2 +/- 35 cm(2), tesamorelin vs. placebo, P < 0.001; treatment effect, -15.4%). No significant changes were observed in abdominal sc adipose tissue (-2 +/- 32 vs. 2 +/- 29 cm(2), P = 0.08; treatment effect, -0.6%). Treatment with tesamorelin resulted in significant decreases in triglycerides (-37 +/- 139 vs. 6 +/- 112 mg/dl, P < 0.001; treatment effect, -12.3%) and cholesterol to high-density lipoprotein ratio (-0.18 +/- 1.00 vs. 0.18 +/- 0.94, P < 0.001; treatment effect, -7.2%) vs. placebo. Tesamorelin improved body image [belly appearance distress (P = 0.002)], patient rating of belly profile (P = 0.003), and physician rating of belly profile (P < 0.001). Mean IGF-I increased 108 +/- 112 vs.-7 +/- 64 ng/ml (P < 0.001 vs. placebo). At wk 52, decreases in VAT [-35 +/- 50 cm(2) (-17.5 +/- 23.3%)], waist circumference (-3.4 +/- 6.0 cm), triglycerides (-48 +/- 182 mg/dl), cholesterol (-8 +/- 38 mg/dl), and non-high-density lipoprotein (-7 +/- 38 mg/dl) were maintained (all P < 0.001 vs. original baseline) in the T-T group. Treatment with tesamorelin was generally well tolerated. No clinically meaningful differences were observed between groups in glucose parameters at wk 26 and 52. Conclusions: Treatment with tesamorelin reduces VAT and maintains the reduction for up to 52 wk, preserves abdominal sc adipose tissue, improves body image and lipids, and is overall well tolerated without clinically meaningful changes in glucose parameters.

The Journal of clinical endocrinology and metabolism · 74 citationsread the source →

An attachment perspective on psychopathology

Attachment theory 1,2,3 has proven to be a very fruitful framework for studying emotion regulation and mental health. In particular, research on adult attachment processes and individual differences in attachment orientations has provided strong evidence for the anxiety-buffering function of what Bowlby 2 called the attachment behavioral system and for the relevance of attachment-related individual differences to coping with stress, managing distress, and retaining psychological resilience 4. In this paper, we offer a brief overview of the attachment perspective on psychopathology. Following a brief account of attachment theory's basic concepts, we review research findings showing that attachment insecurities — called attachment anxiety and avoidance in the theory — are associated with mental disorders, and that increases in attachment security are an important part of successfully treating these disorders. Bowlby 2 claimed that human beings are born with an innate psychobiological system (the attachment behavioral system) that motivates them to seek proximity to significant others (attachment figures) in times of need. Bowlby 1 also outlined major individual differences in the functioning of the attachment system. Interactions with attachment figures who are available in times of need, and who are sensitive and responsive to bids for proximity and support, promote a stable sense of attachment security and build positive mental representations of self and others. But when a person's attachment figures are not reliably available and supportive, proximity seeking fails to relieve distress, felt security is undermined, negative models of self and others are formed, and the likelihood of later emotional problems and maladjustment increases. When testing this theory in studies of adults, most researchers have focused on the systematic pattern of relational expectations, emotions, and behavior that results from one's attachment history — what Hazan and Shaver 5 called attachment style. Research clearly indicates that attachment styles can be measured in terms of two independent dimensions, attachment-related anxiety and avoidance 6. A person's position on the anxiety dimension indicates the degree to which he or she worries that a partner will not be available and responsive in times of need. A person's position on the avoidance dimension indicates the extent to which he or she distrusts relationship partners’ good will and strives to maintain behavioral independence, self-reliance, and emotional distance. The two dimensions can be measured with reliable and valid self-report scales (e.g., 6), and they are associated in theoretically predictable ways with relationship quality and adjustment 4. Mikulincer and Shaver 4 proposed that a person's location in the two-dimensional conceptual space defined by attachment anxiety and avoidance reflects both the person's sense of attachment security and the ways in which he or she deals with threats and distress. People who score low on these dimensions are generally secure and tend to employ constructive and effective affect-regulation strategies. Those who score high on either the attachment anxiety or the avoidance dimension (or both) suffer from insecurity and tend to rely on what Cassidy and Kobak 7 called secondary attachment strategies, either deactivating or hyperactivating their attachment system in an effort to cope with threats. According to Mikulincer and Shaver 4, people scoring high on avoidant attachment tend to rely on deactivating strategies — trying not to seek proximity, denying attachment needs, and avoiding closeness and interdependence in relationships. These strategies develop in relationships with attachment figures who disapprove of and punish closeness and expressions of need or vulnerability 8. In contrast, people scoring high on attachment anxiety tend to rely on hyperactivating strategies — energetic attempts to achieve proximity, support, and love combined with lack of confidence that these resources will be provided and with resentment and anger when they are not provided 7. These reactions occur in relationships in which an attachment figure is sometimes responsive but unreliably so, placing the needy person on a partial reinforcement schedule that rewards persistence in proximity-seeking attempts, because they sometimes succeed. Individual differences in attachment styles begin in interactions with parents during infancy and childhood (e.g., 9). However, Bowlby 