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Internet-Based Cognitive Behavioral Therapy for Depression: A Systematic Review and Individual Patient Data Network Meta-analysis.

Importance: Personalized treatment choices would increase the effectiveness of internet-based cognitive behavioral therapy (iCBT) for depression to the extent that patients differ in interventions that better suit them. Objective: To provide personalized estimates of short-term and long-term relative efficacy of guided and unguided iCBT for depression using patient-level information. Data sources: We searched PubMed, Embase, PsycInfo, and Cochrane Library to identify randomized clinical trials (RCTs) published up to January 1, 2019. Study selection: Eligible RCTs were those comparing guided or unguided iCBT against each other or against any control intervention in individuals with depression. Available individual patient data (IPD) was collected from all eligible studies. Depression symptom severity was assessed after treatment, 6 months, and 12 months after randomization. Data extraction and synthesis: We conducted a systematic review and IPD network meta-analysis and estimated relative treatment effect sizes across different patient characteristics through IPD network meta-regression. Main outcomes and measures: Patient Health Questionnaire-9 (PHQ-9) scores. Results: Of 42 eligible RCTs, 39 studies comprising 9751 participants with depression contributed IPD to the IPD network meta-analysis, of which 8107 IPD were synthesized. Overall, both guided and unguided iCBT were associated with more effectiveness as measured by PHQ-9 scores than control treatments over the short term and the long term. Guided iCBT was associated with more effectiveness than unguided iCBT (mean difference [MD] in posttreatment PHQ-9 scores, -0.8; 95% CI, -1.4 to -0.2), but we found no evidence of a difference at 6 or 12 months following randomization. Baseline depression was found to be the most important modifier of the relative association for efficacy of guided vs unguided iCBT. Differences between unguided and guided iCBT in people with baseline symptoms of subthreshold depression (PHQ-9 scores 5-9) were small, while guided iCBT was associated with overall better outcomes in patients with baseline PHQ-9 greater than 9. Conclusions and relevance: In this network meta-analysis with IPD, guided iCBT was associated with more effectiveness than unguided iCBT for individuals with depression, benefits were more substantial in individuals with moderate to severe depression. Unguided iCBT was associated with similar effectiveness among individuals with symptoms of mild/subthreshold depression. Personalized treatment selection is entirely possible and necessary to ensure the best allocation of treatment resources for depression.

JAMA psychiatry · systematic review · 599 citationsread the source →

Psychotherapy for depression in older veterans via telemedicine: a randomised, open-label, non-inferiority trial.

Background: Many older adults with major depression, particularly veterans, do not have access to evidence-based psychotherapy. Telemedicine could increase access to best-practice care for older adults facing barriers of mobility, stigma, and geographical isolation. We aimed to establish non-inferiority of behavioural activation therapy for major depression delivered via telemedicine to same-room care in largely male, older adult veterans. Methods: In this randomised, controlled, open-label, non-inferiority trial, we recruited veterans (aged ≥58 years) meeting DSM-IV criteria for major depressive disorder from the Ralph H Johnson Veterans Affairs Medical Center and four associated community outpatient-based clinics in the USA. We excluded actively psychotic or demented people, those with both suicidal ideation and clear intent, and those with substance dependence. The study coordinator randomly assigned participants (1:1; block size 2-6; stratified by race; computer-generated randomisation sequence by RGK) to eight sessions of behavioural activation for depression either via telemedicine or in the same room. The primary outcome was treatment response according to the Geriatric Depression Scale (GDS) and Beck Depression Inventory (BDI; defined as a 50% reduction in symptoms from baseline at 12 months), and Structured Clinical Interview for DSM-IV, clinician version (defined as no longer being diagnosed with major depressive disorder at 12 months follow-up), in the per-protocol population (those who completed at least four treatment sessions and for whom all outcome measurements were done). Those assessing outcomes were masked. The non-inferiority margin was 15%. This trial is registered with ClinicalTrials.gov, number NCT00324701. Findings: Between April 1, 2007, and July 31, 2011, we screened 780 patients, and the study coordinator randomly assigned participants to either telemedicine (120 [50%]) or same-room treatment (121 [50%]). We included 100 (83%) patients in the per-protocol analysis in the telemedicine group and 104 (86%) in the same-room group. Treatment response according to GDS did not differ significantly between the telemedicine (22 [22·45%, 90% CI 15·52-29·38] patients) and same-room (21 [20·39%, 90% CI 13·86-26·92]) groups, with an absolute difference of 2·06% (90% CI -7·46 to 11·58). Response according to BDI also did not differ significantly (telemedicine 19 [24·05%, 90% CI 16·14-31·96] patients; same room 19 [23·17%, 90% CI 15·51-30·83]), with an absolute difference of 0·88% (90% CI -10·13 to 11·89). Response on the Structured Clinical Interview for DSM-IV, clinician version, also did not differ significantly (39 [43·33%, 90% CI 34·74-51·93] patients in the telemedicine group and 46 [48·42%, 90% CI 39·99-56·85] in the same-room group), with a difference of -5·09% (-17·13 to 6·95; p=0·487). Results from the intention-to-treat population were similar. MEM analyses showed that no significant differences existed between treatment trajectories over time for BDI and GDS. The criteria for non-inferiority were met. We did not note any adverse events. Interpretation: Telemedicine-delivered psychotherapy for older adults with major depression is not inferior to same-room treatment. This finding shows that evidence-based psychotherapy can be delivered, without modification, via home-based telemedicine, and that this method can be used to overcome barriers to care associated with distance from and difficulty with attendance at in-person sessions in older adults. Funding: US Department of Veterans Affairs.

The lancet. Psychiatry · randomised controlled trial · 123 citationsread the source →

Total hip arthroplasty versus hemiarthroplasty for displaced femoral neck fractures in the healthy elderly: a meta-analysis and systematic review of randomized trials.

Purpose: Displaced femoral neck fractures in healthy elderly patients have traditionally been managed with hemiarthroplasty (HA). Recent data suggest that total hip arthroplasty (THA) may be a better alternative. Methods: A systematic review of the English literature was conducted. Randomized controlled trials comparing all forms of THA with HA were included. Three authors independently extracted articles and predefined data. Results were pooled using a random effects model. Results: Eight trials totalling 986 patients were retrieved. After THA 4 % underwent revision surgery versus 7 % after HA. The one-year mortality was equal in both groups: 13 % (THA) versus 15 % (HA). Dislocation rates were 9 % after THA versus 3 % after HA. Equal rates were found for major (25 % in THA versus 24 % in HA) and minor complications (13 % THA versus 14 % HA). The weighted mean of the Harris hip score was 81 points after THA versus 77 after HA. The subdomain pain of the HHS (weighted mean score after THA was 42 versus 39 points for HA), the rate of patients reporting mild to no pain (75 % after THA versus 56 % after HA) and the score of WOMAC (94 points for THA versus 78 for HA) all favored THA. Quality of life measured with the EQ-5D favored THA (0.69 versus 0.57). Conclusions: Total hip arthroplasty for displaced femoral neck fractures in the fit elderly may lead to higher patient-based outcomes but has higher dislocation rates compared with hemiarthroplasty. Further high-quality randomized clinical trails are needed to provide robust evidence and to definitively answer this clinical question.

International orthopaedics · meta-analysis · 207 citationsread the source →

Effects of Additional Individually Tailored Interventions on Sick-Leave and Symptoms in Patients with Exhaustion Disorder: A Randomized Controlled Trial.

Objective: To evaluate the effects of adding individually tailored interventions to a standard treatment in patients with stress-related exhaustion disorder, with regard to sick-leave days and symptoms of burnout. The study design was a 2-armed randomized controlled intervention, with follow-up after 15 months. Data were obtained from patients referred to the Institute of Stress Medicine, and were collected between 2011 and 2014 in western Sweden. Methods: Inclusion criteria were scoring above cut-off in at least 1 of 4 dimensions; mental and physical exhaustion, disturbed sleep, reduced cognitive function and perceived poor self-esteem. The total study population comprised 142 patients (112 females, 30 males) allocated through block randomization to either the intervention group (n = 71) or the control group (n = 71). The intervention group received 1-4 individually tailored interventions (physical activity, cognitive behaviour therapy for insomnia, computerized memory training, cognitive behavioural therapy for self-esteem), based on the results of screening assessments. The interventions were additional to a standard treatment. The control group received solely the standard treatment. The primary outcome measure was the proportion of participants not sicklisted at the 15-month follow-up. Results: At the 15-month follow-up, 30% of subjects in the intervention group and 34% in the control group had 0% sick-listed (p = 0.58). No change between baseline and follow-up was seen in 42% of the intervention group and 39% of the control group, while an increased sick-leave rate was seen in 1% of the intervention group and 4% of the control group. However, no statistically significant difference was seen between groups. Conclusion: Adding individually tailored interventions to a standard treatment in patients with stress-related exhaustion did not reduce sick-leave days or burnout symptoms.

Journal of rehabilitation medicine · randomised controlled trial · 7 citationsread the source →

Stress-related thinking predicts the cortisol awakening response and somatic symptoms in healthy adults.

Objective: Perseverative cognition (i.e., worry, stress-related thinking) may prolong stress-related physiological activation. However, its role within the context of the written emotional disclosure paradigm has not been examined. This study explored: (1) the effects of stress-related thinking on the cortisol awakening response and upper respiratory infection symptoms and; (2) the efficacy of two expressive writing interventions on these health outcomes. Methods: Participants were randomly assigned to write about their most stressful life experience (using the Guided Disclosure Protocol; n=39) or positive life experiences (n=42) or plans for the day (n=41) for 20 min on 3 consecutive days. Participants reported the extent to which they thought about their assigned writing topic during the study and in the past (event-related thought). Cortisol was measured at 0, 15, 30 and 45 min after awakening on 2 consecutive days at baseline and 4 weeks post-intervention. Upper respiratory infection (URI) symptoms were assessed at baseline, at 4 weeks and at 6 months. Results: Results showed that the writing interventions had no beneficial effects on any of the outcome measures. However, a significant interaction was found between event-related thought and condition on the cortisol awakening response at 1 month follow-up and URI symptoms at 6 months. Among participants who wrote about stressful/traumatic events, higher stress-related thinking during the study predicted increased cortisol levels and URI symptoms compared to participants who reported low stress-related thinking. Discussion: These findings are broadly consistent with Brosschot et al.'s (2006) perseverative cognition hypothesis and highlight the importance of ruminative thinking in understanding stress-health processes.

Psychoneuroendocrinology · randomised controlled trial · 23 citationsread the source →

Fezolinetant for treatment of moderate-to-severe vasomotor symptoms associated with menopause (SKYLIGHT 1): a phase 3 randomised controlled study.

Background: Neurokinin 3 receptor antagonists are potential non-hormonal therapies for the treatment of vasomotor symptoms in menopausal women as options are scarce for those who cannot or do not want to take hormone therapy. Fezolinetant is one of the first non-hormonal neurokinin 3 receptor antagonists in development for the treatment of vasomotor symptoms due to menopause. This study investigated the safety and efficacy of fezolinetant for the treatment of moderate-to-severe vasomotor symptoms associated with menopause. Methods: SKYLIGHT 1 is a randomised, double-blind, placebo-controlled, 12-week, phase 3 trial with a 40-week active treatment extension. This trial was done at 97 facilities across the USA, Canada, Czech Republic, Hungary, Poland, Spain, and the UK. Women aged 40-65 years with an average of seven or more moderate-to-severe hot flashes per day were randomly assigned (1:1:1) to once-daily exact-matched placebo, fezolinetant 30 mg, or fezolinetant 45 mg. Randomisation was done using a web-based interactive response system and investigators, project team members, clinical staff, and participants were masked to treatment assignment. Coprimary endpoints were mean change in frequency and severity of vasomotor symptoms from baseline to weeks 4 and 12. The efficacy and safety analyses comprised all randomly assigned participants who received at least one dose of study drug. This trial is registered with ClinicalTrials.gov (NCT04003155) and is completed. Findings: Between July 11, 2019, and Aug 11, 2021, 2205 women were recruited of whom 175 were assigned to placebo, 176 to fezolinetant 30 mg, and 176 to fezolinetant 45 mg (175 in the placebo group, 174 in the fezolinetant 30 mg group, and 173 in the fezolinetant 45 mg received at least one dose [safety analysis set]). One participant randomly assigned to fezolinetant 45 mg received fezolinetant 30 mg in error, so the efficacy analysis set (full analysis set) consisted of 173 in the fezolinetant 30 mg group and 174 in the fezolinetant 45 mg group. 23 participants in the placebo group, 31 in the fezolinetant 30 mg group, and 13 in the fezolinetant 45 mg group discontinued treatment before week 12, mostly due to adverse events or participant withdrawal. Compared with placebo, fezolinetant 30 mg and fezolinetant 45 mg significantly reduced the frequency of vasomotor symptoms at week 4 (difference in change in least squares mean -1·87 [SE 0·42; p<0·001], -2·07 [SE 0·42; p<0·001]) and week 12 (-2·39 [SE 0·44; p<0·001], -2·55 [SE 0·43; p<0·001]). Compared with placebo, fezolinetant 30 mg and 45 mg significantly reduced the severity of vasomotor symptoms at week 4 (-0·15 [0·06; p=0·012], -0·19 [0·06; p=0·002]) and week 12 (-0·24 [0·08; p=0·002], -0·20 [0·08; p=0·007]). Improvements in frequency and severity of vasomotor symptoms were observed after 1 week and maintained over 52 weeks. During the first 12 weeks, treatment-emergent adverse events occurred in 65 (37%) of 174 women in the fezolinetant 30 mg group, 75 (43%) of 173 in the fezolinetant 45 mg group, and 78 (45%) of 175 in the placebo group. The incidence of liver enzyme elevations was low (placebo n=1; fezolinetant 30 mg n=2; fezolinetant 45 mg n=0) and these events were generally asymptomatic, transient, and resolved while on treatment or after treatment discontinuation. Interpretation: Data support the clinical use of fezolinetant as a non-hormonal treatment for vasomotor symptoms associated with menopause. The study was placebo-controlled for 12 weeks followed by a 40-week blinded extension to assess the maintenance of effect. Furthermore, the population studied was diverse and representative of the potential target population for fezolinetant therapy. Further characterisation of the benefit of fezolinetant on quality of life, including on symptoms of mood and sexual wellbeing, merits investigation. Funding: Astellas Pharma.

Lancet (London, England) · randomised controlled trial · 172 citationsread the source →

Outcomes of childhood epilepsy at age 33 years: a population-based birth-cohort study.

Purpose: There is uncertainty about health and socioeconomic outcomes of children with epilepsy, knowledge of adult outcomes, and factors associated with adverse outcomes are essential to guide prognosis, improve management, and determine appropriate allocation of resources. Methods: A subgroup of 101 children with epilepsy (onset ≤ age 16 years) were previously identified and reported from the 1958 National Child Development Study (NCDS), a national United Kingdom birth cohort study. In the current study we examine outcomes of this unique childhood epilepsy subgroup at age 33 compared to unaffected NCDS cohort members in mental and general health, education and employment, marriage, and parenthood. Multivariable regression analyses were used to investigate factors (including etiology, cognitive development, parental interest, and childhood anxiety/depression at age 11 years) associated with adverse outcomes. key findings: Sixty-five (66%) were still participating at 33 years. Median follow-up after epilepsy onset was 28 years (range 17-33 years). Thirty participants [46%, 95% confidence interval (CI) 35-58] had epilepsy onset <5 years, 32 (49%, 95% CI 37-61) had "symptomatic" epilepsy, and 33 (51%, 95% CI 39-63) had idiopathic epilepsy. Thirty-one participants (48%) reported being seen by their doctor for epilepsy in the preceding year, 27 (42%) were registered disabled, 39 (60%) had a drivers license, and 42 (65%) thought their epilepsy made it harder to get/keep a paid job. People who had childhood epilepsy had an increased risk of death [standardized mortality rate (SMR) 3.1, 95% CI 1.1-6.1]. Childhood epilepsy was associated with poor general and mental health at 33 years on univariable analyses, but not after adjusting for childhood cognitive development/comorbidities and anxiety over acceptance by peers/adults at age 11. Childhood epilepsy was an independent risk factor for not being married [odds ratio (OR) 0.45, 95% CI 0.05-0.94] or being a parent (OR 0.67, 95% CI 0.42-0.91). People with childhood epilepsy and poor cognitive development compared to those with poor cognitive development without epilepsy had a greater proportion with subsequent poor mental health (56% vs. 24%, difference in proportion 33%, 95% CI 12-50), and a lesser proportion who married (39% vs. 78%, difference in proportion -39%, 95% CI -56 to -19). Significance: Compared to the unaffected population, children with epilepsy with good cognitive development/without comorbidities have similar adult health, educational, and employment outcomes but have difficulties with establishing and maintaining personal relationships. A combination of having childhood epilepsy plus poor cognitive development is more likely to be associated with adverse outcomes compared to having poor cognitive development without childhood epilepsy. Children with epilepsy have increased risk of death compared to the rest of the population. Pharmacologic management alone is inadequate and long-term psychosocial support is needed.

