World Federation of Societies of Biological Psychiatry (WFSBP) Guidelines for Biological Treatment of Unipolar Depressive Disorders, Part 1: Update 2013 on the acute and continuation treatment of unipolar depressive disorders Financial Conflicts of Interest and Conclusions About Neuraminidase Inhibitors for Influenza Opioid Modulation With Buprenorphine/Samidorphan as Adjunctive Treatment for Inadequate Response to Antidepressants: A Randomized Double-Blind Placebo-Controlled Trial. Issues related to the conduct of systematic reviews: a focus on the nutrition field. Antidepressant treatment for post-natal depression. Systematic comparison of study quality criteria. Aripiprazole augmentation in major depressive disorder: a double-blind, placebo-controlled study in patients with inadequate response to antidepressants. Improvement in functional outcomes with adjunctive aripiprazole versus placebo in major depressive disorder: a pooled post hoc analysis of 3 short-term studies. Biofeedback for treatment of awake and sleep bruxism in adults: systematic review protocol The effectiveness of yoga to prevent diabetes mellitus type 2 Is the Comparison between Exercise and Pharmacologic Treatment of Depression in the Clinical Practice Guideline of the American College of Physicians Evidence-Based? The Effectiveness of Psychosocial Interventions as Adjuncts to Orthopaedic Surgery: A Systematic Review Protocol Effectiveness of interventions that assist caregivers to support people with dementia living in the community: a systematic review. Serotonergic and Noradrenergic Modulation of Emotion Processing by Single Dose Antidepressants Interventions for domestic violence among pregnant women in low- and middle-income countries: a systematic review protocol The impact of outcome reporting bias in randomised controlled trials on a cohort of systematic reviews Effectiveness of interventions that assist caregivers to support people with dementia living in the community: a systematic review Effectiveness of parent‐centred interventions for the prevention and treatment of childhood overweight and obesity in community settings: a systematic review The B-VITAGE trial: A randomized trial of homocysteine lowering treatment of depression in later life Elusive search for effective provider interventions: a systematic review of provider interventions to increase adherence to evidence-based treatment for depression Efficacy and tolerability of flexibly-dosed adjunct TC-5214 (dexmecamylamine) in patients with major depressive disorder and inadequate response to prior antidepressant Nonoperative Management or ‘Watch and Wait’ for Rectal Cancer with Complete Clinical Response After Neoadjuvant Chemoradiotherapy: A Critical Appraisal How to write an evidence-based clinical review article. Reporting of Sex Effects by Systematic Reviews on Interventions for Depression, Diabetes, and Chronic Pain Evidence-based clinical practice guideline for the evaluation of potentially malignant disorders in the oral cavity: A report of the American Dental Association. Association between response to lithium augmentation and the combined DEX/CRH test in major depressive disorder. Summary: 2017 International Consultation on Incontinence Evidence-Based Surgical Pathway for Pelvic Organ Prolapse Efficacy and safety of adjunctive aripiprazole in major depressive disorder in older patients: a pooled subpopulation analysis. Examining the efficacy of adjunctive aripiprazole in major depressive disorder: a pooled analysis of 2 studies. Identifying effective behavioural components of Intervention and Comparison group support provided in SMOKing cEssation (IC-SMOKE) interventions: a systematic review protocol Technology-adaptable interventions for treating depression in adults with cognitive impairments: protocol for a systematic review Driving up the Quality and Relevance of Research Through the Use of Agreed Core Outcomes Post-herpetic neuralgia Nonpharmacologic Versus Pharmacologic Treatment of Adult Patients With Major Depressive Disorder: A Clinical Practice Guideline From the American College of Physicians Two Phase III randomised double-blind studies of fixed-dose TC-5214 (dexmecamylamine) adjunct to ongoing antidepressant therapy in patients with major depressive disorder and an inadequate response to prior antidepressant therapy
Abstract Objectives . This 2013 up date of the practice guidelines for the biological treatment of unipolar depressive disorders was developed by an international Task Force of the World Federation of Societies of Biological Psychiatry ( WFSBP ) . The goal has been to systematic ally review all available evidence pertaining to the treatment of unipolar depressive disorders , and to produce a series of practice recommendations that are clinical ly and scientifically meaningful based on the available evidence . The guidelines are intended for use by all physicians seeing and treating patients with these conditions . Methods . The 2013 up date was conducted by a systematic up date literature search and appraisal . All recommendations were approved by the Guidelines Task Force . Results . This first part of the guidelines ( Part 1 ) covers disease definition , classification , epidemiology , and course of unipolar depressive disorders , as well as the management of the acute and continuation phase treatment . It is primarily concerned with the biological treatment ( including antidepressants , other psychopharmacological medications , electroconvulsive therapy , light therapy , adjunctive and novel therapeutic strategies ) of adults . Conclusions . To date , there is a variety of evidence -based antidepressant treatment options available . Nevertheless there is still a substantial proportion of patients not achieving full remission . In addition , somatic and psychiatric comorbidities and other special circumstances need to be more thoroughly investigated . Therefore , further high- quality informative r and omized controlled trials are urgently needed Industry funding and author financial conflicts of interest may influence the production and synthesis of scientific evidence ( 1 ) . Associations with the pharmaceutical company developing and marketing a drug have been found to influence the design of trials ( 2 ) , the conduct of trials ( 3 ) , and the reporting of trial results ( 47 ) . Furthermore , financial ties and industry funding seem to result in greater rates of favorable conclusions in clinical trials examining new drugs ( 812 ) . Fewer studies have considered the potential influence of financial conflicts of interest on the synthesis of clinical evidence in systematic review s ( 13 , 14 ) . Neuraminidase inhibitors , which are used in the prophylaxis and treatment of seasonal and p and emic influenza , have been the subject of ongoing uncertainty about their specific clinical benefits ( 15 , 16 ) . This is the result of not only the continuing emergence of strains with unknown drug responses but also the increasing awareness in the medical community that , until recently , its knowledge of the safety and efficacy of these drugs has been incomplete ( 17 ) . Despite the abundance of clinical trials and publications on neuraminidase inhibitors , the details of many key trials had not been disclosed ( 18 , 19 ) . As a