3 claimed that meaningful relational interactions during adolescence and adulthood can move a person from one region to another of the two-dimensional conceptual space defined by attachment anxiety and avoidance. Moreover, a growing body of research shows that attachment style can change, subtly or dramatically, depending on current context, recent experiences, and recent relationships (e.g., 10,11). According to attachment theory, interactions with inconsistent, unreliable, or insensitive attachment figures interfere with the development of a secure, stable mental foundation; reduce resilience in coping with stressful life events; and predispose a person to break down psychologically in times of crisis 3. Attachment insecurity can therefore be viewed as a general vulnerability to mental disorders, with the particular symptomatology depending on genetic, developmental, and environmental factors. Mikulincer and Shaver 4 reviewed hundreds of cross-sectional, longitudinal, and prospective studies of both clinical and non-clinical samples and found that attachment insecurity was common among people with a wide variety of mental disorders, ranging from mild distress to severe personality disorders and even schizophrenia. Consistently compatible results have also been reported in recent studies. For example, attachment insecurities (of both the anxious and avoidant varieties) are associated with depression (e.g., 12), clinically significant anxiety (e.g., 13), obsessive-compulsive disorder (e.g., 14), post-traumatic stress disorder (PTSD) (e.g., 15), suicidal tendencies (e.g., 16), and eating disorders (e.g., 17). Attachment insecurity is also a key feature of many personality disorders (e.g., 18,19). However, the specific kind of attachment insecurity differs across disorders. Anxious attachment is associated with dependent, histrionic, and borderline disorders, whereas avoidant attachment is associated with schizoid and avoidant disorders. Crawford et al 18 found that attachment anxiety is associated with what Livesley 20 called the “emotional dysregulation” component of personality disorders, which includes identity confusion, anxiety, emotional lability, cognitive distortions, submissiveness, oppositionality, self-harm, narcissism, and suspiciousness. Crawford et al 19 also found that avoidant attachment is associated with what Livesley 20 called the “inhibitedness” component of personality problems, including restricted expression of emotions, problems with intimacy, and social avoidance. Another related issue concerning the associations between attachment insecurities and psychopathology is the extent to which attachment insecurities are a sufficient cause of mental disorders. In our view, beyond disorders such as separation anxiety and pathological grief, in which attachment injuries are the main causes and themes, attachment insecurities per se are unlikely to be sufficient causes of mental disorders. Other factors (e.g., genetically determined temperament; intelligence; life history, including abuse) are likely to converge with or amplify the effects of attachment experiences on the way to psychopathology. Consider, for example, the relation between attachment-related avoidance and psychological distress. Many studies of large community samples have found no association between avoidant attachment and self-report measures of global distress 4. However, studies that focus on highly stressful events, such as exposure to missile attacks, living in a dangerous neighborhood, or giving birth to a handicapped infant, have indicated that avoidance is related to greater distress and poorer long-term adjustment 4. Life history factors are also important. For example, the association between attachment insecurity and depression is higher among adults with a childhood history of physical, psychological, or sexual abuse (e.g., 21). Stressful life events, poverty, physical health problems, and involvement in turbulent romantic relationships during adolescence also strengthen the link between attachment insecurity and psychopathology (e.g., 22). The causal links between attachment and psychopathology are also complicated by research findings showing that psychological problems can increase attachment insecurity. Davila et al 23, for example, found that late adolescent women who became less securely attached over periods of 6 to 24 months were more likely than their peers to have a history of psychopathology. Cozzarelli et al 24 found that women who moved in the direction of insecure attachment over a 2-year period following abortion were more likely than other women who had an abortion to have a prior history of depression or abuse. Solomon et al 25 assessed attachment insecurities and PTSD symptoms among Israeli ex-prisoners of war (along with a matched control group of veterans) 18 and 30 years after their release from captivity. Attachment anxiety and avoidance increased over time among the ex-prisoners, and the increases were predicted by the severity of PTSD symptoms at the first wave of measurement. Overall, attachment insecurities seem to contribute nonspecifically to many kinds of psychopathology. However, particular forms of attachment insecurity seem to predispose a person to particular configurations of mental disorders. The attachment-psychopathology link is moderated by a large array of biological, psychological, and socio-cultural factors, and mental disorders per se can erode a person's sense of attachment security. If attachment insecurities are risk factors for psychopathology, then the creation, maintenance, or restoration of a sense of attachment security should increase resilience and improve mental health. According to attachment theory, interactions with available and supportive attachment figures impart a sense of safety, trigger positive emotions (e.g., relief, satisfaction, gratitude, love), and provide psychological resources for dealing with problems and adversities. Secure individuals remain relatively unperturbed during times of stress, recover faster from episodes of