Epilepsia · 46 citationsread the source →

Shared care across the interface between primary and specialty care in management of long term conditions.

Background: Shared care has been used in the management of many chronic conditions with the assumption that it delivers better care than primary or specialty care alone; however, little is known about the effectiveness of shared care. Objectives: To determine the effectiveness of shared care health service interventions designed to improve the management of chronic disease across the primary/specialty care interface. This is an update of a previously published review. Secondary questions include the following:1. Which shared care interventions or portions of shared care interventions are most effective?2. What do the most effective systems have in common? Search methods: We searched MEDLINE, Embase and the Cochrane Library to 12 October 2015. Selection criteria: One review author performed the initial abstract screen; then two review authors independently screened and selected studies for inclusion. We considered randomised controlled trials (RCTs), non-randomised controlled trials (NRCTs), controlled before-after studies (CBAs) and interrupted time series analyses (ITS) evaluating the effectiveness of shared care interventions for people with chronic conditions in primary care and community settings. The intervention was compared with usual care in that setting. Data collection and analysis: Two review authors independently extracted data from the included studies, evaluated study quality and judged the certainty of the evidence using the GRADE approach. We conducted a meta-analysis of results when possible and carried out a narrative synthesis of the remainder of the results. We presented the results in a 'Summary of findings' table, using a tabular format to show effect sizes for all outcome types. Main results: We identified 42 studies of shared care interventions for chronic disease management (N = 18,859), 39 of which were RCTs, two CBAs and one an NRCT. Of these 42 studies, 41 examined complex multi-faceted interventions and lasted from six to 24 months. Overall, our confidence in results regarding the effectiveness of interventions ranged from moderate to high certainty. Results showed probably few or no differences in clinical outcomes overall with a tendency towards improved blood pressure management in the small number of studies on shared care for hypertension, chronic kidney disease and stroke (mean difference (MD) 3.47, 95% confidence interval (CI) 1.68 to 5.25)(based on moderate-certainty evidence). Mental health outcomes improved, particularly in response to depression treatment (risk ratio (RR) 1.40, 95% confidence interval (CI) 1.22 to 1.62; six studies, N = 1708) and recovery from depression (RR 2.59, 95% CI 1.57 to 4.26; 10 studies, N = 4482) in studies examining the 'stepped care' design of shared care interventions (based on high-certainty evidence). Investigators noted modest effects on mean depression scores (standardised mean difference (SMD) -0.29, 95% CI -0.37 to -0.20; six studies, N = 3250). Differences in patient-reported outcome measures (PROMs), processes of care and participation and default rates in shared care services were probably limited (based on moderate-certainty evidence). Studies probably showed little or no difference in hospital admissions, service utilisation and patient health behaviours (with evidence of moderate certainty). Authors' conclusions: This review suggests that shared care improves depression outcomes and probably has mixed or limited effects on other outcomes. Methodological shortcomings, particularly inadequate length of follow-up, may account in part for these limited effects. Review findings support the growing evidence base for shared care in the management of depression, particularly stepped care models of shared care. Shared care interventions for other conditions should be developed within research settings, with account taken of the complexity of such interventions and awareness of the need to carry out longer studies to test effectiveness and sustainability over time.

The Cochrane database of systematic reviews · meta-analysis · 56 citationsread the source →

The anxious heart in whose mind? A systematic review and meta-regression of factors associated with anxiety disorder diagnosis, treatment and morbidity risk in coronary heart disease.

Objective: To (1) report the prognostic association between anxiety disorder subtypes and major adverse cardiac events (MACE), (2) report anxiety disorder prevalence in coronary heart disease (CHD), and (3) report the efficacy of anxiety disorder treatments in CHD. Methods: A comprehensive electronic database search was performed in November 2013 for studies reporting anxiety disorder prevalence according to structured interview in CHD samples or MACE, and randomized controlled trials (RCTs) comparing anxiety disorder treatment with placebo or usual care. From 4041 articles 42 samples were selected for extraction (8 for MACE prognosis, 39 for prevalence, no RCTs were eligible). Results: Five generalized anxiety disorder (GAD) studies reported 883 MACE events (combined n=2851). There was a non-significant association between GAD and MACE (risk ratio=1.20, 95% CI .86-1.68, P=.28) however the effect size was highly significant in outpatient samples (adjusted hazard ratio=1.94, 95% CI 1.45-2.60, P<.001). No other anxiety disorder subtype was associated with MACE. Prevalence data showed high comorbidity with depression (49.06%; 95% CI 34.28-64.01) and substantial heterogeneity between studies. Panic disorder prevalence was higher in psychiatrist/psychologist raters (9.92% vs. 4.74%) as was GAD (18.45% vs. 13.01%). Panic and GAD estimates were also heterogeneous according to DSM-III-R versus DSM-IV taxonomies. Conclusions: The paucity of extant anxiety disorder RCTs, alongside MACE risk for GAD outpatients, should stimulate further anxiety disorder intervention in CHD populations. Research should focus on depression and anxiety, thereby unraveling disorder specific and more generic pathways.

Journal of psychosomatic research · systematic review · 117 citationsread the source →

Charting the Future of Cancer Health Disparities Research: A Position Statement from the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology, and the National Cancer Institute

The academic field of cancer health disparities was stimulated by the U.S. civil rights movement. Concerns about civil rights led to concerns about equality in health care. The first publications to make the observation that black Americans have higher rates of death as a result of certain cancers compared with white Americans were published by the early 1970s (1, 2). The discipline concerned with these differences was first called “minority health research” and later “special populations health” or “special populations research.” The National Cancer Institute (NCI) defines cancer health disparities as adverse differences in cancer incidence, cancer prevalence, cancer mortality, cancer survivorship, and burden of cancer or related health conditions that exist among specific population groups in the United States (3). However, with greater and renewed acknowledgment of health disparities as rooted within the context of historical and contextual inequities in the United States, many health disparities are considered health inequities (4).The National Cancer Act of 1971 created the Surveillance, Epidemiology, and End Results (SEER) program within the NCI. This program began collecting incidence, mortality, and survival data by race in the early 1970s from a number of population-based registries around the United States. The SEER program improved documentation of differences in outcomes and analyzed them through its black–white studies (5). These studies especially demonstrated differences in treatment patterns, with a higher proportion of blacks receiving inappropriate cancer care compared with whites. The discipline grew from a focus on black–white differences to encompass differences in outcomes for a number of racial and ethnic groups, as well as for cohorts defined by age, sex, socioeconomic status (SES), and other social determinants of health. There is now even greater appreciation for disparities among communities, whether rural versus urban or even by state or region. The definition of health outcomes also broadened beyond death rates. The field of health disparities was once simply a description of population differences and a call for cultural competence among health care providers. Today, the field is transdisciplinary, integrating basic science, clinical science, policy, epidemiology, and the social sciences. It involves people trained in diverse nonmedical fields, such as education, economics, sociology, religion, geography, and anthropology. The field is also dynamic. It changes as better and more granular statistics, greater understanding of causes of health disparities, and new challenges to mitigate these underlying causes have emerged. As an example, in the 1970s, the breast cancer death rate for black and white American women was the same. Today, the death rate is substantially higher for blacks compared with whites (6). Policy changes have also created opportunities and challenges. The Affordable Care Act has allowed for Medicaid expansion in each state. Expansion has been adopted by 32 states and the District of Columbia. This will create a new challenge, because poor residents of some states have expanded access to care and residents of other states do not. It is essential that any future policy changes should be carefully designed to increase, rather than decrease, equitable access to care throughout the cancer continuum. Population categorizations also are being redefined. The Asian category includes Korean Americans and Pakistani Americans. The Pacific Islander category, often merged with the Asian category, includes native Hawaiians and Samoans. These populations are incredibly heterogeneous and have dramatically different cancer statistics. In 2015, representatives from four leading cancer organizations, the American Association for Cancer Research, the American Cancer Society, the American Society of Clinical Oncology (ASCO), and the NCI, began to meet to discuss the state of health disparities in the United States. These discussions involved the state of cancer health disparities research and what could be done to move it forward. The discussions were purposely not meant as a comprehensive review of cancer health disparities research. Rather, the meeting and the resulting document aimed to identify issues in health disparities research and make specific recommendations to improve the way disparities research is conducted and disseminated. This statement presents a unified strategy among four of the leading cancer organizations in the United States to promote cooperation among investigators in all areas of the cancer health disparities research community, to ensure that cancer research benefits all populations and patients regardless of race, ethnicity, age, gender identity, sexual orientation, SES, or the communities in which they live. Disparities in outcomes across the cancer continuum have been identified in numerous medically underserved populations, including racial and ethnic minorities and patients of lower SES. In addition to individual social status, social contextual and community factors, such as neighborhood safety, social cohesion, availability of healthy foods, and residential segregation, play an important role in health of both individuals and populations. All of these factors can intersect to generate larger disparities (7, 8).To understand and fully address cancer health disparities, complete, consistent, and accurate collection of patient, community, and structural factors that put people at risk for disparate outcomes is essential. Unfortunately, cancer health disparities research has often been fraught with missing, inaccurate, or overly simplified patient-level data, and most research has failed to consider the community-level factors described above (9–11).For the most part, the manner in which data are collected and integrated in disparities research is suboptimal. The literature is characterized by variable methodology for collection of the factors that put patients and communities at risk for disparate care and outcomes. For example, although race and ethnicity are distinct constructs, they are often conflated such that a person is identified as Hispanic without identification of his or her race. Many studies that investigate cancer care or outcomes according to socioeconomic position have only area-level data on socioeconomic position, whereas others use only composite measures. While valuable in many cases in identifying disparities, such measures fall short in providing the richness of data needed to understand an individual's socioeconomic position. Health literacy and numeracy are rarely assessed in practice and are not available in administrative and research databases. Finally, methods for uniform data collection of information on sexual orientation and gender identity are in their infancy, despite calls for such data collection from the Institute of Medicine, among others (12).Disparities in cancer incidence are pronounced and longstanding. Drivers of these disparities are multifactorial and multilevel, and they include sociodemographic factors, access to health care, risk factor profiles and lifestyle/health habits, cultural perceptions, biologic differences, and genetic predisposition. Disparities in cancers for which single etiologic factors account for a substantial proportion of disease (e.g., human papillomavirus and cervical cancer, or Helicobacter pylori and stomach cancer) can be reasonably understood and explained, but disparities for many of the common etiologically heterogeneous cancers, such as breast, prostate, and colorectal cancers, remain much less well understood. Multilevel approaches are needed to advance knowledge relevant to addressing disparities in cancer incidence rates. One approach is to design and implement observational studies focused on a population in which disparities exist to advance knowledge about etiology and to inform novel prevention strategies. A successful example of such an effort is the African American Breast Cancer Epidemiology and Risk (AMBER) Consortium, a multicenter consortium that has combined data and biospecimens from 7,500 African American patients with breast cancer and 17,000 healthy controls, representing the largest study of breast cancer in African American women in the United States (14). It has yielded a number of insights on multilevel risk factors specific to the major molecular subtypes of breast cancer among African American women (15–17).There is also a need for studies focused on identifying the genetic contributors to cancer health disparities. Recent work has focused on the prioritization of candidate variants relevant to prostate cancer risk within the context of genetic ancestry (based on ancestry informative markers) across those with European, African, Japanese, or Latino ancestry (18). Furthermore, the African Ancestry Prostate Cancer Genome-Wide Association Studies (GWAS) Consortium has reported on susceptibility loci for aggressive prostate cancer specific to men of African ancestry (19).Although some cancer risk factors are well established, the biologic mechanisms through which their impact on cancer risk varies across different populations remain incompletely understood. For example, variations in diet are hypothesized to be the primary driver of the dramatic variations in colorectal cancer incidence rates observed across populations. Recent research has evaluated the impact that different diets have on microbiota composition and function, which in turn affects the production of metabolites that either promote mucosal health or are proinflammatory/neoplastic in the gut. A study that compared Americans with African ancestry (who have a relatively high incidence of colorectal cancer) with rural South Africans (who have a comparatively very low colorectal cancer incidence rate) demonstrated that a typical U.S. diet with high meat and fat intake increases mucosal proliferation rates (a marker of cancer risk) when fed to both populations, whereas typical high-fiber South African diets were associated with low proliferation rates when fed to both groups. This demonstrates that diet can have a profound and fairly immediate impact on the gut microbiome that can either promote or suppress tumors (20).Cancer outcome disparities are well documented for racial and ethnic minorities, and presentation at more advanced stages of cancer explains much of this difference. However, even when controlling for the stage of cancer at diagnosis, the survival disparities persist. What is most concerning is that rather than improving over time, for cancers such as colon cancer, the stage-specific disparities are actually worsening (21). The reason for this growing disparity is not completely clear but involves socioeconomic issues such as education status and the level of insurance and access to medical care. Even in studies that normalize socioeconomic issues (with the limitations cited in the Defining Measures section), disparities that disproportionally affect U.S. minority populations can still be demonstrated for several cancers and may highlight the not-so-well-understood interplay between genetic predisposition and environmental exposure, such as lifestyle and diet, that modifies cancer risk (22, 23). Ultimately, growing postdiagnosis survival disparities are caused by the interplay of system, social, biologic, and environmental factors. Documenting and addressing each of these and their interactions are key to eliminating these disparities. The role of system-level and social determinants in explaining cancer health disparities is best demonstrated by recognizing that disparities vary widely across the United States; some states show almost no disparities, whereas others show striking ones (24). We also know that disparities in treatment of cancer differ and that when treatment differences are accounted for, either through the use of standardized therapies on a clinical trial or through multivariable modeling, cancer-specific survival disparities often disappear. We also have clear examples of successful system-level reform (21, 25, 26). We know, therefore, this is a solvable problem. The key step toward improving care and reducing cancer health disparities requires accurate measurement of meaningful variables, fed back in real time to key stakeholders in the system, followed by meaningful action and continued monitoring to ensure that the action was successful. Determining meaningful measurement across the cancer spectrum may vary by sociocultural factors and require patient and stakeholder input. These system-based practices formed the core of a recent Institute of Medicine report, “Systems Practices for the Care of Socially At-Risk Populations” (27). Systems can be thought of at a macro level, such as state, county, or city governments, all the way down to the individual practice or physician level. Implementation science can inform the best approaches to ensure delivery of high-quality cancer care. Cancers can start as a result of chronic inflammation, and inflammation can modify the behavior of cancer. Biomarkers, such as elevated microsatellite alterations at selected tetranucleotide repeats (EMAST) that can be detected from inflammation-laden cancers, are associated with worse patient outcome and increased metastasis and appear to be more common among African Americans. Microsatellite-unstable (MSI) cancers, which have an overall good prognosis, may be half as common among African Americans compared with whites (28). Both EMAST and MSI have implications for (1) chemotherapeutic response and (2) immunotherapeutic response. In terms of race, these aspects have not been studied. Furthermore, there is much evidence that the microbiome can influence (1) inflammation, (2) response to chemotherapy, and (3) cancer or precancerous lesion formation; also, the microbiome itself can be determined by diet and other factors. These aspects have not been examined with race in mind. Additionally, driver genes may be different within the same type of cancer from patients with different genetic backgrounds, which have implications for correct, definitive therapeutic approaches (29).Most studies that use human specimens to study aspects of cancer and race or ethnicity come from limited individual collections with sparse clinical–epidemiologic information, with rare exception. The exceptions tend to be NCI-funded projects, such as the North Carolina Colon Cancer Study, in which peer review and thoughtful input about how the collection was made with controls, surveys, and linked information to make the collection more meaningful, comprehensive in information, potentially useful for other future studies, and possessed of longevity. However, these types of collections or biorepositories, which include tumor and nontumor specimens, have not been created from diverse samples representative of the U.S. Census population. Current models of health care delivery are highly focused on the use of technology and innovation to improve patient outcomes across disease processes, as demonstrated by the focus on precision medicine in cancer treatment (32–36). Although oncology attempts to embrace this approach, the impact of innovative treatments has been hampered by poor translation of innovation into health care systems and patients from diverse community settings (37, 38). As precision medicine in cancer is accelerated as part of the Beau Biden Cancer Moonshot and other initiatives, the importance of community engagement to ensure that all patients benefit from these advances cannot be overlooked. Cancer health disparities must be taken into consideration in the design, execution, and evaluation of all such programs. Community-engaged research (CER) has been documented as an effective, beneficial method for engaging communities and formulating research that has relevance and impact for both researchers and affected communities (39–42). Involving relevant community stakeholders in research at the planning stages allows for a deeper understanding of community needs, allows researchers to have an iterative method for evaluating research questions in an active realistic milieu, and simultaneously creates a valuable vehicle for active dissemination of the research findings into the communities they are intended to serve. CER offers the potential to improve processes and outcomes in several areas, including care delivery, continuity of care, managing comorbidities, and supportive care (42).Unfortunately, there is a dearth of support for oncology health professionals who choose to work in CER, given its necessity for infrastructure and relationship building, the complex personal interactions with communities and community organizations, and the need to establish long-term benefits to the community after the research project is completed. Importantly, CER requires not only a broad range of expertise across multiple disciplines, but also investigators skilled in a team science approach (43). The benefit of this type of team science has been touted across disciplines; however, its implementation has been limited (44).A lack of workforce diversity has been identified as a barrier to improving access to care for underserved minority groups as well as to advancing research on health disparities (45, 46). Organizations, including ASCO and the American Society of Hematology, have sought to increase workforce diversity in oncology through awards and mentoring programs that expose minorities to in oncology at the medical and In the to Cancer Health Disparities and the American Association for Cancer several programs aimed at the of researchers in cancer and cancer health disparities research. of these types are needed to an oncology workforce that the diversity of the patients it CER not often with most and will require on of the research in both and such an it will remain to create a between CER and the that in cancer are the most important and available to evidence for care and of patients with cancer and individuals at risk for cancer that advanced new approaches from clinical care and diverse oncology the of clinical is to evidence that is both and future must include research questions that consider the multifactorial and multilevel that populations with the cancer This to advance disparities research within the cancer clinical within a new of for in cancer clinical and common for providing trial information have been to for rural patients and patients with lower SES, limited low health and The high and of chronic and of risk factors for chronic such as and must inform to these populations fully in cancer As an example, African Americans a burden of the that from studies, and it is to which could be reasonably as or could be or within the study In addition to those from cancer prevention and treatment also has that populations often are later in the and do not support and rates are key that influence the outcome of clinical cancer studies, those in which minorities have higher disease such as breast, prostate, and cancers In and treatment and rates lower rates exist for those patients who from to and Many such as and to the However, community engagement is to address the and challenges that the clinical CER has been demonstrated to promote building, and the and dissemination of information needed for and long-term As an example, the evaluated the of community health to promote and in and rural populations and that community health can be trained to as research and can be for of and cancer clinical trial and require an of often to be collected at multiple time thought should be given to how best to the of and the study (e.g., and needed to support collection and of specimens from and that to field of cancer health disparities has into a complex science and an field of cancer research. Unfortunately, the to this research has not been and the infrastructure needed to it to the level, can be is The of this which has been by from these four organizations, is to the of advances in this is that this statement will be by both and organizations to inform specific made to improve cancer health disparities eliminating identified disparities in cancer incidence, of care, and recommendations for action have a new in cancer health disparities that has the potential to benefit from across and the in cancer incidence and disparities that affects minorities and the medically it is that in this of cancer research when are being there will be opportunities to this new knowledge to all populations, and cancer health disparities for and future has in a or role for and and as a of the for has research from and has other from the has in a or role for and has research his from and and has and from and has from has in a or role for the and and has research from or other in and has from and has and from for both and an immediate or other in and and has research her from potential of were by the other and and of and of for all aspects of the the of and the for their of this to and