result , systematic review ers analyzing and synthesizing evidence on the effectiveness of these agents have faced incomplete information , unresolved discrepancies in the data , and a high risk of publication and reporting biases among the primary clinical trials ( 20 , 21 ) . This prompted extensive efforts to access complete records of all published and unpublished clinical trials from manufacturers , culminating in the publication of several review s on the basis of comprehensive clinical study reports and potentially changing the way systematic review s will be undertaken in the future ( 2227 ) . Review s of neuraminidase inhibitors exhibit wide variation in their conclusions , ranging from strong endorsements of the use of these agents in the prophylaxis and treatment of influenza ( 28 , 29 ) to more conservative assessment s question ing the evidence on the drugs ' safety and efficacy ( 15 , 30 ) . The reasons for this discordance in review conclusions are likely multifactorial and may be related in part to the manner in which evidence is accessed , synthesized , and presented ( 23 , 27 ) , both in terms of the numerical results and the authors ' emphasis and interpretation ( 31 , 32 ) . Our aim was to determine whether there is an association between financial conflicts of interest and the favorable presentation of evidence in systematic review s on the use of neuraminidase inhibitors for the prophylaxis and treatment of influenza . Methods Data Sources Systematic review s were identified in PubMed , PubMed In Process , EMBASE , and the Cochrane Data base of Systematic Review s. Search es were done using the keywords influenza , neuraminidase inhibitors , oseltamivir , zanamivir , peramivir , and laninamivir . Articles were retrieved if the search terms appeared in the title or abstract or were included as data base-specific keywords . In PubMed and EMBASE , search es were also constrained to review publication types . We limited our search to English- language articles published since 1 January 2005 . These articles were manually review ed to identify those that focused on the use of neuraminidase inhibitors for influenza prophylaxis or treatment ( such as excluded articles primarily about drug development or other manufacturing processes ) . We selected all review s that used a systematic search protocol , which we defined as the inclusion and reporting of an explicit search strategy , including reasons for subsequent exclusion of articles . The final search es were done on 26 May 2014 . Cochrane review s are periodically up date d to incorporate new evidence , and the results and conclusions are resynthesized as indicated . The authors of these review s are typically different , and there may be differences in the methods as well as the results and language of the review . These up date d review s were included separately . Other Cochrane review s are occasionally rewritten by a subset of the authors for publication in medical journals as abridged versions to increase dissemination . These reports have separate peer review s and are prepared on the basis of a selection of the complete results . We considered these review s separately as well but also did a sensitivity analysis in which they were combined with the original Cochrane review s. Data Extraction Financial conflicts of interest were identified for all authors of the review s and included affiliations with or funding from the pharmaceutical company manufacturing any of the neuraminidase inhibitors under review . We defined financial conflicts of interest as employment , the funding of grants paid to an author or an author 's research group , and the funding of medical writers for the systematic review . These financial conflicts of interest were identified using information about affiliations or funding listed in the systematic review s , as well as in any other articles published by one of the authors during the 3 years before the publication of the index systematic review . In addition , we search ed authors ' personal and institutional Web sites ; lists of disclosures from GlaxoSmithKline ( Research Triangle Park , North Carolina ) and Roche Pharmaceuticals ( Basel , Switzerl and ) ; and performed Web search es combining the names of the authors , drugs , and pharmaceutical companies to identify any additional information about financial relationships . Details of the specific financial conflicts of interest identified for each author are listed in Appendix Table 1 . Appendix Table 1 . Financial Conflicts of Interest Among Authors of the Systematic Review s For each systematic review , we recorded whether prophylaxis or treatment was assessed , the forms of evidence to be included ( such as r and omized , controlled trials and observational studies ) , the specific clinical outcomes assessed , the population s examined , and whether meta-analyses were done . We also examined whether the review s included information about the validity or quality of the primary literature . In particular , we recorded whether there were statements addressing nonpublication of primary studies or publication bias , including tests done by the review ers to assess for bias in meta-analyses ( such as the Egger or Begg test [ 33 , 34 ] ) , difficulty in accessing comprehensive study data , and the prevalence or role of industry in conducting and funding the primary studies . Data Analysis Two investigators were provided with redacted copies of each review that did not include the review s ' authors , their affiliations , or information on financial conflicts of interest . These versions also did not contain the journal name , journal formatting , or the article 's acknowledgments or references . The investigators independently evaluated the review s and classified the prophylaxis and treatment assessment s as favorable or not favorable toward the use of neuraminidase inhibitors . They were instructed to do this grading on the basis of the entirety of the review text without restriction to conclusions or recommendations made in any specific section of the review , thus allowing them to take into account the emphasis and interpretation of the authors throughout the review . The agreement between the investigators was strong at 86 % ( Cohen , 0.72 ; P < 0.001 ) . Disagreements were resolved by a third investigator using the same redacted copies . Descriptive analyses were done to examine the associations between financial conflicts of interest and the grading of the systematic review s. A sensitivity analysis excluding the summary review s was done to further examine this association . We also assessed the association between financial conflicts of interest and the inclusion of statements addressing the validity or quality of the primary evidence . Role of the Funding Source This study was funded by the Australian National Health and Medical Research Council . The funding source had no role in the design and conduct of the study , analysis of the results , or the decision to su bmi t the manuscript for publication . Results We identified 827 published articles across the 4 data bases using the specified search criteria , with 26 systematic review s included in the final cohort ( Figure ) . Thirteen review s examined prophylaxis and 24 examined treatment