distress, and experience longer periods of positive affectivity, which contributes to their overall emotional well-being and mental health. In some of our studies, we have examined the effects of increased security on various indicators of mental health by experimentally activating mental representations of supportive attachment figures (e.g., 26,27). These research techniques, which we 11 refer to as “security priming”, include subliminal pictures suggesting attachment-figure availability, subliminal names of people designated by participants as security-enhancing attachment figures, guided imagery highlighting the availability and supportiveness of an attachment figure, and visualization of the faces of security-enhancing attachment figures. Security priming improves participants’ moods even in threatening contexts and eliminates the detrimental effects of threats on positive moods (e.g., 26). Mikulincer et al 28 found that subliminal priming with security-related words mitigated cognitive symptoms of PTSD (heightened accessibility of trauma-related words in a Stroop-color naming task) in a non-clinical sample. Admoni 29 found that priming the names of each participant's security providers mitigated two cognitive symptoms of eating disorders (distorted body perception and heightened accessibility of food-related words in a Stroop task) in a sample of women hospitalized for eating disorders. There is also preliminary evidence that a sense of security provided by a psychotherapist improves a client's mental health. In a study based on data from the multi-site National Institute of Mental Health (NIMH) Treatment of Depression Collaborative Research Program, Zuroff and Blatt 30 found that a client's positive appraisals of his or her therapist's sensitivity and supportiveness predicted relief from depression and maintenance of therapeutic benefits over an 18-month period. The results were not attributable to patient characteristics or severity of depression. In a one-year prospective study of the effectiveness of residential treatment of high-risk adolescents, Gur 31 found that staff members’ provision of a sense of attachment security in the adolescents resulted in lower rates of anger, depression, and behavioral problems. Although these preliminary findings are encouraging, there is still a great need for additional well-controlled research examining the long-term effects of security-enhancing therapeutic figures on clients’ mental health. According to attachment theory 3, the linkage between attachment insecurities (whether in the form of anxiety, avoidance, or both) and psychopathology is mediated by several pathways. In this section, we will review the most important of these pathways. According to attachment theory and research, lack of parental sensitivity and responsiveness contributes to disorders of the self, characterized by lack of self-cohesion, doubts about one's internal coherence and continuity over time, unstable self-esteem, and over-dependence on other people's approval (e.g., 32,33). Insecure people are likely to be overly self-critical, plagued by self-doubts, or prone to using defenses, such as destructive perfectionism, to counter feelings of worthlessness and hopelessness (e.g., 34). These dysfunctional beliefs about oneself increase insecure people's risk for developing mental disorders. Attachment research has also shown that attachment insecurities are associated with pathological narcissism (e.g., 35). Whereas avoidant attachment is associated with overt narcissism or grandiosity, which includes both self-praise and denial of weaknesses 36, attachment anxiety is associated with covert narcissism, characterized by self-focused attention, hypersensitivity to other people's evaluations, and an exaggerated sense of entitlement 36. According to attachment theory, interactions with available attachment figures and the resulting sense of attachment security provide actual and symbolic supports for learning constructive emotion-regulation strategies. For example, interactions with emotionally accessible and responsive others provide a context in which a child can learn that acknowledgment and display of emotions is an important step toward restoring emotional balance, and that it is useful and socially acceptable to express, explore, and try to understand one's feelings 37. Unlike relatively secure people, avoidant individuals often prefer to cordon off emotions from their thoughts and actions. As a result, they tend to present a façade of security and composure, but leave suppressed distress unresolved in ways that impair their ability to deal with life's inevitable adversities. This impairment is particularly likely during prolonged, demanding stressful experiences that require active coping with a problem and mobilization of external sources of support (e.g., 38). People who score high on attachment anxiety, in contrast, often find negative emotions to be congruent with their attachment-system hyperactivation. For them, “emotion regulation” can mean emotion amplification and exaggeration of worries, depressive reactions to actual or potential losses and failures, and PTSD intrusion symptoms following traumas. Attachment anxiety is also associated with socially destructive outbursts of anger and impulsive, demanding behavior toward relationship partners, sometimes including violence 4. According to attachment theory, recurrent failure to obtain support from attachment figures and to sustain a sense of security, and the resulting reliance on secondary attachment strategies (hyperactivation and deactivation), interfere with the acquisition of social skills and create serious problems in interpersonal relations. Bartholomew and Horowitz 32, using as an assessment device the Inventory of Interpersonal Problems 39, found that attachment anxiety was associated with more interpersonal problems in general. Secure individuals did not show notable elevations in any particular sections of the problems circle, but avoidant people generally had problems with nurturance (being