Cancer Research · 84 citationsread the source →

Health of men, women, and children in post-trafficking services in Cambodia, Thailand, and Vietnam: an observational cross-sectional study.

Background: Trafficking is a crime of global proportions involving extreme forms of exploitation and abuse. Yet little research has been done of the health risks and morbidity patterns for men, women, and children trafficked for various forms of forced labour. Methods: We carried out face-to-face interviews with a consecutive sample of individuals entering 15 post-trafficking services in Cambodia, Thailand, and Vietnam. We asked participants about living and working conditions, experience of violence, and health outcomes. We measured symptoms of anxiety and depression with the Hopkins Symptoms Checklist and post-traumatic stress disorder with the Harvard Trauma Questionnaire, and used adjusted logistic regression models to estimate the effect of trafficking on these mental health outcomes, controlling for age, sector of exploitation, and time in trafficking. Findings: We interviewed 1102 people, of whom 1015 reached work destinations. Participants worked in various sectors including sex work (329 [32%]), fishing (275 [27%]), and factories (136 [13%]). 481 (48%) of 1015 experienced physical violence, sexual violence, or both, with 198 (35%) of 566 women and girls reporting sexual violence. 478 (47%) of 1015 participants were threatened and 198 (20%) were locked in a room. 685 (70%) of 985 who had data available worked 7 days per week and 296 (30%) of 989 worked at least 11 hours per day. 222 (22%) of 983 had a serious injury at work. 61·2% (95% CI 58·2-64·2) of participants reported symptom of depression, 42·8% (39·8-45·9) reported symptoms of anxiety, and 38·9% (36·0-42·0) reported symptoms of post-traumatic stress disorder. 5·2% (4·0-6·8) had attempted suicide in the past month. Participants who experienced extremely excessive overtime at work, restricted freedom, bad living conditions, threats, or severe violence were more likely to report symptoms of depression, anxiety, and post-traumatic stress disorder. Interpretation: This is the first health study of a large and diverse sample of men, women, and child survivors of trafficking for various forms of exploitation. Violence and unsafe working conditions were common and psychological morbidity was associated with severity of abuse. Survivors of trafficking need access to health care, especially mental health care. Funding: Anesvad Foundation and International Organization for Migration International Development Fund.

The Lancet. Global health · 87 citationsread the source →

Shame, guilt, and depressive symptoms: a meta-analytic review.

Recent theoretical and empirical work has facilitated the drawing of sharp conceptual distinctions between shame and guilt. A clear view of these distinctions has permitted development of a research literature aimed at evaluating the differential associations of shame and guilt with depressive symptoms. This study quantitatively summarized the magnitude of associations of shame and guilt with depressive symptoms. Two hundred forty-two effect sizes were obtained from 108 studies employing 22,411 participants. Shame showed significantly stronger associations with depressive symptoms (r = .43) than guilt (r = .28). However, the association of shame and depressive symptoms was statistically indistinguishable from the associations of 2 maladaptive variants of guilt and depressive symptoms (contextual-maladaptive guilt, involving exaggerated responsibility for uncontrollable events, r = .39; generalized guilt, involving "free-floating" guilt divorced from specific contexts, r = .42). Other factors also moderated the effects. External shame, which involves negative views of self as seen through the eyes of others, was associated with larger effect sizes (r = .56) than internal shame (r = .42), which involves negative views of self as seen through one's own eyes. Depressive symptom measures that invoked the term guilt yielded stronger associations between guilt and depressive symptoms (r = .33) than depressive symptom measures that did not (r = .21). Age, sex, and ethnicity (proportion of Whites to Asians) did not moderate the effects. Although these correlational data are ambiguous with respect to their causal interpretation, results suggest that shame should figure more prominently in understandings of the emotional underpinnings of depressive symptoms.

Psychological bulletin · meta-analysis · 355 citationsread the source →

The relevance of cognitive emotion regulation to psychotic symptoms - A systematic review and meta-analysis.

Numerous studies emphasise the pivotal role of negative affect in the formation and maintenance of positive symptoms, which moves emotion regulation (ER) as a contributing factor into focus. We systematically reviewed and meta-analysed case-control studies reporting cross-sectional, correlative and experimental data of ER strategies in patients with psychotic disorders. In total, 42 studies were eligible, providing data for 2498 subjects and 3381 healthy controls. Questionnaire-based cross-sectional data (k=39) indicated strongest effects for rumination (g=-0,67 [-0,85 to -0,48]), self-blaming (g=-0,56; [-0,76 to -0,37]) and distraction (g=0,55 [0,11 to 0,98]). Suppression was more frequently (g=-0,36 [-0,56 to -0,16]) and cognitive reappraisal less frequently used (g=0,41 [0,28 to 0,55]), but heterogeneity was high. Correlative data (k=6) supported the assumption of an association between maladaptive strategies and positive symptoms (r=0,34 [0,22 to 0,44]). Less evidence of group differences was found in the experimental studies (k=3). The findings support the notion that ER is markedly impaired in patients with psychotic disorders. However, future research will need to further clarify the extent to which difficulties continue to exist after controlling for context and emotion intensity. The large effects for rumination and self-blaming point to promising treatment targets but also raise questions concerning the specifity of findings.

Clinical psychology review · meta-analysis · 81 citationsread the source →

Effectiveness of brief alcohol interventions in primary care populations.

Background: Excessive drinking is a significant cause of mortality, morbidity and social problems in many countries. Brief interventions aim to reduce alcohol consumption and related harm in hazardous and harmful drinkers who are not actively seeking help for alcohol problems. Interventions usually take the form of a conversation with a primary care provider and may include feedback on the person's alcohol use, information about potential harms and benefits of reducing intake, and advice on how to reduce consumption. Discussion informs the development of a personal plan to help reduce consumption. Brief interventions can also include behaviour change or motivationally-focused counselling. This is an update of a Cochrane Review published in 2007. Objectives: To assess the effectiveness of screening and brief alcohol intervention to reduce excessive alcohol consumption in hazardous or harmful drinkers in general practice or emergency care settings. Search methods: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, and 12 other bibliographic databases to September 2017. We searched Alcohol and Alcohol Problems Science Database (to December 2003, after which the database was discontinued), trials registries, and websites. We carried out handsearching and checked reference lists of included studies and relevant reviews. Selection criteria: We included randomised controlled trials (RCTs) of brief interventions to reduce hazardous or harmful alcohol consumption in people attending general practice, emergency care or other primary care settings for reasons other than alcohol treatment. The comparison group was no or minimal intervention, where a measure of alcohol consumption was reported. 'Brief intervention' was defined as a conversation comprising five or fewer sessions of brief advice or brief lifestyle counselling and a total duration of less than 60 minutes. Any more was considered an extended intervention. Digital interventions were not included in this review. Data collection and analysis: We used standard methodological procedures expected by Cochrane. We carried out subgroup analyses where possible to investigate the impact of factors such as gender, age, setting (general practice versus emergency care), treatment exposure and baseline consumption. Main results: We included 69 studies that randomised a total of 33,642 participants. Of these, 42 studies were added for this update (24,057 participants). Most interventions were delivered in general practice (38 studies, 55%) or emergency care (27 studies, 39%) settings. Most studies (61 studies, 88%) compared brief intervention to minimal or no intervention. Extended interventions were compared with brief (4 studies, 6%), minimal or no intervention (7 studies, 10%). Few studies targeted particular age groups: adolescents or young adults (6 studies, 9%) and older adults (4 studies, 6%). Mean baseline alcohol consumption was 244 g/week (30.5 standard UK units) among the studies that reported these data. Main sources of bias were attrition and lack of provider or participant blinding. The primary meta-analysis included 34 studies (15,197 participants) and provided moderate-quality evidence that participants who received brief intervention consumed less alcohol than minimal or no intervention participants after one year (mean difference (MD) -20 g/week, 95% confidence interval (CI) -28 to -12). There was substantial heterogeneity among studies (I² = 73%). A subgroup analysis by gender demonstrated that both men and women reduced alcohol consumption after receiving a brief intervention. We found moderate-quality evidence that brief alcohol interventions have little impact on frequency of binges per week (MD -0.08, 95% CI -0.14 to -0.02; 15 studies, 6946 participants); drinking days per week (MD -0.13, 95% CI -0.23 to -0.04; 11 studies, 5469 participants); or drinking intensity (-0.2 g/drinking day, 95% CI -3.1 to 2.7; 10 studies, 3128 participants).We found moderate-quality evidence of little difference in quantity of alcohol consumed when extended and no or minimal interventions were compared (-14 g/week, 95% CI -37 to 9; 6 studies, 1296 participants). There was little difference in binges per week (-0.08, 95% CI -0.28 to 0.12; 2 studies, 456 participants; moderate-quality evidence) or difference in days drinking per week (-0.45, 95% CI -0.81 to -0.09; 2 studies, 319 participants; moderate-quality evidence). Extended versus no or minimal intervention provided little impact on drinking intensity (9 g/drinking day, 95% CI -26 to 9; 1 study, 158 participants; low-quality evidence).Extended intervention had no greater impact than brief intervention on alcohol consumption, although findings were imprecise (MD 2 g/week, 95% CI -42 to 45; 3 studies, 552 participants; low-quality evidence). Numbers of binges were not reported for this comparison, but one trial suggested a possible drop in days drinking per week (-0.5, 95% CI -1.2 to 0.2; 147 participants; low-quality evidence). Results from this trial also suggested very little impact on drinking intensity (-1.7 g/drinking day, 95% CI -18.9 to 15.5; 147 participants; very low-quality evidence).Only five studies reported adverse effects (very low-quality evidence). No participants experienced any adverse effects in two studies; one study reported that the intervention increased binge drinking for women and two studies reported adverse events related to driving outcomes but concluded they were equivalent in both study arms. Sources of funding were reported by 67 studies (87%). With two exceptions, studies were funded by government institutes, research bodies or charitable foundations. One study was partly funded by a pharmaceutical company and a brewers association, another by a company developing diagnostic testing equipment. Authors' conclusions: We found moderate-quality evidence that brief interventions can reduce alcohol consumption in hazardous and harmful drinkers compared to minimal or no intervention. Longer counselling duration probably has little additional effect. Future studies should focus on identifying the components of interventions which are most closely associated with effectiveness.

The Cochrane database of systematic reviews · meta-analysis · 409 citationsread the source →

Transcutaneous electrical nerve stimulation (TENS) for fibromyalgia in adults.

Background: Fibromyalgia is characterised by persistent, widespread pain; sleep problems; and fatigue. Transcutaneous electrical nerve stimulation (TENS) is the delivery of pulsed electrical currents across the intact surface of the skin to stimulate peripheral nerves and is used extensively to manage painful conditions. TENS is inexpensive, safe, and can be self-administered. TENS reduces pain during movement in some people so it may be a useful adjunct to assist participation in exercise and activities of daily living. To date, there has been only one systematic review in 2012 which included TENS, amongst other treatments, for fibromyalgia, and the authors concluded that TENS was not effective. Objectives: To assess the analgesic efficacy and adverse events of TENS alone or added to usual care (including exercise) compared with placebo (sham) TENS; no treatment; exercise alone; or other treatment including medication, electroacupuncture, warmth therapy, or hydrotherapy for fibromyalgia in adults. Search methods: We searched the following electronic databases up to 18 January 2017: CENTRAL (CRSO); MEDLINE (Ovid); Embase (Ovid); CINAHL (EBSCO); PsycINFO (Ovid); LILACS; PEDRO; Web of Science (ISI); AMED (Ovid); and SPORTDiscus (EBSCO). We also searched three trial registries. There were no language restrictions. Selection criteria: We included randomised controlled trials (RCTs) or quasi-randomised trials of TENS treatment for pain associated with fibromyalgia in adults. We included cross-over and parallel-group trial designs. We included studies that evaluated TENS administered using non-invasive techniques at intensities that produced perceptible TENS sensations during stimulation at either the site of pain or over nerve bundles proximal (or near) to the site of pain. We included TENS administered as a sole treatment or TENS in combination with other treatments, and TENS given as a single treatment or as a course of treatments. Data collection and analysis: Two review authors independently determined study eligibility by assessing each record and reaching agreement by discussion. A third review author acted as arbiter. We did not anonymise the records of studies before assessment. Two review authors independently extracted data and assessed risk of bias of included studies before entering information into a 'Characteristics of included studies' table. Primary outcomes were participant-reported pain relief from baseline of 30% or greater or 50% or greater, and Patient Global Impression of Change (PGIC). We assessed the evidence using GRADE and added 'Summary of findings' tables. Main results: We included eight studies (seven RCTs, one quasi-RCT, 315 adults (299 women), aged 18 to 75 years): six used a parallel-group design and two used a cross-over design. Sample sizes of intervention arms were five to 43 participants. Two studies, one of which was a cross-over design, compared TENS with placebo TENS (82 participants), one study compared TENS with no treatment (43 participants), and four studies compared TENS with other treatments (medication (two studies, 74 participants), electroacupuncture (one study, 44 participants), superficial warmth (one cross-over study, 32 participants), and hydrotherapy (one study, 10 participants)). Two studies compared TENS plus exercise with exercise alone (98 participants, 49 per treatment arm). None of the studies measured participant-reported pain relief of 50% or greater or PGIC. Overall, the studies were at unclear or high risk of bias, and in particular all were at high risk of bias for sample size. Only one study (14 participants) measured the primary outcome participant-reported pain relief of 30% or greater. Thirty percent achieved 30% or greater reduction in pain with TENS and exercise compared with 13% with exercise alone. One study found 10/28 participants reported pain relief of 25% or greater with TENS compared with 10/24 participants using superficial warmth (42 °C). We judged that statistical pooling was not possible because there were insufficient data and outcomes were not homogeneous. There were no data for the primary outcomes participant-reported pain relief from baseline of 50% or greater and PGIC.There was a paucity of data for secondary outcomes. One pilot cross-over study of 43 participants found that the mean (95% confidence intervals (CI)) decrease in pain intensity on movement (100-mm visual analogue scale (VAS)) during one 30-minute treatment was 11.1 mm (95% CI 5.9 to 16.3) for TENS and 2.3 mm (95% CI 2.4 to 7.7) for placebo TENS. There were no significant differences between TENS and placebo for pain at rest. One parallel group study of 39 participants found that mean ± standard deviation (SD) pain intensity (100-mm VAS) decreased from 85 ± 20 mm at baseline to 43 ± 20 mm after one week of dual-site TENS; decreased from 85 ± 10 mm at baseline to 60 ± 10 mm after single-site TENS; and decreased from 82 ± 20 mm at baseline to 80 ± 20 mm after one week of placebo TENS. The authors of seven studies concluded that TENS relieved pain but the findings of single small studies are unlikely to be correct. One study found clinically important improvements in Fibromyalgia Impact Questionnaire (FIQ) subscales for work performance, fatigue, stiffness, anxiety, and depression for TENS with exercise compared with exercise alone. One study found no additional improvements in FIQ scores when TENS was added to the first three weeks of a 12-week supervised exercise programme. No serious adverse events were reported in any of the studies although there were reports of TENS causing minor discomfort in a total of 3 participants. The quality of evidence was very low. We downgraded the GRADE rating mostly due to a lack of data; therefore, we have little confidence in the effect estimates where available. Authors' conclusions: There was insufficient high-quality evidence to support or refute the use of TENS for fibromyalgia. We found a small number of inadequately powered studies with incomplete reporting of methodologies and treatment interventions.