of influenza , accounting for 37 distinct assessment s ( Appendix Table 2 ) . In terms of review methods , 7 were Cochrane systematic review s and 19 conducted and reported a meta- analysis ( 73 % ) . The evidence inclusion criteria were limited to r and omized , controlled trials for 14 of the systematic review s ( 54 % ) , and 5 included evidence from clinical study reports or patient-level data . The main population s examined were healthy adults ( 18 of 26 systematic review s ) , children ( 13 of 26 ) , and hospitalized patients ( 6 of 24 ) . The outcome measures for prophylaxis assessment s included influenza-like illness and laboratory-confirmed influenza . For the treatment assessment s , the outcomes were illness duration , influenza-related complications , hospitalization , and mortality , mostly in combination . Five review s were up date s of previous Cochrane review s , and 3 were summary review s based on Cochrane review s. Figure . Summary of evidence search and selection . Eligible systematic review s included those with outcomes related to the prophylaxis or treatment of influenza . Appendix Table 2 . Characteristics of Systematic Review s Examining Prophylaxis and Treatment Outcomes for Neuraminidase Inhibitors Association Between Financial Conflicts of Interest and Favorable Assessment s Seven of the 26 systematic review s ( 27 % ) , corresponding to 8 of the 37 assessment s ( 22 % ) , were associated with a financial conflict of interest ( Appendix Table 1 ) . We identified financial conflicts of interest in publications other than the index systematic review in 2 cases , and no additional OBJECTIVE Major depressive disorder has been associated with dysregulation of the endogenous opioid system . The authors sought to determine whether opioid modulation achieved through administration of ALKS 5461 , a combination of a μ- and κ-opioid partial agonist , buprenorphine , and a μ-opioid antagonist , samidorphan , would exhibit antidepressant activity in patients with major depression . METHOD A multicenter , r and omized , double-blind , placebo-controlled , two-stage sequential parallel comparison design study was conducted in adults with major depression who had an inadequate response to one or two courses of antidepressant treatment . Participants were r and omly assigned to receive adjunctive treatment with 2 mg/2 mg of buprenorphine/samidorphan ( the 2/2 dosage group ) , 8 mg/8 mg of buprenorphine/samidorphan ( the 8/8 dosage group ) , or placebo .  Antidepressant effect was measured based on change from baseline to the end of 4 weeks of treatment on the 17-item Hamilton Depression Rating Scale ( HAM-D ) , the Montgomery-Åsberg Depression Rating Scale ( MADRS ) , and the Clinical Global Impressions severity scale ( CGI-S ) . RESULTS Compared with the placebo group , there were significantly greater improvements in the 2/2 dosage group across the three depression outcome measures ( HAM-D : -2.8 , 95 % CI=-5.1 , -0.6 ; MADRS : -4.9 , 95 % CI=-8.2 , -1.6 ; CGI-S : -0.5 , 95 % CI=-0.9 , -0.1 ) . There was also evidence of improvement in the 8/8 dosage group , although it did not achieve statistical significance . Overall , the buprenorphine/samidorphan combinations were well tolerated , and there was no evidence of opioid withdrawal on treatment discontinuation . CONCLUSIONS The buprenorphine/samidorphan combination is a novel and promising c and i date for treatment of major depressive disorder in patients who have an inadequate response to st and ard antidepressants Systematic review s ( SRs ) are an increasingly popular evidence -based tool and are often used to answer complex research questions across many different research domains . Early SR methodology was advanced by social scientists , and the term meta- analysis was coined by a social scientist who also conducted research in psychology . SRs have recently become popular in healthcare and are likely to be beneficial in any field . The aim of this report is to highlight issues in SR conduct with a focus on the field of nutrition and to make recommendations on improving SR conduct in this area . Development of the research question is probably the most important step in conducting an SR . The 4 main components of an answerable question are 1 ) the patient , population , or problem ; 2 ) the intervention , independent variable , or exposure ; 3 ) the comparators ; and 4 ) the dependent variables or outcomes of interest . The question will be used to determine the optimal methods for conducting the SR . SRs often include study design s beyond r and omized trials and do not always include a meta- analysis of the results . Other topics explored include underst and ing and interpreting discordant review s and the importance of reporting tools [ eg , QUality Of Reporting Of Meta-analyses ( QUOROM Statement ) or CONsoli date d St and ards Of Reporting of Trials ( CONSORT Statement ) ] . Recommendations are then provided , such as developing a capacity-building program , search ing the primary literature for research gaps , and extending reporting tools such as the QUOROM Statement to the field of nutrition BACKGROUND : Postnatal depression is a common disorder , which can have profound short and long term effects on maternal morbidity , the new infant and the family as a whole . Social factors appear to be particularly important in the aetiology and prognosis of postnatal depression and treatment is often largely social support and psychological interventions . It is not known whether antidepressants are an effective and safe choice for treatment of this disorder . OBJECTIVES : To evaluate the effectiveness of different antidepressant drugs  and compare their effectiveness with other forms of treatment . To assess any adverse effects of antidepressants in the mother or the nursing baby . SEARCH STRATEGY : The registers of clinical trials maintained and up date d by the Cochrane Depression , Anxiety and Neurosis Group and the Cochrane Pregnancy and Childbirth Group were search ed . Other data bases ( outlined below ) were also search ed and contacts were made with pharmaceutical companies and experts in the field . SELECTION CRITERIA : All trials were considered in which women with depression in the first six months postpartum were r and omised to receive antidepressants alone or in combination with another treatment , or to receive any other treatment including placebo . DATA COLLECTION AND ANALYSIS : Data was extracted independently from the trial reports by the review ers . Missing information was requested from investigators wherever possible . Data was sought to allow an " intention to treat " analysis . MAIN RESULTS : Only one trial could be included in this review , leaving most of the objectives of the review unfulfilled . Appleby et al ( 1997 ) reported that Fluoxetine was significantly more effective than placebo and , after an initial session of counselling , as effective as a full course of cognitive-behavioural counselling in the treatment of postnatal depression . There was no interaction between medication and counselling . REVIEW ER 'S CONCLUSIONS : Women with postnatal depression can be effectively treated with fluoxetine , which is as effective as a course of cognitive-behavioural counselling in the short-term . However , more trials with a longer follow-up period are needed to compare different antidepressants in the treatment of postnatal depression , and to compare antidepressant treatment with psychosocial interventions .  