cold, introverted, or competitive), and anxious people had problems with emotionality (e.g., being overly expressive). These problems seem to underlie insecure individuals’ self-reported loneliness and social isolation (e.g., 40) and their relatively low relationship satisfaction, more frequent relationship breakups, and more frequent conflicts and violence 4. Attachment insecurities are associated with a wide variety of mental disorders, ranging from mild negative affectivity to severe, disorganizing, and paralyzing personality disorders. The evidence suggests that insecure attachment orientations (whether anxious or avoidant) are fairly general pathogenic states. Although many of the research findings supporting these ideas are correlational, several studies show a prospective connection between attachment insecurities and vulnerability to disorders. From a therapeutic standpoint, we have reviewed preliminary evidence that situationally heightening people's sense of attachment security reduces the likelihood and intensity of psychiatric symptoms (e.g., PTSD, eating disorders). This evidence underscores the soothing, healing, therapeutic effects of actual support offered by relationship partners, including therapists, and the comfort and safety offered by mental representations of supportive experiences and loving and caring attachment figures. The research evidence causes us to be optimistic about the utility of clinical interventions that increase clients’ sense of attachment security. In the long run, research on attachment security and insecurity, and on the connections between insecurity and psychopathology, should contribute to a strongly social conception of the human mind and its vulnerability to pathologies. In a pioneering chapter on the social neuroscience of attachment processes, Coan 41 proposed what he calls social baseline theory. According to this theory, the human brain evolved in a highly social environment, and many of its basic functions rely on social co-regulation of emotions and physiological states. This means that, rather than conceptualizing human beings as separate entities whose interactions with each other need to be understood, it makes more sense to consider social relatedness and its mental correlates as the normal “baseline” condition. Using this as a starting point helps us to see why experiences of separation, isolation, rejection, abuse, and neglect are so psychologically painful, and why dysfunctional relationships are often the causes or amplifiers of mental disorders.

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Adjustment disorders: the state of the art

The diagnostic category of adjustment disorder was introduced in the DSM-III-R 1. Prior to that, it was called transient situational disturbance. The DSM-IV 2 and ICD-10 3 descriptions of adjustment disorder are broadly similar. The main features are the following: a) the symptoms arise in response to a stressful event; b) the onset of symptoms is within 3 months (DSM-IV) or 1 month (ICD-10) of exposure to the stressor; c) the symptoms must be clinically significant, in that they are distressing and in excess of what would be expected by exposure to the stressor and/or there is significant impairment in social or occupational functioning (the latter is mandatory in ICD-10); d) the symptoms are not due to another axis I disorder (or bereavement in DSM-IV); e) the symptoms resolve within 6 months once the stressor or its consequences are removed. Adjustment disorders are divided into subgroups based on the dominant symptoms of anxiety, depression or behaviour. Since its introduction, the category of adjustment disorder has been the subject of criticism on three fronts. The first was that it constituted an attempt to medicalize problems of living and did not conform to the criteria for traditional disorders such as having a specific symptom profile 4. The second was that it was a “wastebasket diagnosis” which was assigned to those who failed to meet the criteria for other disorders 5. The third was on its diagnostic instability 6 and that its main utility was to serve as a “justification” for diagnosis-based reimbursement operating in the healthcare system of the US. Despite this, the category has been retained in the further classifications, in large measure due to its clinical utility. Adjustment disorder continues to be diagnosed in a range of clinical settings. Consultation-liaison psychiatry is the context in which the diagnosis is most likely to be made. Around 12% of referrals are so diagnosed in university hospitals in the US 7, a figure that resembles that in European hospitals 8. Nevertheless, the frequency with which adjustment disorder is now diagnosed seems to be declining, in parallel with an increase in the diagnosis of major depression 9, possibly due to the availability of psychotropic drugs, especially selective serotonin reuptake inhibitors (SSRIs), that are safer in those who are medically ill than the older agents. So, changes in the prevalence of adjustment disorders may reflect a change in the “culture of prescribing”, stimulating changes in the “culture of diagnosis” 10. Adjustment disorder has been reported to be almost three times as common as major depression (13.7 vs. 5.1%) in acutely ill medical in-patients 11 and to be diagnosed in up to one third of cancer patients experiencing a recurrence 12. In obstetric/gynaecology consultation-liaison 13, adjustment disorders predominated over other mood disorders. Among those assessed in an emergency department following self harm, a diagnosis of adjustment disorder was made in 31.8% of those interviewed, while a diagnosis of major depression was made in 19.5% of cases 14. None of the major epidemiological studies carried out in the community, such as the Epidemiological Catchment Area Study 15, the National Comorbidity Survey Replication 16 or the National Psychiatric Morbidity Surveys 17 included adjustment disorder among the conditions examined. An exception was the Outcome of Depression International Network (ODIN) study 