The Cochrane database of systematic reviews · meta-analysis · 48 citationsread the source →

Comparison of paediatric emergency department visits for attempted suicide, self-harm, and suicidal ideation before and during the COVID-19 pandemic: a systematic review and meta-analysis.

Background: There is a lack of consensus about the effect of the COVID-19 pandemic on the mental health of children and adolescents. We aimed to compare rates of paediatric emergency department visits for attempted suicide, self-harm, and suicidal ideation during the pandemic with those before the pandemic. Methods: For this systematic review and meta-analysis, we searched MEDLINE, Embase, and PsycINFO for studies published between Jan 1, 2020, and Dec 19, 2022. Studies published in English with data on paediatric (ie, those aged <19 years) emergency department visits before and during the COVID-19 pandemic were included. Case studies and qualitative analyses were excluded. Changes in attempted suicide, self-harm, suicidal ideation, and other mental-illness indicators (eg, anxiety, depression, and psychosis) were expressed as ratios of the rates of emergency department visits during the pandemic compared with those before the pandemic, and we analysed these with a random-effects meta-analysis. This study was registered with PROSPERO, CRD42022341897. Findings: 10 360 non-duplicate records were retrieved, which yielded 42 relevant studies (with 130 sample-estimates) representing 11·1 million emergency department visits for all indications of children and adolescents across 18 countries. The mean age of the samples of children and adolescents across studies was 11·7 years (SD 3·1, range 5·5-16·3), and there were on average 57·6% girls and 43·4% boys as a proportion of emergency department visits for any health reasons (ie, physical and mental). Only one study had data related to race or ethnicity. There was good evidence of an increase in emergency department visits for attempted suicide during the pandemic (rate ratio 1·22, 90% CI 1·08-1·37), modest evidence of an increase in emergency department visits for suicidal ideation (1·08, 0·93-1·25), and good evidence for only a slight change in self-harm (0·96, 0·89-1·04). Rates of emergency department visits for other mental-illness indications showed very good evidence of a decline (0·81, 0·74-0·89), and paediatric visits for all health indications showed strong evidence of a reduction (0·68, 0·62-0·75). When rates for attempted suicide and suicidal ideation were combined as a single measure, there was good evidence of an increase in emergency department visits among girls (1·39, 1·04-1·88) and only modest evidence of an increase among boys (1·06, 0·92-1·24). Self-harm among older children (mean age 16·3 years, range 13·0-16·3) showed good evidence of an increase (1·18, 1·00-1·39), but among younger children (mean age 9·0 years, range 5·5-12·0) there was modest evidence of a decrease (0·85, 0·70-1·05). Interpretation: The integration of mental health support within community health and the education system-including promotion, prevention, early intervention, and treatment-is urgently needed to increase the reach of mental health support that can mitigate child and adolescent mental distress. In future pandemics, increased resourcing in some emergency department settings would help to address their expected increase in visits for acute mental distress among children and adolescents. Funding: None.

The lancet. Psychiatry · meta-analysis · 164 citationsread the source →

Psychosocial and psychological interventions for relapse prevention in schizophrenia: a systematic review and network meta-analysis.

Background: Many psychosocial and psychological interventions are used in patients with schizophrenia, but their comparative efficacy in the prevention of relapse is not known. We aimed to evaluate the efficacy, acceptability, and tolerability of psychosocial and psychological interventions for relapse prevention in schizophrenia. Methods: To conduct this systematic review and network meta-analysis we searched for published and unpublished randomised controlled trials that investigated psychosocial or psychological interventions aimed at preventing relapse in patients with schizophrenia. We searched EMBASE, MEDLINE, PsycINFO, BIOSIS, Cochrane Library, WHO International Clinical Trials Registry Platform, and ClinicalTrials.gov up to Jan 20, 2020, and searched PubMed up to April 14, 2020. We included open and masked studies done in adults with schizophrenia or related disorders. We excluded studies in which all patients were acutely ill, had a concomitant medical or psychiatric disorder, or were prodromal or "at risk of psychosis". Study selection and data extraction were done by two reviewers independently based on published and unpublished reports, and by contacting study authors. Data were extracted about efficacy, tolerability, and acceptability of the interventions; potential effect moderators; and study quality and characteristics. The primary outcome was relapse measured with operationalised criteria or psychiatric hospital admissions. We did random-effects network meta-analysis to calculate odds ratios (ORs) or standardised mean differences (SMDs) with 95% CIs. The study protocol was registered with PROSPERO, CRD42019147884. Findings: We identified 27 765 studies through the database search and 330 through references of previous reviews and studies. We screened 28 000 records after duplicates were removed. 24 406 records were excluded by title and abstract screening and 3594 full-text articles were assessed for eligibility. 3350 articles were then excluded for a variety of reasons, and 244 full-text articles corresponding to 85 studies were included in the qualitative synthesis. Of these, 72 studies with 10 364 participants (3939 females and 5716 males with sex indicated) were included in the network meta-analysis. The randomised controlled trials included compared 20 psychological interventions given mainly as add-on to antipsychotics. Ethnicity data were not available. Family interventions (OR 0·35, 95% CI 0·24-0·52), relapse prevention programmes (OR 0·33, 0·14-0·79), cognitive behavioural therapy (OR 0·45, 0·27-0·75), family psychoeducation (OR 0·56, 0·39-0·82), integrated interventions (OR 0·62, 0·44-0·87), and patient psychoeducation (OR 0·63, 0·42-0·94) reduced relapse more than treatment as usual at 1 year. The confidence in the estimates ranged from moderate to very low. We found no indication of publication bias. Interpretation: We found robust benefits in reducing the risk of relapse for family interventions, family psychoeducation, and cognitive behavioral therapy. These treatments should be the first psychosocial interventions to be considered in the long-term treatment for patients with schizophrenia. Funding: German Ministry for Education and Research.

The lancet. Psychiatry · systematic review · 149 citationsread the source →

Drugs for preventing postoperative nausea and vomiting in adults after general anaesthesia: a network meta-analysis.

Background: Postoperative nausea and vomiting (PONV) is a common adverse effect of anaesthesia and surgery. Up to 80% of patients may be affected. These outcomes are a major cause of patient dissatisfaction and may lead to prolonged hospital stay and higher costs of care along with more severe complications. Many antiemetic drugs are available for prophylaxis. They have various mechanisms of action and side effects, but there is still uncertainty about which drugs are most effective with the fewest side effects. Objectives: • To compare the efficacy and safety of different prophylactic pharmacologic interventions (antiemetic drugs) against no treatment, against placebo, or against each other (as monotherapy or combination prophylaxis) for prevention of postoperative nausea and vomiting in adults undergoing any type of surgery under general anaesthesia • To generate a clinically useful ranking of antiemetic drugs (monotherapy and combination prophylaxis) based on efficacy and safety • To identify the best dose or dose range of antiemetic drugs in terms of efficacy and safety SEARCH METHODS: We searched the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, Embase, the Cumulative Index to Nursing and Allied Health Literature (CINAHL), the World Health Organization International Clinical Trials Registry Platform (WHO ICTRP), ClinicalTrials.gov, and reference lists of relevant systematic reviews. The first search was performed in November 2017 and was updated in April 2020. In the update of the search, 39 eligible studies were found that were not included in the analysis (listed as awaiting classification). Selection criteria: Randomized controlled trials (RCTs) comparing effectiveness or side effects of single antiemetic drugs in any dose or combination against each other or against an inactive control in adults undergoing any type of surgery under general anaesthesia. All antiemetic drugs belonged to one of the following substance classes: 5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, corticosteroids, antihistamines, and anticholinergics. No language restrictions were applied. Abstract publications were excluded. Data collection and analysis: A review team of 11 authors independently assessed trials for inclusion and risk of bias and subsequently extracted data. We performed pair-wise meta-analyses for drugs of direct interest (amisulpride, aprepitant, casopitant, dexamethasone, dimenhydrinate, dolasetron, droperidol, fosaprepitant, granisetron, haloperidol, meclizine, methylprednisolone, metoclopramide, ondansetron, palonosetron, perphenazine, promethazine, ramosetron, rolapitant, scopolamine, and tropisetron) compared to placebo (inactive control). We performed network meta-analyses (NMAs) to estimate the relative effects and ranking (with placebo as reference) of all available single drugs and combinations. Primary outcomes were vomiting within 24 hours postoperatively, serious adverse events (SAEs), and any adverse event (AE). Secondary outcomes were drug class-specific side effects (e.g. headache), mortality, early and late vomiting, nausea, and complete response. We performed subgroup network meta-analysis with dose of drugs as a moderator variable using dose ranges based on previous consensus recommendations. We assessed certainty of evidence of NMA treatment effects for all primary outcomes and drug class-specific side effects according to GRADE (CINeMA, Confidence in Network Meta-Analysis). We restricted GRADE assessment to single drugs of direct interest compared to placebo. Main results: We included 585 studies (97,516 randomized participants). Most of these studies were small (median sample size of 100); they were published between 1965 and 2017 and were primarily conducted in Asia (51%), Europe (25%), and North America (16%). Mean age of the overall population was 42 years. Most participants were women (83%), had American Society of Anesthesiologists (ASA) physical status I and II (70%), received perioperative opioids (88%), and underwent gynaecologic (32%) or gastrointestinal surgery (19%) under general anaesthesia using volatile anaesthetics (88%). In this review, 44 single drugs and 51 drug combinations were compared. Most studies investigated only single drugs (72%) and included an inactive control arm (66%). The three most investigated single drugs in this review were ondansetron (246 studies), dexamethasone (120 studies), and droperidol (97 studies). Almost all studies (89%) reported at least one efficacy outcome relevant for this review. However, only 56% reported at least one relevant safety outcome. Altogether, 157 studies (27%) were assessed as having overall low risk of bias, 101 studies (17%) overall high risk of bias, and 327 studies (56%) overall unclear risk of bias. Vomiting within 24 hours postoperatively Relative effects from NMA for vomiting within 24 hours (282 RCTs, 50,812 participants, 28 single drugs, and 36 drug combinations) suggest that 29 out of 36 drug combinations and 10 out of 28 single drugs showed a clinically important benefit (defined as the upper end of the 95% confidence interval (CI) below a risk ratio (RR) of 0.8) compared to placebo. Combinations of drugs were generally more effective than single drugs in preventing vomiting. However, single NK₁ receptor antagonists showed treatment effects similar to most of the drug combinations. High-certainty evidence suggests that the following single drugs reduce vomiting (ordered by decreasing efficacy): aprepitant (RR 0.26, 95% CI 0.18 to 0.38, high certainty, rank 3/28 of single drugs); ramosetron (RR 0.44, 95% CI 0.32 to 0.59, high certainty, rank 5/28); granisetron (RR 0.45, 95% CI 0.38 to 0.54, high certainty, rank 6/28); dexamethasone (RR 0.51, 95% CI 0.44 to 0.57, high certainty, rank 8/28); and ondansetron (RR 0.55, 95% CI 0.51 to 0.60, high certainty, rank 13/28). Moderate-certainty evidence suggests that the following single drugs probably reduce vomiting: fosaprepitant (RR 0.06, 95% CI 0.02 to 0.21, moderate certainty, rank 1/28) and droperidol (RR 0.61, 95% CI 0.54 to 0.69, moderate certainty, rank 20/28). Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol showed clinically important benefit, but low doses showed no clinically important benefit. Aprepitant was used mainly at high doses, ramosetron at recommended doses, and fosaprepitant at doses of 150 mg (with no dose recommendation available). Frequency of SAEs Twenty-eight RCTs were included in the NMA for SAEs (10,766 participants, 13 single drugs, and eight drug combinations). The certainty of evidence for SAEs when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to low. Droperidol (RR 0.88, 95% CI 0.08 to 9.71, low certainty, rank 6/13) may reduce SAEs. We are uncertain about the effects of aprepitant (RR 1.39, 95% CI 0.26 to 7.36, very low certainty, rank 11/13), ramosetron (RR 0.89, 95% CI 0.05 to 15.74, very low certainty, rank 7/13), granisetron (RR 1.21, 95% CI 0.11 to 13.15, very low certainty, rank 10/13), dexamethasone (RR 1.16, 95% CI 0.28 to 4.85, very low certainty, rank 9/13), and ondansetron (RR 1.62, 95% CI 0.32 to 8.10, very low certainty, rank 12/13). No studies reporting SAEs were available for fosaprepitant. Frequency of any AE Sixty-one RCTs were included in the NMA for any AE (19,423 participants, 15 single drugs, and 11 drug combinations). The certainty of evidence for any AE when using one of the best and most reliable anti-vomiting drugs (aprepitant, ramosetron, granisetron, dexamethasone, ondansetron, and droperidol compared to placebo) ranged from very low to moderate. Granisetron (RR 0.92, 95% CI 0.80 to 1.05, moderate certainty, rank 7/15) probably has no or little effect on any AE. Dexamethasone (RR 0.77, 95% CI 0.55 to 1.08, low certainty, rank 2/15) and droperidol (RR 0.89, 95% CI 0.81 to 0.98, low certainty, rank 6/15) may reduce any AE. Ondansetron (RR 0.95, 95% CI 0.88 to 1.01, low certainty, rank 9/15) may have little or no effect on any AE. We are uncertain about the effects of aprepitant (RR 0.87, 95% CI 0.78 to 0.97, very low certainty, rank 3/15) and ramosetron (RR 1.00, 95% CI 0.65 to 1.54, very low certainty, rank 11/15) on any AE. No studies reporting any AE were available for fosaprepitant. Class-specific side effects For class-specific side effects (headache, constipation, wound infection, extrapyramidal symptoms, sedation, arrhythmia, and QT prolongation) of relevant substances, the certainty of evidence for the best and most reliable anti-vomiting drugs mostly ranged from very low to low. Exceptions were that ondansetron probably increases headache (RR 1.16, 95% CI 1.06 to 1.28, moderate certainty, rank 18/23) and probably reduces sedation (RR 0.87, 95% CI 0.79 to 0.96, moderate certainty, rank 5/24) compared to placebo. The latter effect is limited to recommended and high doses of ondansetron. Droperidol probably reduces headache (RR 0.76, 95% CI 0.67 to 0.86, moderate certainty, rank 5/23) compared to placebo. We have high-certainty evidence that dexamethasone (RR 1.00, 95% CI 0.91 to 1.09, high certainty, rank 16/24) has no effect on sedation compared to placebo. No studies assessed substance class-specific side effects for fosaprepitant. Direction and magnitude of network effect estimates together with level of evidence certainty are graphically summarized for all pre-defined GRADE-relevant outcomes and all drugs of direct interest compared to placebo in http://doi.org/10.5281/zenodo.4066353. Authors' conclusions: We found high-certainty evidence that five single drugs (aprepitant, ramosetron, granisetron, dexamethasone, and ondansetron) reduce vomiting, and moderate-certainty evidence that two other single drugs (fosaprepitant and droperidol) probably reduce vomiting, compared to placebo. Four of the six substance classes (5-HT₃ receptor antagonists, D₂ receptor antagonists, NK₁ receptor antagonists, and corticosteroids) were thus represented by at least one drug with important benefit for prevention of vomiting. Combinations of drugs were generally more effective than the corresponding single drugs in preventing vomiting. NK₁ receptor antagonists were the most effective drug class and had comparable efficacy to most of the drug combinations. 5-HT₃ receptor antagonists were the best studied substance class. For most of the single drugs of direct interest, we found only very low to low certainty evidence for safety outcomes such as occurrence of SAEs, any AE, and substance class-specific side effects. Recommended and high doses of granisetron, dexamethasone, ondansetron, and droperidol were more effective than low doses for prevention of vomiting. Dose dependency of side effects was rarely found due to the limited number of studies, except for the less sedating effect of recommended and high doses of ondansetron. The results of the review are transferable mainly to patients at higher risk of nausea and vomiting (i.e. healthy women undergoing inhalational anaesthesia and receiving perioperative opioids). Overall study quality was limited, but certainty assessments of effect estimates consider this limitation. No further efficacy studies are needed as there is evidence of moderate to high certainty for seven single drugs with relevant benefit for prevention of vomiting. However, additional studies are needed to investigate potential side effects of these drugs and to examine higher-risk patient populations (e.g. individuals with diabetes and heart disease).