This is an area that has been neglected despite the large public health impact described above Approaches for the systematic review and evaluation of chemical toxicity are currently being reconsidered , with a specific focus on the evaluation of individual studies and their integration into the overall body of evidence . This renewed interest has arisen , in part , as a result of several prominent review s of these approaches by special committees of the National Research Council ( NRC ) , among others . We conducted a critical evaluation of several available frameworks for evaluating study quality . We assessed the criteria separately for human , animal , and in vitro studies as well as for systematic review s. We then evaluated commonalities across disciplines . We also considered the potential implication s of applying criteria frameworks and how they bear on fundamental risk assessment questions . We found that the available frameworks within each discipline differed in terms of their intended purpose and level of guidance for decision making . All the frameworks across disciplines shared common themes , however , including the adequate reporting of specific details of study conditions and design / protocol , selection and r and omization of study groups ( where applicable ) , outcome assessment methods and applicability ( e.g. , validity and reliability ) , avoidance of selective reporting , and the consideration of potential confounders or bias . We identified the most informative study quality considerations , which will enable research ers to implement more objective and st and ardized methods for evaluating studies and , ultimately , improve risk assessment methods INTRODUCTION Effective management of  major depressive disorder ( MDD ) continues to be a challenging task for psychiatrists and primary care physicians . This trial evaluated the efficacy and safety of adjunctive aripiprazole versus antidepressant monotherapy in patients with MDD and independently replicated the positive findings of two similar trials . METHODS Patients ( N=1,147 ) with MDD experiencing a major depressive episode and a history of inadequate response to antidepressant monotherapy were enrolled ( week 0 ) ; 827 received single-blind adjunctive placebo plus open-label antidepressant ( escitalopram , fluoxetine , paroxetine controlled release , sertraline , or venlafaxine extended release ) for 8 weeks to confirm inadequate response to antidepressants ; 349 patients with inadequate response were r and omized ( 1:1 ) to double-blind , adjunctive placebo ( n=172 ) or adjunctive aripiprazole ( n=177 ; 2 - 20 mg/day ) . Primary outcome was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) Total score from baseline ( week 8) to endpoint ( week 14 ) . RESULTS Clinical ly significant improvements in depressive symptoms as assessed by decreases in the MADRS Total score were greater with adjunctive aripiprazole ( -10.1 ) than placebo ( -6.4 ; P<.001 ) . Remission rates were greater for adjunctive aripiprazole than for adjunctive placebo ( week 14 , 36.8 % vs 18.9 % ; P<.001 ) . Completion rates with adjunctive aripiprazole and placebo were high ( 83 % vs. 87 % ) and discontinuations due to adverse events were low ( 6.2 % vs 1.7 % ) . CONCLUSION For some patients with MDD who do not obtain adequate symptom relief with antidepressant monotherapy , adjunctive therapies can significantly improve depressive symptoms . As reported , adjunctive aripiprazole was associated with a two-fold higher remission rate than adjunctive placebo . This , and previous studies , have shown that discontinuations due to adverse events were low and completion rates were high , and has indicated that both antidepressant and aripiprazole in combination were relatively well-tolerated and safe . This is the third consecutive clinical trial , in the absence of a failed trial , to demonstrate that aripiprazole augmentation to antidepressants is an efficacious and well-tolerated treatment for patients with MDD who do not respond adequately to st and ard antidepressant monotherapy ( Clinical Trials.gov study NCT00105196 ) OBJECTIVE To evaluate the effect of adjunctive aripiprazole to antidepressant therapy ( ADT ) on functional outcomes , as assessed by the Sheehan Disability Scale ( SDS ) . METHOD A post hoc analysis of pooled data from 3 similarly design ed r and omized , placebo-controlled trials was conducted ( CN138 - 139 [ September 2004-December 2006 ] , CN138 - 163 [ June 2004-April 2006 ] , and CN138 - 165 [ March 2005-April 2008 ] ) . Patients with DSM-IV major depressive disorder who had a prior inadequate response to ADT received adjunctive aripiprazole or placebo to st and ard ADT . The change from baseline to endpoint on total SDS score and on individual SDS domains and the distributional categorical shifts of patient-reported severity of functional impairment on the SDS were assessed . RESULTS Aripiprazole compared to placebo augmentation produced significant improvements in self-reported functioning levels in the SDS mean total score ( -1.2 vs -0.7 , P ≤ .001 ) and social life ( -1.4 vs -0.7 , P ≤ .001 ) and family life ( -1.4 vs -0.7 , P ≤ .001 ) domains . Additionally , a significant number of patients exhibited a shift from a severe/moderate level of impairment at baseline to a mild level of functional impairment after 6 weeks of adjunctive aripiprazole treatment compared with placebo in the SDS mean total score ( P = .001 ) and social life ( P ≤ .001 ) and family life ( P = .001 ) scores . CONCLUSIONS Aripiprazole augmentation of st and ard antidepressant therapy result ed in significant improvements in both total and individual domains of functioning , as assessed by the SDS , with significant categorical shifts from severe/moderate to mild levels of functioning compared with placebo augmentation . TRIAL REGISTRATION Clinical Trials.gov identifiers : NCT00095823 , NCT00095758 , and NCT00105196 Background Bruxism is a disorder of jaw-muscle activity characterised by repetitive clenching or grinding of the teeth which results in discomfort and damage to dentition . The two clinical manifestations of the condition ( sleep and awake bruxism ) are thought to have unrelated aetiologies but are palliated using similar techniques . The lack of a definitive treatment has prompted renewed interest in biofeedback , a behaviour change method that uses electronic detection to provide a stimulus whenever bruxism occurs . This systematic review aims to provide a comprehensive overview of the state of research into biofeedback for bruxism ; to assess the efficacy and acceptability of  biofeedback therapy in management of awake bruxism and , separately , sleep bruxism in adults ; and to compare findings between the two variants . Methods A systematic review of published literature examining biofeedback as an intervention directed at controlling primary bruxism in adults . We will search electronic data bases and the grey literature using a predefined search strategy to identify r and omised and non-r and omised studies , technical