18, which found a prevalence of only 1% for adjustment disorder in five European countries. A possible reason for this was that mild depression was included in the depressive episode category, inflating that category at the expense of adjustment disorder. By contrast, a study of elderly people from the general population 19 found the prevalence of adjustment disorder to be 2.3%, similar to that of major depression. Adjustment disorder is reported to be very common in primary care, but relevant epidemiological studies in this setting are rare and report rates of the disorder range from 1 to 18% 20,21 among consulters with mental health problems. Concerning psychiatric settings, a study of intake diagnoses into outpatient clinics 22, combining clinical evaluation and the use of the Structured Clinical Interview for DSM-IV (SCID, 23), found that adjustment disorder was the most common clinical diagnosis, made in 36% of patients, whereas the diagnosis was made in about 11% of cases using SCID. Among psychiatric inpatients, 9% of consecutive admissions to an acute public sector unit were diagnosed with adjustment disorder 24. Quantifying the prevalence of adjustment disorder in child and adolescent populations is difficult, due to changes in the diagnostic criteria over time 25. In the younger age groups, unlike adults, adjustment disorder carries with it significant morbidity and a poor outcome, frequently developing into major psychiatric illness 25,26. A general population study in Puerto Rico 27 found a rate of 4.2% among 14–16 year old people, while the total psychiatric morbidity was 17.8%. A similar rate was found in children aged 8–9 in Finland 28. Among outpatients, figures of 5.9–7% have been reported 29,30. In child liaison psychiatry, over one third of those with recent onset diabetes were so diagnosed 31, making it the most common psychiatric disorder to follow this well defined stressor. The current diagnosis of adjustment disorder assumes that there is a stressor which acts as a trigger and that the condition is self-limiting. So, adjustment disorder is closer to the definition of a discrete disorder as proposed by Kendell 32 than most other disorders in psychiatry, since its etiology and course are encapsulated within the diagnosis, while the definition of many other mental disorders is cross-sectional and based on symptoms alone. Yet, the current classifications impose a hierarchical model that assumes equivalence in how adjustment disorder and other diagnoses are construed. As currently classified, adjustment disorder is a sub-threshold diagnosis, that is trumped once the symptom threshold for another diagnosis is met. There is an inherent belief that a sub-threshold condition is less severe than a full-blown disorder such as major depression, the diagnosis by which adjustment disorder is most often superseded. Yet, the evidence for this is lacking, and there is empirical data 33 that, when measures of symptom severity or social functioning are examined, there is no difference between those with mood disorders and adjustment disorder. Furthermore, up to 25% of adolescents with a diagnosis of adjustment disorder engage in suicidal behaviour 34, while among adults with this disorder the figure is 60% 35. Adjustment disorder is the diagnosis in up to one third of young people who die by suicide 36, while among all suicide deaths in the developing world it is the most common diagnosis 37. These data show that, far from being a mild condition, adjustment disorder has a significant impact on behaviour. On the other hand, the current classifications fail to distinguish between adaptive and maladaptive reactions to stress. The DSM-IV tries to address this problem by stating that a diagnosis of adjustment disorder is only made when the distress is of clinical significance 38. There are two components to this: the distress must be in excess of what would normally be expected and/or there is an impairment in social or occupational function. In relation to the first of these, one of the most insightful critics of the DSM-IV, J. Wakefield 39, points out that it would allow the top third in the normal distribution of mood reactivity to be classified as disordered, and that it does not take into account the contextual factors that might cause this excess in distress. For example, the loss of a job for one person might be manageable while for another it could heap poverty on a family resulting in distress that might not be inappropriate under the circumstances. Cultural differences in the expression of emotion also need to be considered. In liaison psychiatry, where the diagnosis of adjustment disorder is most frequently made, a knowledge of “normal” coping with illness in that specific culture is essential and the diagnostic process will be guided by the extent to which an individual's symptoms are in excess of this. Some might argue that the fact of visiting a doctor indicates abnormal distress, yet the tendency to consult is also determined by factors additional to illness, including cultural and personal attitudes to symptoms. So, the mere fact of a consultation should not of itself be taken as a proxy measure of excessive distress. Neither should the decision to refer to psychiatric services, since this too is governed by factors that are not always related to symptom severity (e.g., a wish “to do something” under pressure from a patient in the face of continuing distress). Because adjustment disorder is a diagnosis made in the context of a stressor, there is a danger that any distress following such an event might be labelled as a disorder 40. Clinical judgement, therefore, plays a large part in making the diagnosis of adjustment disorder in the current criterion vacuum and future classifications should accord weight to culture, context and personal circumstances in differentiating normal from pathological distress. The second criterion, requiring impairment in functioning, is arguably a more robust indicator of disorder, since it is this which leads to treatment seeking. For example, the