The Cochrane database of systematic reviews · systematic review · 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 →

Metabolic and bariatric surgery versus intensive non-surgical treatment for adolescents with severe obesity (AMOS2): a multicentre, randomised, controlled trial in Sweden.

Background: Severe obesity in adolescents has a profound impact on current and future health. Metabolic and bariatric surgery (MBS) is increasingly used in adolescents internationally. However, to our knowledge, there are no randomised trials examining the currently most used surgical techniques. Our aim was to evaluate changes in BMI and secondary health and safety outcomes after MBS. Methods: The Adolescent Morbid Obesity Surgery 2 (AMOS2) study is a randomised, open-label, multicentre trial done at three university hospitals in Sweden (located in Stockholm, Gothenburg, and Malmö). Adolescents aged 13-16 years with a BMI of at least 35 kg/m2, who had attended treatment for obesity for at least 1 year, passed assessments from a paediatric psychologist and a paediatrician, and had a Tanner pubertal stage of at least 3, were randomly assigned (1:1) to MBS or intensive non-surgical treatment. Exclusion criteria included monogenic or syndromic obesity, major psychiatric illness, and regular self-induced vomiting. Computerised randomisation was stratified for sex and recruitment site. Allocation was concealed for both staff and participants until the end of the inclusion day, and then all participants were unmasked to treatment intervention. One group underwent MBS (primarily gastric bypass), while the other group received intensive non-surgical treatment starting with 8 weeks of low-calorie diet. The primary outcome was 2-year change in BMI, analysed as intention-to-treat. The trial is registered at ClinicalTrials.gov, NCT02378259. Findings: 500 people were assessed for eligibility between Aug 27, 2014, and June 7, 2017. 450 participants were excluded (397 did not meet inclusion criteria, 39 declined to participate, and 14 were excluded for various other reasons). Of the 50 remaining participants, 25 (19 females and six males) were randomly assigned to receive MBS and 25 (18 females and seven males) were assigned to intensive non-surgical treatment. Three participants (6%; one in the MBS group and two in the intensive non-surgical treatment group) did not participate in the 2-year follow-up, and in total 47 (94%) participants were assessed for the primary endpoint. Mean age of participants was 15·8 years (SD 0·9) and mean BMI at baseline was 42·6 kg/m2 (SD 5·2). After 2 years, BMI change was -12·6 kg/m2 (-35·9 kg; n=24) among adolescents undergoing MBS (Roux-en-Y gastric bypass [n=23], sleeve gastrectomy [n=2]) and -0·2 kg/m2 (0·4 kg; [n=23]) among participants in the intensive non-surgical treatment group (mean difference -12·4 kg/m2 [95% CI -15·5 to -9·3]; p<0·0001). Five (20%) patients in the intensive non-surgical group crossed over to MBS during the second year. Adverse events (n=4) after MBS were mild but included one cholecystectomy. Regarding safety outcomes, surgical patients had a reduction in bone mineral density, while controls were unchanged after 2 years (z-score change mean difference -0·9 [95% CI -1·2 to -0·6]). There were no significant differences between the groups in vitamin and mineral levels, gastrointestinal symptoms (except less reflux in the surgical group), or in mental health at the 2-year follow-up. Interpretation: MBS is an effective and well tolerated treatment for adolescents with severe obesity resulting in substantial weight loss and improvements in several aspects of metabolic health and physical quality of life over 2 years, and should be considered in adolescents with severe obesity. Funding: Sweden's Innovation Agency, Swedish Research Council Health.

The Lancet. Child & adolescent health · randomised controlled trial · 45 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). 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Epidemiologic Reviews · meta-analysis · 394 citationsread the source →

Association of Early-Life Antibiotic Use and Protective Effects of Breastfeeding: Role of the Intestinal Microbiota.

Importance: Long duration of breastfeeding is known to reduce the frequency of infections and the risk of overweight, both of which are prevalent health problems among children, but the mechanisms are unclear. Objectives: To test whether early-life antibiotic use in children prevents the beneficial long-term effects of breastfeeding on weight development and lifetime antibiotic use, and to investigate whether the duration of breastfeeding is associated with long-term microbiota development. Design, setting, and participants: Retrospective cohort study, conducted from June 2015 to December 2015, of the association between the duration of breastfeeding and lifetime antibiotic use by children as well as body mass index (BMI; calculated as weight in kilograms divided by height in meters squared) z score in a cohort of 226 healthy children aged 2 to 6 years attending day care at the study area in northern Finland and participating in a probiotic trial from October 1, 2009, through April 30, 2010. Fecal microbiota composition analysis was performed in a subcohort of 42 of these children. Exposures: Duration of breastfeeding and the number of different antibiotic courses purchased for the child. Main outcomes and measures: The BMI z score, lifetime antibiotic use after weaning, and fecal microbiota composition. Results: A total of 226 children (mean [SD] age, 55 [1.4] months; 54% male) were included in the study. Among the 113 children with no antibiotics before weaning, each month of breastfeeding decreased the mean number of postweaning antibiotic courses by 5% (95% CI, 2% to 8%; P = .001) and mean BMI z scores by 0.08 unit (95% CI, 0.04 to 0.11; P < .001). Among the 113 early-life antibiotic users, the effect of breastfeeding on postweaning antibiotic use was borderline significant (estimated 4% decrease per month; 95% CI, 0% to 7%; P = .04) and the effect on BMI z score disappeared (estimated 1% increase; 95% CI, -3% to 5%; P = .50). In the subcohort of 42 children with fecal microbiota composition analysis, the children with short breastfeeding duration (0-6 months) and no early-life antibiotic use or with long breastfeeding duration (8-16 months) and early-life use of antibiotics had a significantly lower abundance of Bifidobacterium (by 55%; 95% CI, 43% to 87%; P = .006; and 39%, 95% CI, 30% to 68%; P < .001, respectively) and Akkermansia (by 71%; 95% CI, 28% to 87%; P = .008; and 69%; 95% CI, 22% to 90%; P = .02, respectively) compared with those with long duration of breastfeeding and no early-life antibiotics. Conclusions and relevance: Antibiotic use in a child during breastfeeding may weaken the beneficial effects of long breastfeeding duration. The results suggest that particularly the long-term metabolic benefits of breastfeeding are conveyed by the intestinal microbiota.

JAMA pediatrics · clinical trial · 75 citationsread the source →

Experiential virtual scenarios with real-time monitoring (interreality) for the management of psychological stress: a block randomized controlled trial.

Background: The recent convergence between technology and medicine is offering innovative methods and tools for behavioral health care. Among these, an emerging approach is the use of virtual reality (VR) within exposure-based protocols for anxiety disorders, and in particular posttraumatic stress disorder. However, no systematically tested VR protocols are available for the management of psychological stress. Objective: Our goal was to evaluate the efficacy of a new technological paradigm, Interreality, for the management and prevention of psychological stress. The main feature of Interreality is a twofold link between the virtual and the real world achieved through experiential virtual scenarios (fully controlled by the therapist, used to learn coping skills and improve self-efficacy) with real-time monitoring and support (identifying critical situations and assessing clinical change) using advanced technologies (virtual worlds, wearable biosensors, and smartphones). Methods: The study was designed as a block randomized controlled trial involving 121 participants recruited from two different worker populations-teachers and nurses-that are highly exposed to psychological stress. Participants were a sample of teachers recruited in Milan (Block 1: n=61) and a sample of nurses recruited in Messina, Italy (Block 2: n=60). Participants within each block were randomly assigned to the (1) Experimental Group (EG): n=40; B1=20, B2=20, which received a 5-week treatment based on the Interreality paradigm; (2) Control Group (CG): n=42; B1=22, B2=20, which received a 5-week traditional stress management training based on cognitive behavioral therapy (CBT); and (3) the Wait-List group (WL): n=39, B1=19, B2=20, which was reassessed and compared with the two other groups 5 weeks after the initial evaluation. Results: Although both treatments were able to significantly reduce perceived stress better than WL, only EG participants reported a significant reduction (EG=12% vs. CG=0.5%) in chronic "trait" anxiety. A similar pattern was found for coping skills: both treatments were able to significantly increase most coping skills, but only EG participants reported a significant increase (EG=14% vs CG=0.3%) in the Emotional Support skill. Conclusions: Our findings provide initial evidence that the Interreality protocol yields better outcomes than the traditionally accepted gold standard for psychological stress treatment: CBT. Consequently, these findings constitute a sound foundation and rationale for the importance of continuing future research in technology-enhanced protocols for psychological stress management. Trial registration: ClinicalTrials.gov: NCT01683617; http://clinicaltrials.gov/show/NCT01683617 (Archived by WebCite at http://www.webcitation.org/6QnziHv3h).

Journal of medical Internet research · randomised controlled trial · 68 citationsread the source →

Relaxin for the treatment of patients with acute heart failure (Pre-RELAX-AHF): a multicentre, randomised, placebo-controlled, parallel-group, dose-finding phase IIb study.

Background: Most patients admitted for acute heart failure have normal or increase blood pressure. Relaxin is a natural human peptide that affects multiple vascular control pathways, suggesting potential mechanisms of benefit for such patients. We assessed the dose response of relaxin's effect on symptom relief, other clinical outcomes, and safety. Methods: In a placebo-controlled, parallel-group, dose-ranging study, 234 patients with acute heart failure, dyspnoea, congestion on chest radiograph, and increased brain natriuretic peptide (BNP) or N-terminal prohormone of BNP, mild-to-moderate renal insufficiency, and systolic blood pressure greater than 125 mm Hg were recruited from 54 sites in eight countries and enrolled within 16 h of presentation. Patients were randomly assigned, in a double-blind manner via a telephone-based interactive voice response system, to standard care plus 48-h intravenous infusion of placebo (n=62) or relaxin 10 microg/kg (n=40), 30 microg/kg (n=43), 100 microg/kg (n=39), or 250 microg/kg (n=50) per day. Several clinical endpoints were explored to assess whether intravenous relaxin should be pursued in larger studies of acute heart failure, to identify an optimum dose, and to help to assess endpoint selection and power calculations. Analysis was by modified intention to treat. This study is registered with ClinicalTrials.gov, number NCT00520806. Findings: In the modified intention-to-treat population, 61 patients were assessed in the placebo group, 40 in the relaxin 10 microg/kg per day group, 42 in the relaxin 30 microg/kg per day group, 37 in the relaxin 100 microg/kg per day group, and 49 in the relaxin 250 microg/kg per day group. Dyspnoea improved with relaxin 30 microg/kg compared with placebo, as assessed by Likert scale (17 of 42 patients [40%] moderately or markedly improved at 6 h, 12 h, and 24 h vs 14 of 61 [23%]; p=0.044) and visual analogue scale through day 14 (8214 mm x h [SD 8712] vs 4622 mm x h [9003]; p=0.053). Length of stay was 10.2 days (SD 6.1) for relaxin-treated patients versus 12.0 days (7.3) for those given placebo, and days alive out of hospital were 47.9 (10.1) versus 44.2 (14.2). Cardiovascular death or readmission due to heart or renal failure at day 60 was reduced with relaxin (2.6% [95% CI 0.4-16.8] vs 17.2% [9.6-29.6]; p=0.053). The number of serious adverse events was similar between groups. Interpretation: When given to patients with acute heart failure and normal-to-increased blood pressure, relaxin was associated with favourable relief of dyspnoea and other clinical outcomes, with acceptable safety.

Lancet (London, England) · randomised controlled trial · 314 citationsread the source →

The Surgeon as the Second Victim? Results of the Boston Intraoperative Adverse Events Surgeons' Attitude (BISA) Study.

Background: An intraoperative adverse event (iAE) is often directly attributable to the surgeon's technical error and/or suboptimal intraoperative judgment. We aimed to examine the psychological impact of iAEs on surgeons as well as the surgeons' attitude about iAE reporting. Study design: We conducted a web-based cross-sectional survey of all surgeons at 3 major teaching hospitals of the same university. The 29-item questionnaire was developed using a systematic closed and open approach focused on assessing the surgeons' personal account of iAE incidence, emotional response to iAEs, available support systems, and perspective about the barriers to iAE reporting. Results: The response rate was 44.8% (n = 126). Mean age of respondents was 49 years, 77% were male, and 83% performed >150 procedures/year. During the last year, 32% recalled 1 iAE, 39% recalled 2 to 5 iAEs, and 9% recalled >6 iAEs. The emotional toll of iAEs was significant, with 84% of respondents reporting a combination of anxiety (66%), guilt (60%), sadness (52%), shame/embarrassment (42%), and anger (29%). Colleagues constituted the most helpful support system (42%) rather than friends or family; a few surgeons needed psychological therapy/counseling. As for reporting, 26% preferred not to see their individual iAE rates, and 38% wanted it reported in comparison with their aggregate colleagues' rate. The most common barriers to reporting iAEs were fear of litigation (50%), lack of a standardized reporting system (49%), and absence of a clear iAE definition (48%). Conclusions: Intraoperative AEs occur often, have a significant negative impact on surgeons' well-being, and barriers to transparency are fear of litigation and absence of a well-defined reporting system. Efforts should be made to support surgeons and standardize reporting when iAEs occur.

Journal of the American College of Surgeons · cohort or longitudinal · 110 citationsread the source →

Nausea and vomiting of pregnancy: Effects on quality of life and day-to-day function.

Aims: To investigate the effect of nausea and vomiting of pregnancy (NVP) on quality of life (QoL) and activities of daily living/socioeconomic function in a contemporary Australian setting. Materials and methods: Observational, single centre prospective cohort study using validated survey instruments in pregnant women at 9-16 weeks gestation at a tertiary metropolitan women's hospital in Sydney, Australia. QoL measured by the Short-Form Health Survey (SF-12) was compared between those with and without NVP. NVP severity scores were correlated with QoL scores, work patterns and medication use. Results: Of 116 participants, 72% had NVP, with no baseline (including mental health) differences between women with or without NVP. As classified by modified Pregnancy-Unique-Quantified-Emesis (PUQE) survey, 42% had mild symptoms, 55% moderate and 1% severe. SF-12 Physical Component Summary (PCS) scores were significantly lower for those with NVP (P < 0.001), but not Mental Component Summary (MCS) scores (P = 0.11). Decreasing QoL was associated with increasing NVP severity (P < 0.001), most markedly in the physical domain (P < 0.001). Only 39% of women used any NVP treatment and 15% pharmacotherapy. Most used treatments were vitamin B6 , ginger, metoclopramide and natural remedies. Significantly more women with NVP required time off work (45% vs 16%, P = 0.003). Conclusions: NVP is a physically morbid disease, affecting most pregnancies. NVP has a significant detrimental impact on QoL, especially physical QoL and work function. Despite this, we found low treatment utilisation, even in those with moderate/severe symptoms. Women should be encouraged to seek assistance for NVP and further education is required to improve practitioner awareness and management.

The Australian & New Zealand journal of obstetrics & gynaecology · cohort or longitudinal · 40 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 →

Psychosexual outcome after labiaplasty: a prospective case-comparison study.

Introduction and hypothesis: Our goal was to determine psychosexual outcome after labiaplasty in the long-term with specific measures of genital body image and sexual dysfunction. Method: We conducted a prospective study with a matched-comparison group of women not wanting labiaplasty. Forty-nine women were compared against a group of 39 women matched for age, sexual orientation, ethnicity, and marital status. The labiaplasty group was assessed before, 3 months after and between 11 and 42 months after surgery. The comparison group was assessed at two time points 3 months apart to control for the passage of time. The primary outcome measure was the Genital Appearance Satisfaction (GAS) scale. Results: Of the 49 women receiving labiaplasty, 19 (38.8 %) were lost to follow-up but were reassessed clinically. Twenty-four of 25 (96 %) women in the labiaplasty group showed a reliable and clinically significant improvement on the GAS scale 3 months after the procedure; 21/23 (91.3 %) showed an improvement at the long-term follow-up. A large effect size was found for improvements on the GAS scale in the labiaplasty group. Small-effect sizes were found for improvements in sexual functioning. Nine women obtaining labiaplasty met diagnostic criteria for body dysmorphic disorder before the operation; eight lost that diagnosis at the 3-month follow-up; 26 % reported minor side effects. Conclusions: Labiaplasty is effective in improving genital appearance and sexual satisfaction, but larger studies are required to determine the prevalence of potential side effects.