reports and patents . Search es will not be restricted by language or date and will be exp and ed through contact with authors and experts , and by following up reference lists and citations . Two authors , working independently , will conduct screening of search results , study selection , data extraction and quality assessment and a third will resolve any disagreements . The primary outcomes of acceptability and effectiveness will be assessed using only r and omised studies , segregated by bruxism subtype . A meta- analysis of these data will be conducted only if pre-defined conditions for quality and heterogeneity are met , otherwise the data will be summarized in narrative form . Data from non-r and omised studies will be used to augment a narrative synthesis of the state of technical developments and any safety-related issues . PROSPERO registration number : CRD42013006880 . Discussion Biofeedback is not new , but its place in the clinical management of bruxism remains unclear . New research , and the availability of miniaturized consumer- grade devices , makes a systematic review timely to guide treatment decisions and inform future research Background : Type 2 diabetes mellitus ( T2DM ) is becoming a leading problem worldwide . Emerging reports reveal alarming evidence of increasing prevalence of T2DM that has reached p and emic levels . Despite the significant incidence , there are limited reliable data re sources and comprehensive systematic review and meta- analysis on the effects of yoga on people who are a prediabetic or high risk for developing T2DM . Objective : The objective of this protocol is to conduct a full-scale systematic review and meta-analyses on the effects of yoga on people who are prediabetes or high risk of developing T2DM . Methods : The articles enrolled in the study will be retrieved from the online data bases between 2002 and the date the search es are executed . The search es will be repeated just before the final analyses and further relevant studies for inclusion . We will conduct a bibliographic search in data bases : Medline / PubMed , Scopus , Cochrane Library , EBSCO , and IndMED using keywords including prediabetes state , high risk for diabetes , metabolic syndrome , and yoga . A defined search strategy will be implemented along with selection criteria to obtain full-text articles of relevant studies . This study protocol was prepared according to the Preferred Reporting Items for Systematic Review s and Meta- Analysis for Protocol s 2015 guidelines . There will be no language restrictions . Ethics and dissemination : The proposed study will be based on published studies and publicly available anonymized data without directly involving human participants and therefore requires neither formal human ethical review nor approval by a human research ethics committee . We published an outline of the protocol in the International Prospect i ve Register of Systematic Review s ( PROSPERO ) in 2018 . We plan to disseminate the findings of this systematic review and meta- analysis through publication in a peer- review ed journal and presentation at relevant conference proceedings . In addition , we believe the results of the systematic review will have implication s for policy and practice . We will prepare policymaker summary using a vali date d format , disseminate through social media and email discussion groups . Review registration number : PROSPERO registration number CRD Major depression disorder is most commonly treated with antidepressants . However , due to their side effects clinicians seek non-pharmacologic options , and one of these is exercise . The literature on the benefits of exercise for depression is extensive . Nevertheless , two recent review s focusing on antidepressants vs. other therapies as a basis for clinical practice guidelines recommended mainly antidepressants , excluding exercise as a viable choice for treatment of depression . The aim of this perspective is to analyze the literature exploring the reasons for this discrepancy . Two categories of publications were examined : r and omized controlled trials ( RCTs ) and meta-analyses or systematic review s. Based on this re assessment , RCTs comparing exercise to antidepressants reported that exercise and antidepressants were equally effective . RCTs comparing exercise combined with antidepressants to antidepressants only reported a significant improvement in depression following exercise as an adjunctive treatment . Almost all the review s examining exercise vs. other treatments of depression , including antidepressants , support the use of exercise in the treatment of depression , at least as an adjunctive therapy . The two review s examining pharmacologic vs. non-pharmacologic therapies as a basis for clinical practice guidelines examined limited evidence on exercise vs. antidepressants . In addition , it is possible that academics and health care practitioners are skeptical of viewing exercise as medicine . Maybe , there is a reluctance to accept that changes in lifestyle as opposed to pharmacological treatment can alter biological mechanisms . Longitudinal studies are needed for assessing the effectiveness of exercise in real clinical setting s , as well as studies exploring dose-response relationship between exercise and depression AIMS Pain and anxiety are commonly reported among those undergoing orthopaedic surgery . Improvement in anxiety and pain control might be achieved by supplementing st and ard care with psychological interventions . However , the effectiveness of adjunctive psychosocial interventions in anxiety and pain control have not been addressed sufficiently by previous systematic review s in orthopaedic surgeries . The present study aim ed to assess the effectiveness of adjunctive psychosocial techniques to improve perioperative clinical care in orthopaedic surgery , to identify the most effective intervention types and to evaluate potential moderators . METHODS We will perform a systematic review and meta- analysis to address the study aims . PubMed , PsycINFO , CINAHL and ProQuest Dissertations & Theses will be search ed between 1980 and 2015 . Prospect i ve controlled clinical trials completed in adults , contrasting st and ard care and st and ard care supplemented with psychosocial methods  , will be eligible for inclusion . Effectiveness will be assessed through the outcomes of postoperative pain intensity , analgesic requirement , perioperative anxiety , quality of life and postoperative recovery . The results of a r and om-effect meta- analysis will be reported . To aid implementation of best practice , moderating effects of the type and timing of psychosocial intervention , type of surgical intervention and type of anaesthesia will be evaluated through meta-regression . Sensitivity analyses and subgroup contrasts will follow as necessary . DISCUSSION Recommendations will be made to improve medical care in orthopaedic procedures . The quality of evidence will be rated using GRADE criteria . Copyright © 2016 John Wiley & Sons , OBJECTIVES The objective of this review was to assess the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . INCLUSION CRITERIA Types of participants Adult caregivers who provide support for people with dementia living in the community ( non-institutional care).Types of interventions Interventions design ed to support caregivers in their role such as skills training , education to assist in caring for a person living with dementia and support groups/programs . Interventions of formal approaches to care design ed to support caregivers in their role , care planning , case management and specially design ated members of the healthcare team - for example dementia nurse specialist or volunteers trained in caring for someone with dementia . Types of studies This review considered any meta-analyses , systematic review s , r and omised control trials , quasi-experimental studies , cohort studies , case control studies and observational studies without control groups that addressed the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . SEARCH STRATEGY The search sought to identify published studies from 2000 to 2005 through the use of electronic data bases . Only studies in English were considered for inclusion . The initial search was conducted of the data bases , CINAHL , MEDLINE and PsychINFO using search strategies adapted from the Cochrane Dementia and Cognitive Improvement Group . A second more extensive search was then conducted using the appropriate Medical Subject Headings ( MeSH ) and keywords for other available data bases . Finally , h and search ing of reference lists of articles retrieved and of core dementia , geriatric and psycho geriatric journals was undertaken . ASSESSMENT OF QUALITY Method ological quality of each of the articles was assessed by two independent review ers using appraisal checklist developed by the Joanna Briggs Institute and based on the work of the Cochrane Collaboration and Centre for Review s and Dissemination . DATA COLLECTION AND ANALYSIS St and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each included study reported in the meta- analysis . Results from comparable groups of studies were pooled in statistical meta- analysis using Review Manager Software from the Cochrane Collaboration . Heterogeneity between combined studies was tested using st and ard chi-square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . RESULTS A comprehensive search of relevant data bases , h and search ing and cross referencing found 685 articles that were assessed for relevance to the review . Eighty-five papers appeared to meet the inclusion criteria based on title and abstract , and the full paper was retrieved . Of the 85 full papers review ed , 40 were accepted for inclusion , three were systematic review s , three were meta- analysis , and the remaining 34 were r and omised controlled trials . For the r and omised controlled trials that were able to be included in a meta- analysis , st and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each . Results from comparable groups of studies were pooled in statistical meta- analysis using Review Manager Software and heterogeneity between combined studies was assessed by using the chi-square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . The results are discussed in two main sections . Firstly it was possible to assess the effectiveness of different types of caregiver interventions on the outcome categories of depression , health , subjective well-being , self-efficacy and burden . Secondly , results are reported by main outcome category . For each of these sections , meta- analysis was conducted where it was possible ; otherwise , a narrative summary describes the findings . EFFECTIVENESS OF INTERVENTION TYPE Four categories of intervention were included in the review - psycho-educational , support , multi-component and other . Psycho-educational Thirteen studies used  psycho-educational interventions  , and all but one showed positive results across a range of outcomes . Eight studies were entered in a meta- analysis . No significant impact of psycho-educational interventions was found for the outcome categories of subjective well-being , self-efficacy or health . However , small but significant results were found for the categories of depression and burden . Support Seven studies discussed support only interventions and two of these showed significant results . These two studies were suitable for meta- analysis and demonstrated a small but significant improvement on caregiver burden . Multi-component Twelve of the studies report multi-component interventions and 10 of these report significant outcomes across a broad range of outcome measures including self-efficacy , depression , subjective well-being and burden . Unfortunately because of the heterogeneity of study design s and outcome measures , no meta- analysis was possible . Other interventions Other interventions included the use of exercise or nutrition which result ed in improvements in psychological distress and health benefits . Case management and a computer aided support intervention provided mixed results . One cognitive behavioural therapy study reported a reduction in anxiety and positive impacts on patient behaviour . EFFECTIVENESS OF INTERVENTIONS USING SPECIFIC OUTCOME CATEGORIES In addition to analysis by type of intervention it was possible to analyse results based on some outcome categories that were used across the studies . In particular the impact of interventions on caregiver depression was available for meta- analysis from eight studies . This indicated that multi-component and psycho-educational interventions showed a small but significant positive effect on caregiver depression . Five studies using the outcome category of caregiver burden  were entered into a meta- analysis and findings indicated that there were no significant effects of any of interventions . No meta- analysis was possible for the outcome categories of health , self-efficacy or subjective well-being . IMPLICATION S FOR PRACTICE From this review there is evidence to support the use of well- design ed psycho-educational or multi-component interventions for caregivers of people with dementia who live in the community . Factors that appear to positively contribute to effective interventions are those which : Factors which do not appear to have benefit in interventions are those which Serotonergic and noradrenergic pathways are the main targets of antidepressants . Their differential effects on emotion processing-related brain activation are , however , to be further characterized . We aim ed at elucidating the neural sites of action of an acute differential serotonergic and noradrenergic influence on an emotion-processing task , which was earlier shown to be associated with depressiveness . In a single-blind pseudo-r and omized crossover study , 21 healthy subjects ( 16 subjects finally included in the analysis ) participated to ingest a single dose at three time points of either 40 mg citalopram , a selective serotonin-reuptake inhibitor , 8 mg reboxetine , a selective noradrenaline-reuptake inhibitor , or placebo 2–3 h before functional magnetic resonance imaging ( fMRI ) . During fMRI , subjects performed a task comprising the anticipation and perception of pictures of either ‘ known ’ ( positive , negative , neutral ) or ‘ unknown ’ valence ( r and omly 50 % positive or negative ) . In direct comparison with citalopram and with placebo , reboxetine increased brain activity in the medial thalamus . Citalopram modulated certain prefrontal and insular areas more prominently . Other frontal and parieto-occipital areas were modulated by both drugs . In conclusion , the functional network involved in emotional information processing could be modulated by the acute application of selective noradrenergic and serotonergic drugs revealing a noradrenergic effect in thalamic and frontal areas , and a prefrontal and insular focus of serotonergic modulation . These findings could have implication s for future selection criteria concerning personalized antidepressant medication in depression Background Violence during pregnancy is a global problem , associated with serious health risks for both the mother and baby . Evaluation of interventions targeted for reducing or controlling domestic violence ( DV ) is still in its infancy , and the majority of findings are primarily from high-income countries ( HICs ) . Therefore , there is an urgent need for generating evidence of DV interventions among pregnant women in low- and middle-income countries ( LMICs ) . Methods Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines will be employed to structure the review . A comprehensive search will be carried out via electronic data bases including MEDLINE , CINAHL , Scopus , Embase , Web of Science , PsycINFO , and The Cochrane library . Gray literature will also be scrutinized for potential articles . An optimal search strategy has been developed following consultations with subject-matter experts and librarians . This search strategy will be adapted to the different data bases . Experimental studies evaluating DV interventions among pregnant women from LMICs will be included in the review . The review will only include literature written in English . Two review ers will independently screen and assess studies for inclusion in the review . A third author will resolve any discrepancies between the review ers . Risk of bias will be assessed based on the Cochrane risk of bias assessment tool , and overall quality of the evidence will be judged using Grading of Recommendations , Assessment , Development , and Evaluation ( GRADE ) criteria . Findings will be presented with the narrative synthesis , and if applicable , they will be further quantified using r and om-effects meta- analysis . Effect size , risk ratio for dichotomous variables , and st and ardized mean differences for continuous variables will be calculated for each outcome using Review Manager 5.3 . Discussion Systematic review s to evaluate the efficacy of interventions to address DV within the perinatal context have been limited . Hence , no one intervention has emerged as substantially effective towards addressing perinatal DV and associated health consequences . The evidence generated from this systematic review will inform research ers and policy makers about the effectiveness of existing DV interventions among pregnant women in LMICs and provide recommendations for future research in this area . This in turn will contribute towards violence prevention in LMICs . Systematic review registration PROSPERO Objective To examine the prevalence of outcome reporting bias — the selection for publication of a subset of the original recorded outcome variables on the basis of the results — and its impact on Cochrane review s. Design A nine point classification system for missing outcome data in r and omised trials was developed and applied to the trials assessed in a large , unselected cohort of Cochrane systematic review s. Research ers who conducted the trials were contacted and the reason sought for the non-reporting of data . A sensitivity analysis was undertaken to assess the impact of outcome reporting bias on review s that included a single meta- analysis of the review primary outcome . Results More than half ( 157/283 ( 55 % ) ) the review s did not include full data for the review primary outcome of interest from all eligible trials . The median amount of review outcome data missing for any reason was 10 % , whereas 50 % or more of the potential data were missing in 70 ( 25 % ) review s. It was clear from the publications for 155 ( 6 % ) of the 2486 assessable trials that the research ers had measured and analysed the review primary outcome but did not report or only partially reported the results . For reports that did not mention the review primary outcome , our classification regarding the presence of outcome reporting bias was shown to have a sensitivity of 88 % ( 95 % CI 65 % to 100 % ) and specificity of 80 % ( 95 % CI 69 % to 90 % ) on the basis of responses from 62 trialists . A third of Cochrane review s ( 96/283 ( 34 % ) ) contained at least one trial with high suspicion of outcome reporting bias for the review primary outcome . In a sensitivity analysis undertaken for 81 review s with a single meta- analysis of the primary outcome of interest , the treatment effect estimate was reduced by 20 % or more in 19 ( 23 % ) . Of the 42 meta-analyses with a statistically significant result only , eight ( 19 % ) became non-significant after adjustment for outcome reporting bias and 11 ( 26 % ) would have overestimated the treatment effect by 20 % or more . Conclusions Outcome reporting bias is an under-recognised problem that affects the conclusions in a substantial proportion of Cochrane review s. Individuals conducting systematic review s need to address explicitly the issue of missing outcome data for their review to be considered a reliable source of evidence . Extra care is required during data extraction , review ers should identify when a trial reports that an outcome was measured but no results were reported or events observed , and contact with trialists should be encouraged Objectives The objective of this review was to assess the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . Inclusion criteria Types of participants Adult caregivers who provide support for people with dementia living in the community ( non‐institutional care ) . Types of interventions Interventions design ed to support caregivers in their role such as skills training , education to assist in caring for a person living with dementia and support groups/programs . Interventions of formal approaches to care design ed to support caregivers in their role , care planning , case management and specially design ated members of the healthcare team ‐ for example dementia nurse specialist or volunteers trained in caring for someone with dementia . Types of studies This review considered any meta‐analyses , systematic review s , r and omised control trials , quasi‐experimental studies , cohort studies , case control studies and observational studies without control groups that addressed the effectiveness of interventions that assist caregivers to provide support for people living with dementia in the community . Search strategy The search sought to identify published studies from 2000 to 2005 through the use of electronic data bases . Only studies in English were considered for inclusion . The initial search was conducted of the data bases , CINAHL , MEDLINE and PsychINFO using search strategies adapted from the Cochrane Dementia and Cognitive Improvement Group . A second more extensive search was then conducted using the appropriate Medical Subject Headings ( MeSH ) and keywords