inability to work is potentially a significant indicator of impairment. However, there may be situations where functioning is reduced in the presence of non-pathological reactions. For instance, if the circumstances are especially traumatic, such as the loss of a child, the period of impaired function may be longer than anticipated in those with non-pathological responses. The evaluation of functioning in children places special demands on the assessor, since it has to be set against the demands of the developmental stage, and the degree of dependency and autonomy in key relationships. The presence of pre-existing impairment and extant vulnerabilities, such as learning disability and developmental disorders, must also be considered when making the evaluation. The ICD-10, contrary to the DSM-IV, requires the presence of both excessive symptoms and functional impairment for the diagnosis of adjustment disorder, thus narrowing the application of this category. Because of the hierarchical nature of ICD-10 and DSM-IV, adjustment disorder cannot be diagnosed once the criteria for another condition are met. The condition that most frequently trumps adjustment disorder is major depression/depressive episode. This is evident from studies that compare the clinical with the research approach. For example, in a study of those presenting because of self-harm, a clinical diagnosis of adjustment disorder was made in 31.8% and one of major depression in 19.5% of cases, but using SCID the proportions changed to 7.8% and 36.4% respectively 14. However, there is a point of departure between the two conditions when other variables are considered. Suicidal behaviour occurs earlier in the course of adjustment disorder as compared to major depression 41 and the interval from suicidal communication to completion of suicide is shorter 42. The socio-demographic profile and childhood risk variables differ between the two groups 41. Among adolescents dying by suicide, there is much less evidence of prior emotional or behavioural problems 42. In addition, the readmission rates for those with adjustment disorder are significantly lower than for those with major depression, generalized anxiety or dysthymia 43 and hospitalization is also shorter 6. This highlights the need for the clearer operationalization of adjustment disorder in future classifications. A further but lesser area of potential overlap is with post-traumatic stress disorder (PTSD). The conflation is not so much related to the symptoms of these disorders but to the stressors themselves. There has been an expansion in the stressors that are deemed to trigger PTSD, from those that are potentially life threatening, as originally described, to events that are less traumatic, such as financial problems or watching distressing images on television – a phenomenon called “criterion creep” 44. In clinical practice, a diagnosis of PTSD is often made reflexively 45 once such an event is identified, although adjustment disorder might be a more appropriate diagnosis. Overall, it is clear from the data available that adjustment disorder is sufficiently severe and distinct from other disorders, especially major depression, to from its to that of a full-blown and mental disorder. for the DSM-IV have been The Clinical Interview and the International Interview do not adjustment disorder at The for Clinical in do adjustment disorder, but only at the of the in 13, which with and This the criteria for all other disorders have been and there are no specific with to adjustment disorder to the on clinical The SCID also a with adjustment disorder, but the to that this diagnosis is not made if the criteria for any other mental disorder are with the of it to a In of the very threshold for major depression, in studies using SCID and to be of adjustment disorder, major depression will often adjustment disorder, of the context in which the symptoms have The International Interview also a on adjustment disorder as in that disorder is trumped when any other diagnosis is made. So, while have epidemiological research in psychiatry, the that they are having been for use by cannot be This is especially for a diagnosis such as adjustment disorder, which on clinical judgement, context and course than symptoms alone. As a of the problems with the current of diagnostic have been made to for adjustment disorder. Because there is symptom overlap with major depression, there is a that which for depression might people with adjustment disorder. A of have been for this including the Depression which has been to be an for adjustment disorder and major depression but when compared to SCID has and A study of health with an diagnosis but one which the of adjustment disorder most found with the to a using a coping measure have also been The and Depression has been for in cancer patients, but it does not distinguish between major depression and adjustment disorder problems when the Interview and the were for to for adjustment disorder. The of might have a in adjustment disorder from major depression and has been in one study that disorder more symptoms and a to the mood changes compared to disorder of this is Adjustment disorder cannot be diagnosed in the of a stressor. The event must be and in time to the onset of symptoms. The longer the time period between the event and the onset of the less likely is the diagnosis to be adjustment disorder. For this a period between the event and symptom onset of 3 months in DSM-IV and 1 month in ICD-10 is must be when this is for two those who are often significance to that in were in at the in an at may to an of the The 3 month may to be and it is to the empirical data on which this is Concerning the of there is to the in adjustment disorder from major depression. of those with a diagnosis of adjustment disorder have recent life of those with major depression also report such with more related to problems and to occupational or family stressors in the adjustment disorder while significant, are to be clinically in an since they are not as to major depression