International urogynecology journal · cohort or longitudinal · 66 citationsread the source →

Persistence of multiple illnesses in World Trade Center rescue and recovery workers: a cohort study.

Background: More than 50,000 people participated in the rescue and recovery work that followed the Sept 11, 2001 (9/11) attacks on the World Trade Center (WTC). Multiple health problems in these workers were reported in the early years after the disaster. We report incidence and prevalence rates of physical and mental health disorders during the 9 years since the attacks, examine their associations with occupational exposures, and quantify physical and mental health comorbidities. Methods: In this longitudinal study of a large cohort of WTC rescue and recovery workers, we gathered data from 27,449 participants in the WTC Screening, Monitoring, and Treatment Program. The study population included police officers, firefighters, construction workers, and municipal workers. We used the Kaplan-Meier procedure to estimate cumulative and annual incidence of physical disorders (asthma, sinusitis, and gastro-oesophageal reflux disease), mental health disorders (depression, post-traumatic stress disorder [PTSD], and panic disorder), and spirometric abnormalities. Incidence rates were assessed also by level of exposure (days worked at the WTC site and exposure to the dust cloud). Findings: 9-year cumulative incidence of asthma was 27·6% (number at risk: 7027), sinusitis 42·3% (5870), and gastro-oesophageal reflux disease 39·3% (5650). In police officers, cumulative incidence of depression was 7·0% (number at risk: 3648), PTSD 9·3% (3761), and panic disorder 8·4% (3780). In other rescue and recovery workers, cumulative incidence of depression was 27·5% (number at risk: 4200), PTSD 31·9% (4342), and panic disorder 21·2% (4953). 9-year cumulative incidence for spirometric abnormalities was 41·8% (number at risk: 5769); three-quarters of these abnormalities were low forced vital capacity. Incidence of most disorders was highest in workers with greatest WTC exposure. Extensive comorbidity was reported within and between physical and mental health disorders. Interpretation: 9 years after the 9/11 WTC attacks, rescue and recovery workers continue to have a substantial burden of physical and mental health problems. These findings emphasise the need for continued monitoring and treatment of the WTC rescue and recovery population. Funding: Centers for Disease Control and Prevention and National Institute for Occupational Safety and Health.

Lancet (London, England) · 230 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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Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and in heart rate variability. J Physiol | ISI | Google and function and cardiovascular interactions and Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and interval variability in isolated working rat hearts at various conditions and Res | PubMed | Google A, A, and and autonomic of in patients with mild Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google Malpas SC. Neural on cardiovascular and Am J Physiol Heart Physiol 2002.Link | ISI | Google and thermoregulation in and rats in a Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and effects on reflex responses to mental stress in Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and reflex during orthostatic in Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and and responses to and are in rats. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and and in a by cycle. Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google and of humoral heart rate regulation in the Am J Physiol Regul Integr Comp Physiol 281: 2001.Link | ISI | Google Armour and within the intrinsic cardiac nervous system contribute to chronotropic regulation. Am J Physiol Regul Integr Comp Physiol 285: 2003.Link | ISI | Google Rentero N, A, and McAllen of cardiac vagal motoneurons in rat nucleus ambiguus. Am J Physiol Regul Integr Comp Physiol 283: 2002.Link | ISI | Google and modulate control of heart rate in conscious rats. Am J Physiol Regul Integr Comp Physiol 2002.Link | ISI | Google and central actions of angiotensin to increase arterial pressure. Am J Physiol Regul Integr Comp Physiol 280: 2001.Link | ISI | Google and modulate control of renal sympathetic nerve activity. 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American Journal of Physiology-Regulatory, Integrative and Comparative Physiology · review · 309 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 →

Associations between religious and spiritual variables and neuroimmune activity in survivors of breast cancer: a feasibility study.

Purpose: Chronic stress is associated with neuroimmune inflammation and adverse outcomes in breast cancer survivors. Some breast cancer survivors rely on religious and spiritual (R/S) variables to manage stress after breast cancer treatment. A spiritually based psychoneuroimmunological (PNI) model of health suggests that R/S variables influence neuroimmune activity; however, these associations are not well-established. A pilot study was conducted to assess the feasibility of studying associations between R/S variables and neuroimmune biomarkers in breast cancer survivors. Method: Salivary alpha-amylase (sAA) and interleukin-6 (IL-6) were sampled among women previously treated for breast cancer. The primary aim was to assess feasibility and acceptability of the sampling protocol. A secondary aim explored associations between sAA, IL-6, R/S variables, and health outcomes. Result: Forty-one women completed the study. Biomarker sampling yielded 246 acceptable specimens used for analysis. SAA was detectable in 96% of specimens and IL-6 was detectable in 44% of specimens. The R/S variables with the strongest associations to sAA were spiritual self-rank (rs = .39; p < .05) and forgiveness (rs = .40; p < .05). The R/S variable with the strongest association to salivary IL-6 was positive congregational support (rs = .42; p < .05). Conclusion: Feasibility and acceptability of the sampling protocol were confirmed. Reference ranges for sAA and IL-6 for female breast cancer survivors are presented. Results suggest that spiritual beliefs and religious practices are associated with neuroimmune activity, adding credence to a spiritually based PNI model of health. Findings lay the foundations for future R/S-based interventions to promote health and well-being in breast cancer survivors.

Supportive care in cancer : official journal of the Multinational Association of Supportive Care in Cancer · 3 citationsread the source →

Yoga at Every Size: A Preliminary Evaluation of a Brief Online Size-Inclusive Yoga and Body Gratitude Journaling Intervention to Enhance Positive Embodiment in Higher Weight College Women.

The present pilot randomized controlled trial (RCT) evaluated the feasibility, acceptability, and preliminary efficacy of a 4-week online yoga and body gratitude journaling intervention for strengthening positive embodiment among racially-diverse higher weight college women. Seventy-five participants were initially randomized to either the yoga condition (n = 36) or to a wait-list control (n = 39). Participants completed measures of positive and negative body image, weight bias internalization, self-compassion, drive for leanness, and physical activity acceptance at both baseline and post. Preliminary results among the 42 analyzed completers (mean age = 20.9, SD = 2.4; 30% Black or African American) revealed acceptable feasibility given the low-intensity nature of the intervention reflected in a 36% attrition rate. Self-reported adherence was strong for the yoga component with 81% of participants indicating that they practiced with the videos ≥3-4 times per week as suggested. Although 71% reported completing the body gratitude journal ≥1-2 times per week, daily adherence was minimal. Acceptability was also high among participants randomized to the yoga condition as indicated by 86% expressing at least moderate levels of satisfaction with the overall program. Qualitative feedback from participants further supported the acceptability of the program and pointed to important areas in further refining the protocol in the future. Preliminary efficacy was supported by significant reductions in internal body shame and gains in body appreciation, functional body appreciation, functional body satisfaction, functional body awareness, and behavioral commitment to physical activity engagement among the yoga vs. wait-list control participants. These promising findings once replicated in larger, higher-powered trials may have important implications for extending the reach and accessibility of mind-body wellness practices like yoga to benefit racially-/ethnically-diverse college women of higher weight. This research is further responsive to the growing need for efficacious remotely-delivered, and scalable behavioral health interventions in the ongoing era of the COVID-19 pandemic. However, additional research is warranted to explore ways of enhancing engagement of participants with lower levels of positive embodiment and to further incentivize the journaling component of the intervention.

Frontiers in global women's health · 10 citationsread the source →

Mental and psychosocial health among current and former professional footballers.

Background: In common with elite athletes from other sport disciplines, severe or recurrent injuries in professional footballers are considered to be major physical and psychosocial stressors, which may predispose to mental health problems during and after their career. Aims: To determine the prevalence of mental health problems and psychosocial difficulties in current and former professional footballers, and to explore the association between psychosocial stressors and the health conditions studied. Methods: Based on validated scales, a paper and electronic questionnaire was developed for current and former professional footballers and distributed by the World Footballers' Union (FIFPro) and players' unions in six countries. Prevalence was calculated and cross-sectional analyses were conducted. Results: The response rate was 29% with 253 responses available for analysis. The prevalence of mental health complaints ranged from 5% (burnout) to 26% (anxiety/depression) in 149 current players and from 16% (burnout) to 39% (anxiety/depression) in 104 former footballers. The prevalence of psychosocial problems ranged from 3% (low self-esteem) to 26% (adverse nutrition behaviour) in current players and from 5% (low self-esteem) to 42% (adverse nutrition behaviour) in former footballers. In both current and former players, mental health problems were significantly associated with low social support (odds ratio [OR] = 1.1) and recent life events (OR = 1.4-1.6). In former players, previous surgery was significantly associated with smoking (OR = 1.9). Conclusions: The prevalence of mental health problems and/or psychosocial difficulties in current and former professional footballers was found to be high. The presence of mental health problems was associated with low social support and recent life events.

Occupational medicine (Oxford, England) · 101 citationsread the source →

Emotional responses and psychological health among young people amid climate change, Fukushima's radioactive water release, and wars in Ukraine and the Middle East, and the mediating roles of media exposure and nature connectedness: a cross-national analysis.

Background: New global crises are emerging, while existing global crises remain unabated. Coping with climate change, the radioactive water released into the Pacific Ocean subsequent to the Fukushima nuclear accident in Japan, and the wars in Ukraine and the Middle East (hereafter referred to as the wars) as individual crises can negatively affect the psychological health of young people, but little is known about the compounded impact of multiple crises. We aimed to examine: (1) the emotional responses of young people towards each individual crisis, (2) how aggregate levels of emotional engagement in global crises might pose different potential trajectories in psychological health, and (3) the protective or exacerbating role of media exposure and nature connectedness as mediators on psychological health outcomes of young people. Methods: We conducted a cross-national online survey among young people (aged 18-29 years) from China, Portugal, South Africa, the USA, and the UK. We adopted stratified purposive sampling and distributed the survey using online platforms (www.wenjuan.com and www.prolific.com). Individuals were eligible for inclusion in our analysis if they were literate in Chinese or English and had no mental disorders diagnosed within the past 12 months. Participants were asked questions on their demographic characteristics and time spent on social media, including proportion of time exposed to media pertaining to global crises of interest, and they completed surveys based on validated scales that measure depression, anxiety, stress, and wellbeing, as well as emotional responses to each global crisis and nature relatedness. We assessed the survey results using descriptive statistics, ANOVA tests, cluster analysis for individual emotional responses, and structural equation modelling for the aggregate measure of emotional engagement towards individual global crises. Findings: Between Oct 20 and Nov 3, 2023, 2579 individuals participated in the survey, of whom 400 participants from each country (200 male and 200 female participants) were included in our analysis (mean age 24·36 years [SD 2·86]). The mean emotional engagement varied between the global crises of interest (on a scale from 0 to 68, where 0 indicates no emotional response and 68 indicates strong emotional responses across 17 different emotions; wars: 32·42 [SD 14·57]; climate change: 28·79 [14·17]; radioactive water: 21·26 [16·08]), and emotional engagement also varied by country; for instance, for respondents from China, mean emotional engagement in radioactive water was relatively high (39·15 [10·72]) compared with the other countries, and for respondents from the USA, engagement with the wars was relatively low (29·45 [15·78]). We found significant variations in the level of emotional engagement between different crises, with distinct emotional profiles observed among individual countries. To assess the role of media exposure and nature connectedness on psychological outcomes, using structural equation modelling, we constructed a multi-country model comprising Portugal, South Africa, the USA, and the UK, and a standalone model for China. These models elucidated associations between emotional engagement and psychological distress and wellbeing, explaining substantial portions of the variance in both. Notably, while greater emotional engagement in the ecological crises (ie, climate change and radioactive water) generally predicted worse psychological health outcomes, we found the direction of effect for war crises to have positive outcomes for mental health in the standalone China model. Additionally, we found that media exposure mediated the negative effect of wars on psychological distress in the multi-country model, and positive psychological wellbeing in the standalone China model. Moreover, nature connectedness emerged as a potent mediator, effectively mitigating the adverse mental health effects of emotional engagement with some crises, such as radioactive water and climate change. Interpretation: Our findings offer valuable insights into the nuanced dynamics of emotional engagement in global crises and its implications for mental health outcomes among young people across diverse global contexts. Further research is needed to understand the contribution of ongoing and new global crises towards a compounded negative future outlook on young people's mental health to identify effective communication and intervention strategies that can mitigate the effect of this global challenge. Funding: Research Grants Council of Hong Kong, China.

The Lancet. Planetary health · 9 citationsread the source →

Establishing Clinically Relevant Severity Levels for the Central Sensitization Inventory.

Objectives: The aim of this study was to create and validate severity levels for the central sensitization inventory (CSI), a valid and reliable patient-reported outcome instrument designed to identify patients whose presenting symptoms may be related to a central sensitivity syndrome (CSS; eg, fibromyalgia, chronic fatigue syndrome, irritable bowel syndrome), with a proposed common etiology of central sensitization (CS). Methods: Based on CSI score means and standard deviations from previously published subject samples, the following CSI severity levels were established: subclinical = 0 to 29; mild = 30 to 39; moderate = 40 to 49; severe = 50 to 59; and extreme = 60 to 100. The concurrent validity of the CSI severity levels was then confirmed in a separate chronic pain patient sample (58% with a CSS diagnosis and 42% without) by demonstrating associations between CSI scores and (1) the number of physician-diagnosed CSSs; (2) CSI score distributions in both CSS and non-CSS patient samples; (3) patient-reported history of CSSs; and (4) patient-reported psychosocial measures, which are known to be associated with CSSs. Results: Compared to the non-CSS patient subsample, the score distribution of the CSS patient subsample was skewed toward the higher severity ranges. CSI mean scores moved into higher severity levels as the number of individual CSS diagnoses increased. Patients who scored in the extreme CSI severity level were more likely to report previous diagnoses of fibromyalgia, chronic fatigue syndrome, temporomandibular joint disorder, tension/migraine headaches, and anxiety or panic attacks (P < 0.01). CSI severity levels were also associated with patient-reported depressive symptoms, perceived disability, sleep disturbance, and pain intensity (P ≤ 0.02). Conclusion: This study provides support for these CSI severity levels as a guideline for healthcare providers and researchers in interpreting CSI scores and evaluating treatment responsiveness.

Pain practice : the official journal of World Institute of Pain · 199 citationsread the source →

Psychological distress, depression, anxiety, and life satisfaction following COVID-19 infection: evidence from 11 UK longitudinal population studies.

Background: Evidence on associations between COVID-19 illness and mental health is mixed. We aimed to examine whether COVID-19 is associated with deterioration in mental health while considering pre-pandemic mental health, time since infection, subgroup differences, and confirmation of infection via self-reported test and serology data. Methods: We obtained data from 11 UK longitudinal studies with repeated measures of mental health (psychological distress, depression, anxiety, and life satisfaction; mental health scales were standardised within each study across time) and COVID-19 status between April, 2020, and April, 2021. We included participants with information available on at least one mental health outcome measure and self-reported COVID-19 status (suspected or test-confirmed) during the pandemic, and a subset with serology-confirmed COVID-19. Furthermore, only participants who had available data on a minimum set of covariates, including age, sex, and pre-pandemic mental health were included. We investigated associations between having ever had COVID-19 and mental health outcomes using generalised estimating equations. We examined whether associations varied by age, sex, ethnicity, education, and pre-pandemic mental health, whether the strength of the association varied according to time since infection, and whether associations differed between self-reported versus confirmed (by test or serology) infection. Findings: Between 21 Dec, 2021, and July 11, 2022, we analysed data from 54 442 participants (ranging from a minimum age of 16 years in one study to a maximum category of 90 years and older in another; including 33 200 [61·0%] women and 21 242 [39·0%] men) from 11 longitudinal UK studies. Of 40 819 participants with available ethnicity data, 36 802 (90·2%) were White. Pooled estimates of standardised differences in outcomes suggested associations between COVID-19 and subsequent psychological distress (0·10 [95% CI 0·06 to 0·13], I2=42·8%), depression (0·08 [0·05 to 0·10], I2=20·8%), anxiety (0·08 [0·05 to 0·10], I2=0·0%), and lower life satisfaction (-0·06 [-0·08 to -0·04], I2=29·2%). We found no evidence of interactions between COVID-19 and sex, education, ethnicity, or pre-pandemic mental health. Associations did not vary substantially between time since infection of less than 4 weeks, 4-12 weeks, and more than 12 weeks, and were present in all age groups, with some evidence of stronger effects in those aged 50 years and older. Participants who self-reported COVID-19 but had negative serology had worse mental health outcomes for all measures than those without COVID-19 based on serology and self-report. Participants who had positive serology but did not self-report COVID-19 did not show association with mental health outcomes. Interpretation: Self-reporting COVID-19 was longitudinally associated with deterioration in mental health and life satisfaction. Our findings emphasise the need for greater post-infection mental health service provision, given the substantial prevalence of COVID-19 in the UK and worldwide. Funding: UK Medical Research Council and UK National Institute for Health and Care Research.