or adjustment disorder. the events range in severity from those that are as such as a with a to those that are more This will be by In the to the on adjustment disorder, the ICD-10 that and risk plays a than in other such as PTSD or acute stress reactions. However, it is on what evidence this is By contrast, the DSM-IV is on this The that a model is of and is arguably the most There have been studies adjustment disorder against other disorders to allow about the of and is in the current of The relevant studies be classified in two those adjustment disorder and those diagnoses to adjustment disorder. The prevalence of disorder among those with adjustment disorder in to those with other depressive disorders seems to be not although studies are and Among as a to adjustment disorder in a has also been examined, and was found to be a risk for adjustment disorder while was with the severity of the disorder using that a diagnosis of adjustment disorder, such as or depression, are also of although there is a that these conditions may not be to adjustment disorder due to differences in the in the earlier classifications. such study found that the was between and a symptom and evidence of The in relation to and a of symptoms were by in studies of and The of clear criteria for adjustment disorder in DSM-IV or ICD-10 that weight is to clinical than in most other current of anxiety, poor having onset following a recent stressful event are likely of a diagnosis of adjustment disorder, although it must be in that major depression also is often more when the person is with the such as when about while at other times mood is normal and The of the person from the stressful is with a general in symptoms. In the of those who adjustment disorder in response to illness, changes in mood are related to changes in the illness The more the symptoms are loss of mood reactivity the less likely is the diagnosis of adjustment disorder. A family of depression might also a depressive episode. to the symptom threshold for major depression, it is to a diagnosis of this condition than adjustment disorder. the National for Clinical on depression a period of so as to allow for the of under pressure from the patient and or the “to do a diagnosis of major depression (or generalized may be made and also arise when the stressor, and the is and has of may be on as there is no of if the symptoms are likely to or if they are now of the trigger and major depression. The of a response to should the that this is an adjustment disorder, so that are than in of A further is that what to be a stressor (e.g., a diagnosis of a may be with symptoms as of the diagnosis the patient (e.g., the of treatment to that stressors symptoms might to an diagnosis of major depression. The of the consequences of the stressor in symptoms is in the DSM-IV definition of adjustment disorder. on the of adjustment disorder are by DSM-IV and ICD-10 The are broadly similar in the two classifications from adjustment disorder with they have The is the most common in adults, while the with of or of and are more diagnosed among children and The between adjustment disorder and a normal stress response is based on the severity of symptoms and the impact on functioning into account the nature of the stressor; the personal and context in which it has cultural with to such responses. PTSD and acute stress disorder the presence of a stressor of a that would be for almost and the symptom is also although both of these have been 40. not to such events by developing PTSD and the that other disorders follow to be considered. For those not the PTSD diagnostic but with significant symptoms and/or functional adjustment disorder should be considered a possible may to be an adjustment disorder, because of the sub-threshold of the symptoms or the of functional might be an axis I disorder in that only as a a period of the of an diagnosis of adjustment disorder may be at especially if there are symptoms in of of the stressor. studies have the disorders that are with adjustment disorder, an that is by the fact that the criteria for this disorder axis I Yet, a recent study 19 found that almost of patients with major depression or and adjustment disorder were not significantly The between and adjustment disorder is also of since it may the instability of the adjustment disorder diagnosis. may be for of symptoms such as anxiety and depression, which are in adjustment disorder. such as are and may with mood changes to This may in one study 6 patients with an diagnosis of adjustment disorder were on as having a primary diagnosis of The evidence for the treatment of adjustment disorder is due to the of A further problem is that these are so that of may fail to any due to In are as being the most with the exception that, when stressors are measures may be However, there is a for children and adolescents diagnosed with adjustment disorder, since there is evidence that a of adolescents major mental disorders. measures may be to the person in the stressful A person being at work might to an system or may the of the A person in an might a A person on too much work may from family such as social or in a or may distress. or in groups, the range including and symptoms of the of and and the that the stressor has for the might also symptoms. In who engage in self-harm, in that do not may be of and to behaviour has the evidence was found to be of in older patients a including and was in patients with adjustment disorder to was when to patients with adjustment disorder who stress and among with adjustment disorder In a study of cancer patients similar were found in those with adjustment disorder and other psychiatric Some of these have been in specific medically ill groups, such as those with or in coping have been it is if adjustment disorder, were studies (e.g., and and of life than symptoms were the measures in (e.g., The of adjustment disorder of treatment of anxiety and The use of to these is common are by especially if there has been no from there is evidence to Nevertheless, those with and