The lancet. Psychiatry · 52 citationsread the source →

Long-term developmental effect of withholding parenteral nutrition in paediatric intensive care units: a 4-year follow-up of the PEPaNIC randomised controlled trial.

Background: The PEPaNIC randomised controlled trial, which recruited 1440 critically ill infants and children in 2012-15, showed that withholding parenteral nutrition for 1 week (late-parenteral nutrition), compared with early supplementation within 24 h of admission to the paediatric intensive care unit (early-parenteral nutrition), prevented infections, accelerated recovery, and improved neurocognitive development assessed 2 years later. Because several neurocognitive domains can only be thoroughly assessed from age 4 years onwards, we aimed to determine the effect of late-parenteral nutrition versus early-parenteral nutrition on physical, neurocognitive, and emotional and behavioural development 4 years after randomisation. Methods: This is a preplanned, blinded, 4-year follow-up study of participants included in the PEPaNIC trial (done at University Hospitals Leuven, Belgium; Erasmus Medical Centre Sophia Children's Hospital, Rotterdam, Netherlands; and Stollery Children's Hospital, Edmonton, AB, Canada) and of matched healthy children. Studied outcomes were anthropometrics; health status; parent-reported or caregiver-reported executive functions, and emotional and behavioural problems; and clinical tests for intelligence, visual-motor integration, alertness, motor coordination, and memory. Through multivariable linear and logistic regression analyses, after imputation for missing values (≤30%) and adjustment for risk factors, we investigated the effect of early-parenteral nutrition versus late-parenteral nutrition. This trial is registered with ClinicalTrials.gov, NCT01536275. Findings: Between March 8, 2016, and Nov 8, 2019, 684 children from the original PEPaNIC trial (356 from the late-parenteral nutrition group and 328 from the early-parenteral nutrition group) were assessed for neurocognitive development at 4-years follow-up. Compared with the control group (369 healthy children), children who had critical illness had lower height (β-estimate -2·11 [95% CI -3·15 to -1·06]; p<0·0001) and head circumference (-0·42 [-0·67 to -0·18]; p=0.00077); and worse health status (eg, hospital admission odds ratio 4·27 [95% CI 3·12 to 5·84]; p<0·0001), neurocognitive (eg, parent-reported or caregiver-reported total executive functioning β-estimate 3·57 [95% CI 1·95 to 5·18], p<0·0001; total intelligence quotient -7·35 [-9·31 to -5·39], p<0·0001), and parent-reported or caregiver-reported emotional and behavioural developmental outcomes (internalising 2·73 [1·19 to 4·28], p=0·00055; externalising 1·63 [0·19 to 3·08], p=0·027; and total behavioural problems 2·95 [1·44 to 4·46], p=0·00013), adjusted for risk factors. Outcomes were never worse in the late-parenteral nutrition group compared with the early-parenteral nutrition group, but patients in the late-parenteral nutrition group had fewer parent-reported or caregiver-reported internalising (β-estimate -1·88 [95% CI -3·69 to -0·07]; p=0·042), externalising (-1·73 [-3·43 to -0·03]; p=0·046), and total emotional and behavioural problems (-2·44 [-4·22 to -0·67]; p=0·0070) than patients who had received early-parenteral nutrition, after adjusting for risk factors, and were no longer different from healthy controls for these outcomes. Interpretation: Omitting early parenteral nutrition use for critically ill children did not adversely affect long-term outcomes 4 years after randomisation and protected against emotional and behavioural problems, further supporting the deimplementation of early parenteral nutrition. Funding: European Research Council, Methusalem, Flanders Institute for Science and Technology, Research Foundation Flanders, Sophia Foundation, Stichting Agis Zorginnovatie, Erasmus Trustfonds, and the European Society for Clinical Nutrition and Metabolism.

The Lancet. Child & adolescent health · 46 citationsread the source →

6-month multidisciplinary follow-up and outcomes of patients with paediatric inflammatory multisystem syndrome (PIMS-TS) at a UK tertiary paediatric hospital: a retrospective cohort study.

Background: Paediatric inflammatory multisystem syndrome temporally associated with SARS-CoV-2 (PIMS-TS) is a new, rare, post-infectious complication of SARS-CoV-2 infection in children. We aimed to describe the 6-month outcomes of PIMS-TS. Methods: This retrospective cohort study comprised children (aged <18 years) who fulfilled the UK Royal College of Paediatrics and Child Health (RCPCH) diagnostic criteria for PIMS-TS and were admitted to Great Ormond Street Hospital (London, UK) between April 4 and Sept 1, 2020. Patients were followed up by a multidisciplinary team of specialists at 6 weeks and 6 months after admission. Biochemical and functional outcomes were analysed. Findings: 46 children were included in this study. The median age at presentation was 10·2 years (IQR 8·8-13·3), 30 (65%) patients were male and 16 (35%) were female, 37 (80%) were from minority ethnic groups, and eight (17%) had pre-existing comorbidities. All patients had elevated markers of systemic inflammation at baseline. None of the patients died. By 6 months, systemic inflammation was resolved in all but one patient. 38 (90%) of 42 patients who had positive SARS-CoV-2 IgG antibodies within 6 weeks of admission remained seropositive at 6 months. Echocardiograms were normal in 44 (96%) of 46 patients by 6 months, and gastrointestinal symptoms that were reported in 45 (98%) of 46 patients at onset were present in six (13%) of 46 patients at 6 months. Renal, haematological, and otolaryngological findings largely resolved by 6 months. Although minor abnormalities were identified on neurological examination in 24 (52%) of 46 patients at 6 weeks and in 18 (39%) of 46 at 6 months, we found minimal functional impairment at 6 months (median Expanded Disability Status Scale score 0 [IQR 0-1]). Median manual muscle test-8 scores improved from 53 (IQR 43-64) during hospital admission to 80 (IQR 68-80) at 6 months, but 18 (45%) of 40 patients showed 6-min walk test results below the third centile for their age or sex at 6 months. PedsQL responses revealed severe emotional difficulties at 6 months (seven [18%] of 38 by parental report and eight [22%] of 38 by self report). 45 (98%) of 46 patients were back in full-time education (virtually or face to face) by 6 months. Interpretation: Despite initial severe illness, few organ-specific sequelae were observed at 6 months. Ongoing concerns requiring physical re-conditioning and mental health support remained, and physiotherapy assessments revealed persisting poor exercise tolerance. Longer-term follow-up will help define the extended natural history of PIMS-TS. Funding: None.

The Lancet. Child & adolescent health · 151 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 →

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 →

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 →

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 →

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 →

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 →

Emotional intelligence, emotional labor, and job satisfaction among physicians in Greece.

Background: There is increasing evidence that psychological constructs, such as emotional intelligence and emotional labor, play an important role in various organizational outcomes in service sector. Recently, in the "emotionally charged" healthcare field, emotional intelligence and emotional labor have both emerged as research tools, rather than just as theoretical concepts, influencing various organizational parameters including job satisfaction. The present study aimed at investigating the relationships, direct and/or indirect, between emotional intelligence, the surface acting component of emotional labor, and job satisfaction in medical staff working in tertiary healthcare. Methods: Data were collected from 130 physicians in Greece, who completed a series of self-report questionnaires including: a) the Wong Law Emotional Intelligence Scale, which assessed the four dimensions of emotional intelligence, i.e. Self-Emotion Appraisal, Others' Emotion Appraisal, Use of Emotion, and Regulation of Emotion, b) the General Index of Job Satisfaction, and c) the Dutch Questionnaire on Emotional Labor (surface acting component). Results: Emotional intelligence (Use of Emotion dimension) was significantly and positively correlated with job satisfaction (r=.42, p<.001), whereas a significant negative correlation between surface acting and job satisfaction was observed (r=-.39, p<.001). Furthermore, Self-Emotion Appraisal was negatively correlated with surface acting (r=-.20, p<.01). Self-Emotion Appraisal was found to influence job satisfaction both directly and indirectly through surface acting, while this indirect effect was moderated by gender. Apart from its mediating role, surface acting was also a moderator of the emotional intelligence-job satisfaction relationship. Hierarchical multiple regression analysis revealed that surface acting could predict job satisfaction over and above emotional intelligence dimensions. Conclusions: The results of the present study may contribute to the better understanding of emotion-related parameters that affect the work process with a view to increasing the quality of service in the health sector.

BMC health services research · 29 citationsread the source →

Spirituality, religiosity, and spiritual pain among caregivers of patients with advanced cancer.

Background: Caregivers of patients with advanced cancer often face physical, social, and emotional distress as well as spiritual pain. Limited research has focused on the spiritual aspects of caregivers' suffering in the palliative care setting. Methods: We interviewed 43 caregivers of patients with advanced cancer in our palliative care outpatient clinic. We determined demographic characteristics, religious affiliation, and relationship to the patient. Levels of spirituality, religiosity, and spiritual pain were self-reported using numeric rating scales (0 = lowest; 10 = highest). The participants completed various validated questionnaires to assess sleep disturbances, psychosocial distress, coping skills, and quality of life (QOL). Results: The median age was 52 years (range, 21-83); 29 (67%) were women, 34 (78%) were white, 7 (17%) were African American, and 2 (5%) were Hispanic; 39 (91%) were Christian, 1 (2%) was Jewish, and 1 (2%) was agnostic; 37 (86%) were married; 18 (42%) were working full time; and 25 (58%) were spouses. All considered themselves spiritual, and 98% considered themselves religious, with median scores of 8 (interquartile range, 6-10) and 8 (interquartile range, 4-9), respectively. All the caregivers reported that spirituality and religiosity helped them cope with their loved one's illness, and many reported that spirituality and religiosity had a positive impact on their loved one's physical (58%) and emotional (76%) symptoms. Spiritual pain was reported by 23 (58%), with a median score of 5 (interquartile range, 2-8). Caregivers with spiritual pain had higher levels of anxiety (median 10 vs 4; P = .002), depression (6 vs 2; P = .006), and denial (3 vs 2; P = .01); more behavioral disengagement (3 vs 2; P = 0.011) more dysfunctional coping strategies (19 vs 16; P < .001) and worse QOL (70 vs 51; P < .001) than those who did not have spiritual pain. Conclusions: The majority of caregivers of patients with advanced cancer considered themselves spiritual and religious. Despite this, there is high prevalence of spiritual pain in this population. Caregivers with spiritual pain experienced worse psychological distress and worse QOL. These findings support the importance of spiritual assessment of and spiritual support for caregivers in this setting.

The American journal of hospice & palliative care · 65 citationsread the source →

Pomegranate phenolics from the peels, arils, and flowers are antiatherogenic: studies in vivo in atherosclerotic apolipoprotein e-deficient (E 0) mice and in vitro in cultured macrophages and lipoproteins.

We have analyzed in vivo and in vitro the antiatherogenic properties and mechanisms of action of all pomegranate fruit parts: peels (POMxl, POMxp), arils (POMa), seeds (POMo), and flowers (POMf), in comparison to whole fruit juice (PJ). Atherosclerotic E 0 mice consumed POM extracts [200 microg of gallic acid equivalents (GAE)/mouse/day] for 3 months. Blood samples, peritoneal macrophages (MPM), and aortas were then collected. All POM extracts possess antioxidative properties in vitro. After consumption of PJ, POMxl, POMxp, POMa, or POMf by E (0) mice, the atherosclerotic lesion area was significantly decreased by 44, 38, 39, 6, or 70%, respectively, as compared to placebo-treated group, while POMo had no effect. POMf consumption reduced serum lipids, and glucose levels by 18-25%. PJ, POMxl, POMxp, POMf, or POMa consumption resulted in a significant decrement, by 53, 42, 35, 27, or 13%, respectively, in MPM total peroxides content, and increased cellular paraoxonase 2 (PON2) activity, as compared to placebo-treated mice. The uptake rates of oxidized-LDL by E (0)-MPM were significantly reduced by approximately 15% after consumption of PJ, POMxl, or POMxp. Similar results were obtained on using J774A.1 macrophage cell line. Finally, pomegranate phenolics (punicalagin, punicalin, gallic acid, and ellagic acid), as well as pomegranate unique complexed sugars, could mimic the antiatherogenic effects of pomegranate extracts. We conclude that attenuation of atherosclerosis development by some of the POM extracts and, in particular, POMf, could be related to the combined beneficial effects on serum lipids levels and on macrophage atherogenic properties.

Journal of agricultural and food chemistry · 145 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 →

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 →

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 →

STAR*D: revising conventional wisdom.

The STAR*D (Sequenced Treatment Alternatives to Relieve Depression) study used a series of sequenced, randomized treatment trials following a first and, if needed, subsequent treatment steps to define the tolerability and effectiveness of various options in both acute and longer term treatment. Adult outpatients (n=4041) with nonpsychotic major depressive disorder, substantial chronic and recurrent depression, and co-morbid psychiatric and general medical conditions were enrolled in 41 representative primary and specialty care settings. About one-third of participants remitted in first step treatment with citalopram, 50% of these within 6 weeks. Poorer outcomes were associated with minority status, socioeconomic disadvantage, more axis I and III co-morbid disorders, lower function and quality of life, and anxious and melancholic features. In step 2 medication switch, there were no significant differences in remission among within-class, out-of-class or dual-action agents: sertraline (27%), bupropion-sustained release (26%) and venlafaxine-extended release (25%). In step 2 medication augmentation of citalopram, there was no significant difference in remission between bupropion-sustained release (39%) and buspirone (33%), although participants using bupropion-sustained release had greater symptom reduction and better tolerability. There were no significant differences in remission in step 2 between cognitive therapy and medication treatment in either the switch (31% vs 27%) or augmentation (31% vs 33%) strategies, although participants in cognitive therapy augmentation had a longer time to remission than those in medication augmentation (55 vs 40 days). In step 3, there were no differences in remission between a switch to mirtazapine (8%) or nortriptyline (12%), or between augmentation with lithium (13%) or T(3) (triiodothyronine, liothyronine) [25%], although more participants discontinued lithium due to adverse effects than discontinued T(3). In the fourth step, there was no difference in remission between tranylcypromine (14%) or venlafaxine-extended release plus mirtazapine (16%), although the combination treatment had fewer adverse effects and had the advantages of not requiring a washout period or diet restrictions. Participants requiring more than two well delivered treatments may be characterized as treatment resistant given the substantially lower remission rates after that point. Treatment resistance was associated with more concurrent axis I or III co-morbid conditions, socioeconomic disadvantage, chronicity and melancholic or anxious features. However, if participants remained in treatment for up to four steps, about 67% reached remission. Times to remission were not substantially longer for later treatment steps. The importance of reaching remission is highlighted by the lower relapse rates in naturalistic follow-up for participants entering in remission compared with those entering with response but not remission (step 1: 34% vs 59%; step 2: 47% vs 68%; step 3: 42% vs 76%; step 4: 50% vs 83%). Clinical decision making based on the itemized measurement of symptoms and adverse effects at each treatment visit was feasible in STAR*D's real world settings and resulted in adequate dosages and durations of treatment that generally exceeded those typically found in practice settings. Although switch and augmentation strategies could not be directly compared due to the equipoise stratified randomized design, the higher remission rates at step 2 with medication augmentation are intriguing and merit further study.

CNS drugs · 236 citationsread the source →

Maternal depression and child development

Maternal depression is considered a risk factor for the socioemotional and cognitive development of children [1]. The current prevalence of depression in Canada averages at 6%, which is similar to the rates in other western countries [2] (the female-to-male ratio average is 2:1 [3]). However, the prevalence of postpartum depression is approximately 13% [4]. Women of childbearing age are particularly at risk for depression, and many of them experience high levels of social morbidity and depressive symptoms that are often unrecognized and untreated. Mothers already at risk for depression are particularly fragile during the first months postpartum. Maternal depression has consequences on the child’s development. Because physicians who care for infants and children encounter mothers repeatedly, it is important that they have the knowledge and skills for the detection of symptoms of maternal depression. The objectives of this statement are: To review the present knowledge on the consequences of maternal depression on the development of children at various ages; To review the evidence-based literature on the treatment of maternal depression and its impact on newborns, infants and children; and To review the role of the child’s physician in the detection of symptoms of maternal depression, and the coordination of appropriate support and management. A literature search for the past 15 years was conducted using the MEDLINE database, and by reviewing the bibliographies of the retrieved articles. Of particular interest were the prospective longitudinal cohort studies in which mothers were recruited during their pregnancy or postpartum period, and the children were assessed at regular intervals. Postpartum psychiatric disorders are generally divided into three categories: postpartum blues, postpartum psychosis and postpartum depression. Postpartum blues is a relatively common emotional disturbance with crying, confusion, mood lability, anxiety and depressed mood. The symptoms appear during the first week postpartum, last for a few hours to a few days and have few negative sequelae. At the other end of the spectrum, postpartum psychosis refers to a severe disorder beginning within four weeks postpartum, with delusions, hallucinations and gross impairment in functioning. Postpartum depression begins in or extends into the postpartum period and core features include dysphoric mood, fatigue, anorexia, sleep disturbances, anxiety, excessive guilt and suicidal thoughts [5]. The diagnosis requires that symptoms be present for at least one month and result in some impairment in the woman’s functioning [6]. Women who have experienced postpartum depression have a 50% to 62% risk for future depressions [7]. Other risk factors for postpartum depression include a history of mood disorders, depression symptoms during the pregnancy and a family history of psychiatric disorders [4]. Stress factors, such as negative life events, poor marital relationships, having a special needs infant or medically ‘fragile’ infant, lack of social support, drug abuse, and personal and family psychopathology, have been associated with postpartum depression in some studies, but other studies have found no association [6]. Postpartum depression tends to be milder than episodes of depression that occur at other times, with lower levels of anxiety, agitation, insomnia and somatic symptoms [8]. However, the duration seems to be the same in postpartum and nonpostpartum depression, and lasts several months [6]. The consequences on the child of maternal postpartum depression are not restricted to infancy, but can extend into toddlerhood, preschool age and even school age. Maternal depression that occurs later influences the development of the school-age child and the adolescent. Table 1 summarizes the consequences of maternal depression from prenatal issues to adolescence. Consequences of maternal depression Consequences of maternal depression The associations between maternal depression, maternal behaviour and child outcomes are complex, and not all studies have found a relationship between maternal depression and indicators of poor parenting. Variations in the type, severity, chronicity and timing of maternal depression [9], heterogeneity in sampling (community versus high-risk multiproblem samples), and potentiating risk factors, such as family adversity, low social support and financial stress [10], all contribute to differences in outcomes in children. On the other hand, stress factors can be responsible for adverse child outcomes in the absence of maternal depression. On a daily basis, infants repeatedly participate in interactive routines with their mothers. Maternal depression compromises the dyad’s capacity to mutually regulate the interaction, through two interactive patterns, intrusiveness or withdrawal. Intrusive mothers display a hostile affect, and disrupt the infant’s activity. The infants experience anger, turn away from the mother to limit her intrusiveness and internalize an angry and protective style of coping. Withdrawn mothers are disengaged, unresponsive, affectively flat and do little to support the infant’s activity. The infants are unable to cope or self-regulate this negative state, and develop passivity, withdrawal and self-regulatory behaviours (eg, looking away or sucking on thumb) [11],[12]. Infants of postnatally depressed mothers have been reported to show patterns of dysregulated attention and arousal. In a study by Murray [13], cognitive performance regarding the independent existence of objects was worse for infants of 61 postnatally depressed mothers than the infants of 42 nondepressed mothers, even after adjustment for contextual adversity. Depressed mothers are less likely to offer contingent stimulation to their infants [14], and this disrupts their performance on nonsocial learning tasks [15]. Another factor that may interfere with learning is the negative affect shown by infants of depressed mothers, even when they are interacting with nondepressed adults [16]. It has been documented that an infant’s own negative affect interferes with learning and the ability to process information [17]. Depressed mothers generally show less attentiveness and responsiveness to their children’s needs. They are also poor models for negative mood regulation and problem solving. Longitudinal studies have compared the behaviours of depressed and nondepressed mothers, and the outcome of their children. They showed that depressed mothers were less likely to set limits on their children and to follow through if they did set limits [18]. Children of depressed mothers appeared more passively noncompliant, with less mature expressions of age-appropriate autonomy [19]. They were rated by their dysphoric mothers as being more vulnerable, and having more internalizing (depressed) and externalizing problems (aggressive and destructive), which are associated with lower interaction ratings [20]. They were also more likely to respond negatively to friendly approaches, more likely to engage in low-level physical play and less likely to engage in individual creative play than control children [21]. These aspects of child behaviour were associated with postnatal depression, even when taking adverse situations such as marital conflict, and demographic variables, such as maternal age, ethnicity, socioeconomic status, marital status, child’s age and number of siblings, into account. Studies on large samples all agree on the negative impact of maternal postpartum depression on a child’s cognitive development. Early experience with insensitive maternal interactions (as in maternal postpartum depression) appears to be predictive of poorer cognitive functioning [22]. Boys may be more sensitive than girls to the effects of the mother’s illness. In a study by Sharp et al [23], only boys showed a decrease on standardized tests of intellectual attainment (mainly on indexes of abstract intelligence, reasoning about opposites and analogies) and the “draw-a-child” task. Other aspects of cognitive development, such as cognitive-linguistic functioning [24], have also been shown to be negatively affected, and there were also deficits on the perceptual and performance scale [25]. Outcome effects were independent of birth order, maternal education, family income, marital status and social support. Various studies have shown that school-age children of depressed mothers display impaired adaptive functioning, including internalizing and externalizing problems. Although the studies reviewed by Beardslee et al [26] were uncontrolled studies, a more recent review by Downey and Coyne [27] included studies using control groups (matched for age of parents, occupational status, ethnicity, marital status, and number and age of children), standardized diagnostic criteria to identify parental depression and valid measures of psychological functioning in children. Billings and Moos [28] showed that family stress and low support added to the prediction of child disturbance beyond that accounted for by having a depressed parent. However, the study of Lee and Gotlib [29] comparing children of depressed psychiatric mothers and nondepressed psychiatric mothers showed that the child’s adjustment was more strongly related to the severity of maternal psychopathology than to diagnosis status. Children of depressed parents are also at higher risk of psychopathology, including affective (mainly depression), anxiety and conduct disorders. Hammen et al [30] compared children from four groups of mothers (mothers with unipolar disorder, bipolar disorder and chronic medical illness, and normal mothers) with no differences in ethnicity, age, socioeconomic status or educational level. They showed that, even with the effects of chronic stress statistically controlled, there were still differences in the psychosocial outcome variables among groups, and there was particular impairment in children of unipolar mothers [30]. Other studies [31]–[34], in which there were no demographic differences (age, marital status and socioeconomic level) between depressed and nondepressed parents, have confirmed an increased risk of psychopathology in the children of depressed parents. It seems that onset of a major depression disorder before 30 years of age in parents increases the risk of their children developing depression quite early during childhood [33],[34]. It is somewhat difficult to delineate which behavioural disorders are due to maternal depression and other environmental factors, and which are due to genetic susceptibility. There seems to be an association between attention deficit/hyperactivity disorder (ADHD) in children and maternal mental health, as shown by a cross-sectional study by Lesesne et al [35]. Using the 1998 National Health Interview Study on 9529 mother-child dyads, they found an association between an activity-limiting depression, anxiety or emotional problem in mothers, and ADHD in their children aged four to 17 years, even after adjusting for the child’s age, sex, race, household income and type of family structure [35]. In a longitudinal study of 132 children by Hay et al [36], lower IQ scores, attentional problems, difficulties in mathematical reasoning and special educational needs were significantly more frequent in children whose mothers were depressed at three months postpartum than in controls. In addition, boys were more affected than girls. However, academic difficulties in children of depressed mothers were not mediated by parental IQ, sociodemographic variables or the mother’s mental health after the postpartum depressive episode. Generally, adolescence is a vulnerable period for affective illness and major depressive disorder, which are observed twice as often in girls than in boys [37]. Two cross-sectional studies showed that adolescents with a depressed parent suffered from psychosocial maladjustment [38] and experienced a significantly higher rate of affective disorder than adolescents of nonaffective psychiatric control parents [39]. Longitudinal studies have consistently reported higher rates of major depression and other psychopathology (anxiety disorders, conduct disorders and substance abuse disorders) in adolescents with an affectively ill parent than in control families with similar demographic characteristics (age, ethnicity, socioeconomic status and educational level). Hammen et al [40] followed a cohort of 92 children/adolescents between the ages of eight and 16 years over a three-year They found that children/adolescents with mothers from unipolar depression higher rates of affective disorders, with frequent the disorders in children/adolescents with mothers from bipolar depression were less et al families with children between and years over a They observed higher rates of major depression, disorder and in the of depressed parents than in the major depression onset was between the ages of 15 and Beardslee et al at an of a health with children between the ages of and At the of the children/adolescents with an affectively ill parent at least one of an affective illness compared with in the control years the rates of affective disorders were and and of affectively ill parents onset and a number of in school-age ADHD and learning into adolescence [35]. It has been in many studies that some children with depressed do not display behavioural and that some factors may or the effects of parental depression contextual risk factors, marital life social support lower social and lower maternal are factors that may parental depression and parenting. In a study of mothers with major depressive disorder the child’s et al showed that contextual risk factors mediated the between maternal depression and child behaviour problems. The role of and in child development are to be on mothers, the for the infant is the However, in their study of to et al showed that infants of depressed mothers with their nondepressed who the effects of the mother’s depression on infant interaction In addition, a cross-sectional study of families with children between the ages of and years showed that in families in which the mother was children showed lower social and emotional if the also a psychiatric The role of has been in the of marital to a review by Downey and Coyne marital to children externalizing problems, and increases their risk for depression by and parental depression. differences have been in some studies with boys being more vulnerable and by maternal depression than girls. of the child also to the of parental depression. It has been shown that mothers more negative of their child’s less in their parental and more often A child with a more and be more to their depressed mother’s negative behaviour and not show a of Other of in children include social and cognitive skills that them attention from adults other than their depressed parents and their depressed of and It seems that an of the illness and by the child that or is not to for the behaviour is important to the development of in a child Although the interaction between parents and their child is beyond the of the present it has been that parents of children higher depression than control parents and that is a of maternal depression Because many depressive episodes occur during childbearing years, the to be between the mother’s and a who from depression with is at high risk of [7]. during pregnancy is associated with prenatal poor higher low birth substance abuse and The morbidity of depression during pregnancy be the risk of have been by that are associated with a low risk of and the However, et al did not in major or in taking compared with controls. Another study on taking showed an in when the was during the In the period, it seems that behavioural and rate to are in infants to in et al compared children of mothers with a during children of mothers with and control children of nondepressed mothers who did not during adjusting for the duration and severity of maternal depression, duration of number of depressive episodes after maternal IQ and socioeconomic status, the study showed that and no adverse effects on the IQ, development or behaviour of children between 15 and months of age In a et al compared children to depressed mothers who not to during pregnancy and children to mothers with Although the on the indexes were similar in groups of children to children to lower on the indexes and the factors of the of the of is the of It is important that a depressed mother who to be the is in the postnatal period, there is a risk of with negative consequences on the emotional and behavioural development of the On the other hand, all are in of the information from and to a review by and the and are the of or have been in children or through To infant when postpartum depressed mothers, it is important to all maternal of and and to the of environmental and maternal illness is interaction with the infant or other it is to on the of treatment it is to the of the be on the mother’s and experience of adverse effects with a particular risk of interactions with and adverse effects associated with a particular on mothers and their Maternal be to for the that control of the depressive is and the in pregnancy be in the postnatal The infant’s to can be by the of and it and approximately to after the mother has the Although there is no on the of during pregnancy and be considered in the of a as by the of et al be considered in who have to severe symptoms and who have not to show that and appear to be quite during pregnancy and the postnatal period, and may be during pregnancy and Because of the consequences of maternal depression on an infant’s development, many studies have postnatal mothers. have on the mother’s mood state, her to or of the infant’s and the negative about the infant’s behaviours [16]. to the of by mothers to their infants or by mothers to and their attention support and have been in depressed and as as their and development treatment have been an interactive treatment at problems by the mother in the of her infant that support, and education, with of depressed mothers and their a and in a infant over a period to of months mothers from the showed more interaction and their infants and scores, as as more interaction behaviours than in the control children and adolescents from families with a depressed parent may from a on about the illness within the family and on the development of in the In a study by Beardslee et al families who an to child and a parent with an affective disorder were to a or a parents information about the and symptoms of childhood and depression, and the for within the However, the cognitive to the life of the in the showed more behaviour and among parents and including higher levels of from parents to children about the illness and by the child of the affective illness et al compared with interaction The treatment on the mother’s of her infant and her relationship with the infant, and aspects of the mother’s own childhood and early already the interaction to identify behaviours and to of an infant’s a of there was a in The sleep and difficulties maternal to increased and control In addition, maternal and infants more less and showed more on and problems experienced by depressed postpartum mothers. In a study of depressed postpartum depressive symptoms and social adjustment in the compared with the control on the has also been in the of postpartum depression in with at least one risk factor for postpartum depression and are and is the in Canada seems to be for to depression, it has many drug interactions There are no on its and it be as during pregnancy on its during are a it was observed that was in at a low and the lower limit of in the infant’s A prospective study of found no differences in the of in over the first of life compared with a control to the of the on the Health to of for depression using the Health or the of of from the Health However, it is strongly that a high of for depression among their In their statement the adults for depression in that have in to treatment and of of In their for the of on the that the physical and mental health of the parents in their and review the of attention to their own mental health needs. In a of three et al reported that more than of mothers the impact of depression on the child’s health and and that more than of mothers the role in and to However, a recent study showed that maternal depression was by health care et al reported that in their ability to maternal depression and their of knowledge and The role in maternal depression be one of followed by for and There be a about family history of depression and about episodes of maternal depression. have been and to postpartum depression of that may information about postpartum depression are in Table depression is the can and with the mother’s physician or an appropriate to psychiatric between the mother’s physician and the child’s physician is to information about postpartum depression are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in to information about postpartum depression are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in are about being a that is or difficult to care are in is the past have often been by depressed or the past have often been by having little interest or in many mothers, care may be their with health care The child’s physician may be the first to of the and difficulties of a the child’s physician can the depressed mother her mood affect her and contribute to the child’s problems. of include infant sleep problems, child social and family It is important to a high of of maternal depression when child behaviour problems are during a medical for the depression of the mother over behavioural for the Because postpartum depression can have effects on mothers and children and its prevalence occurs at approximately three it has been to for postpartum depression at the and care In school-age children and the of difficulties in child adjustment and impaired functioning at and in school the physician to the of maternal depression. in families with a history of depression, one in that may depressed or display other psychopathology, at adolescence. These often and for a for the The child’s physician has a role in to the appropriate for the and the parent. that children of depressed mothers are at risk for and behavioural problems, as as their for developing a depressive disorder the physician conduct regular of the offer and them early for more and of and behavioural disorders. Postpartum depression occurs in approximately 13% of and often it is there is often a of between and psychiatric and treatment of the lack of The infant of a depressed mother is at risk for developing negative affect and dysregulated attention and arousal. and of depressed mothers are at risk for developing poor internalizing and externalizing problems, and difficulties in cognitive functioning and in social interactions with parents and and children of depressed parents are at risk for impaired adaptive functioning and psychopathology, including conduct disorders, affective disorders and anxiety disorders. They are also at risk for ADHD and learning risk factors such as marital and life may parental depression and child behaviour problems. On the other hand, some children develop through an social cognitive skills and of the illness. with during pregnancy and is but no major or physical and to the or the infant have been The of the mother’s depression to the low of on the or the the of the and development of infants and the physician to of mother-child interaction and behavioural and problems in the such they in the of maternal depression, a few and with the mother’s physician or psychiatric Mothers who have during pregnancy be that of the to that there is no increased risk of or Mothers who have during pregnancy be about the of their child studies have not shown adverse for differences whose to be Mothers who have during be that of the to that there are no or in children to such through Mothers be that on are and that such not be during pregnancy and on of and of of The in this statement do not an of treatment or to be taking into individual may be are current at of

Paediatrics & Child Health · 312 citationsread the source →

Greater striatopallidal adaptive coding during cue-reward learning and food reward habituation predict future weight gain.

Animal experiments indicate that after repeated pairings of palatable food receipt and cues that predict palatable food receipt, dopamine signaling increases in response to predictive cues, but decreases in response to food receipt. Using functional MRI and mixed effects growth curve models with 35 females (M age=15.5±0.9; M BMI=24.5±5.4) we documented an increase in BOLD response in the caudate (r=.42) during exposure to cues predicting impending milkshake receipt over repeated exposures, demonstrating a direct measure of in vivo cue-reward learning in humans. Further, we observed a simultaneous decrease in putamen (r=-.33) and ventral pallidum (r=-.45) response during milkshake receipt that occurred over repeated exposures, putatively reflecting food reward habitation. We then tested whether cue-reward learning and habituation slopes predicted future weight over 2-year follow-up. Those who exhibited the greatest escalation in ventral pallidum responsivity to cues and the greatest decrease in caudate response to milkshake receipt showed significantly larger increases in BMI (r=.39 and -.69 respectively). Interestingly, cue-reward learning propensity and food reward habituation were not correlated, implying that these factors may constitute qualitatively distinct vulnerability pathways to excess weight gain. These two individual difference factors may provide insight as to why certain people have shown obesity onset in response to the current obesogenic environment in western cultures, whereas others have not.

NeuroImage · 88 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 →

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

World Psychiatry · 157 citationsread the source →