anxiety may have a when are such as in those with a of There are to the treatment of adjustment disorder and these are on with the anxiety A study a with a found that the of were although more to the including from and other and a on symptoms. A study found that and were while a study of cancer patients with and mood found to a study in primary the response of patients with major depression and with adjustment disorder to using reported changes in functional disability based on Overall, the adjustment disorder was as likely to to However, as this was a the of the is study compared and in with adjustment disorder assigned to an a or and found that all significantly Overall, these studies for the of and arguably for any specific in the of adjustment disorder, but further studies are Adjustment disorders are common mental disorders, especially in consultation-liaison prevalence seems to be in children and in they are with significant morbidity and a than in Suicidal behaviour is common in both adolescents and adults with these disorders, and adjustment disorder is the diagnosis in up to one third of young people who die by There are major problems with the diagnostic criteria for adjustment disorder in both ICD-10 and The most of these is the as This has in being the subject of Furthermore, current classifications fail to on these disorders from normal adaptive reactions to and the diagnosis of major depression in people with reactions to for adjustment disorders are although are likely to be the

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Death Anxiety in the Elderly: The Role of Spiritual Health and Perceived Social Support

Aging as one of the most important periods of life is associated with many challenges including death anxiety. Therefore, the aim of the current study was to investigate the role of spiritual health and perceived social support in predicting death anxiety in the elderly. The present study was a descriptive-correlational one. The study population consisted of the elderly living in Shahrekord in 2020, among whom 385 were selected using convenience sampling method and were assessed by the scales of Templer Death Anxiety, Zemen Perceived Social Support and Paloutzian & Ellison spiritual health. Data were analyzed using correlation coefficient and linear regression analysis in SPSS software version 22. The results indicated that there is a significant relationship between spiritual health (r=-0.51), perceived social support by family (r=-0.37), friends (r=-0.30) and significant other (r=-0.16) with death anxiety in the elderly. The results of linear regression analysis releaved that spiritual health (P=0.001, β=-0.46) and perceived social support by the family (P=0.001, β=-0.29) can predict negatively the death anxiety in the elderly and explain 26.7% of the variance of death anxiety in the elderly. Consequently, counselors and psychologists in the field of aging are suggested to reduce death anxiety in the elderly, using strategies to promote spiritual health and social support. ReferencesAbdel-Khalek, A. M. (2001). Death, anxiety, and depression in Kuwaiti undergraduates. OMEGA-Journal of Death and Dying, 42(4), 309-320.Abdel-Khalek, A. M. (2005). Death anxiety in clinical and non-clinical groups. Death Studies, 29(3), 251-259.Alipour, A., Aliakbari Dehkord, D. M., Amini, F., & Hashemi Jashni, J. A. (2016). Relationship between perceived social support and adherence of treatment in Diabetes Mellitus type 2: mediating role of resiliency and rope. Journal of Research in Psychological Health, 10(2), 53-67. 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B., Rocha, G. P., Fernandez, L. L., de Padua, A. C., & Reppold, C. T. (2018). Association of lower spiritual well-being, social support, self-esteem, subjective well-being, optimism and hope scores with mild cognitive impairment and mild dementia. Frontiers in psychology, 9, 1-10.Ebrahimi, B., Hosseini, M., & Rashedi, V. (2018). The Relationship between social support and death anxiety among the elderly. Elderly Health Journal, 4(2), 37-42.Emamirad, A., Amiri, H. (2018). The Relationship between spiritual health and meaning of life with death anxiety in elders. Aging Psychology, 4(3), 251-261. [Persian]Esmaeilishad, B. (2020). The Effectiveness of self-care training on quality of life, self-care behaviors and blood sugar in elderly lacking self-Care behaviors. Aging Psychology, 6(1), 1-11. [Persian].Fortner, V., Robert A. Neimeyer, B. (1999). Death anxiety in older adults: A quantitative review. Death studies, 23(5), 387-411.Ghasempour, A., Sooreh, J., & Seid Tazeh Kand., M.T (2017). 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The influence of social support and coping on quality of life among elderly with age-related hearing loss. American Journal of Audiology, 26(2), 170-179.Poordad, S., Momeni, K., & karami, J. (2019). Death anxiety and its relationship with social support and gratitude in older adults. Salmand: Iranian Journal of Ageing, 14(1), 26-39. [Persian].Rajabi, G.R., & Bahrani, M. (2001). Factor analysis of death anxiety scale questions. Journal of Psychology, 5 (4), 331-341. [Persian].Razavi, V. (2015). Relationship between social support and hope and death anxiety among the old people of Tehran Omid Cultural Center. International Journal of Life Sciences, 9(2), 65-70.Rocha, A. C. A. L. D., & Ciosak, S. I. (2014). Chronic disease in the elderly: spirituality and coping. Revista da Escola de Enfermagem da USP, 48(2), 87-93.Rostami, M., nosrati, K., Mahdinejad Gorji, G., kabiri, M. (2020). Death anxiety in the elderly: the role of psychological hardiness and practical commitment to prayer. 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Prayer and spiritual well-being in cancer patients. Health Monitor Journal of the Iranian Institute for Health Sciences Research, 5(4), 0-0. [Persian].Sharma, P., Asthana, H. S., Gambhir, I. S., & Ranjan, J. K. (2019). Death anxiety among elderly people: role of gender, spirituality and mental health

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