for other available data bases . Finally , h and search ing of reference lists of articles retrieved and of core dementia , geriatric and psycho geriatric journals was undertaken . Assessment of quality Method ological quality of each of the articles was assessed by two independent review ers using appraisal checklist developed by the Joanna Briggs Institute and based on the work of the Cochrane Collaboration and Centre for Review s and Dissemination . Data collection and analysis St and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each included study reported in the meta‐ analysis . Results from comparable groups of studies were pooled in statistical meta‐ analysis using Review Manager Software from the Cochrane Collaboration . Heterogeneity between combined studies was tested using st and ard chi‐square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . Results A comprehensive search of relevant data bases , h and search ing and cross referencing found 685 articles that were assessed for relevance to the review . Eighty‐five papers appeared to meet the inclusion criteria based on title and abstract , and the full paper was retrieved . Of the 85 full papers review ed , 40 were accepted for inclusion , three were systematic review s , three were meta‐ analysis , and the remaining 34 were r and omised controlled trials . For the r and omised controlled trials that were able to be included in a meta‐ analysis , st and ardised mean differences or weighted mean differences and their 95 % confidence intervals were calculated for each . Results from comparable groups of studies were pooled in statistical meta‐ analysis using Review Manager Software and heterogeneity between combined studies was assessed by using the chi‐square test . Where statistical pooling was not appropriate or possible , the findings are summarised in narrative form . The results are discussed in two main sections . Firstly it was possible to assess the effectiveness of different types of caregiver interventions on the outcome categories of depression , health , subjective well‐being , self‐efficacy and burden . Secondly , results are reported by main outcome category . For each of these sections , meta‐ analysis was conducted where it was possible ; otherwise , a narrative summary describes the findings . Effectiveness of intervention type Four categories of intervention were included in the review ‐ psycho‐educational , support , multi‐component and other . Psycho‐educational Thirteen studies used  psycho‐educational interventions , and all but one showed positive results across a range of outcomes . Eight studies were entered in a meta‐ analysis . No significant impact of psycho‐educational interventions was found for the outcome categories of subjective well‐being , self‐efficacy or health . However , small but significant results were found for the categories of depression and burden . Support Seven studies discussed support only interventions and two of these showed significant results . These two studies were suitable for meta‐ analysis and demonstrated a small but significant improvement on caregiver burden . Multi‐component Twelve of the studies report multi‐component interventions and 10 of these report significant outcomes across a broad range of outcome measures including self‐efficacy , depression , subjective well‐being and burden . Unfortunately because of the heterogeneity of study design s and outcome measures , no meta‐ analysis was possible . Other interventions Other interventions included the use of exercise or nutrition which result ed in improvements in psychological distress and health benefits .  Case management and a computer aided support intervention provided mixed results . One cognitive behavioural therapy study reported a reduction in anxiety and positive impacts on patient behaviour . Effectiveness of interventions using specific outcome categories In addition to analysis by type of intervention it was possible to analyse results based on some outcome categories that were used across the studies . In particular the impact of interventions on  caregiver depression was available for meta‐ analysis from eight studies . This indicated that multi‐component and psycho‐educational interventions showed a small but significant positive effect on caregiver depression . Five studies using the outcome category of caregiver burden  were entered into a meta‐ analysis and findings indicated that there were no significant effects of any of interventions . No meta‐ analysis was possible for the outcome categories of health , self‐efficacy or subjective well‐being . Implication s for practice From this review there is evidence to support the use of well‐ design ed psycho‐educational or multi‐component interventions for caregivers of people with dementia who live in the community . Factors that appear to positively contribute to effective interventions are those which : Provide opportunities within the intervention for the person with dementia as well as the caregiver to be involved Encourage active participation in educational interventions for caregivers Offer individualised programs rather than group sessions Provide information on an ongoing basis , with specific information about services and coaching regarding their new role Target the care recipient particularly by reduction in behaviours Factors which do not appear to have benefit in interventions are those which : Simply refer caregivers to support groups Only provide self help material s Only offer peer Background Worldwide in 2000 , 10 % of children aged five to 17 years were reported as being overweight with an additional 2‐3 % being obese . Overweight and obesity in childhood can adversely impact on both physical and psychological health . The rise in the prevalence of childhood obesity is a complex issue but widely recognised contributors include increased energy intake , decreased levels of physical activity and greater time spent in sedentary pursuits . A large number of environmental and cultural factors have also been identified as contributing to the problem . Evidence to support an optimal approach to treating childhood obesity is limited with many studies showing only modest results at best in the long‐term . However , the importance of family‐based treatment that combines diet , physical activity and behavioral components has been acknowledged in a recent Cochrane Systematic Review . It has also been suggested that interventions offered in the community setting may help overcome barriers to participation , by making programs more accessible and allowing the targeting of specific sub‐groups of the population . Objectives The objective of this review was to identify the effectiveness of parent‐centred interventions implemented in the community setting in modifying eating and physical activity behaviors or weight‐related outcomes of children . Inclusion criteria Types of participants This review considered studies that included free‐living children of pre‐school , primary and secondary school age and /or their parents/guardians aged > 18 years . Types of intervention(s)/phenomena of interest Intervention programs were required to have a parental component , to target eating and /or exercise behaviors for the prevention or treatment of obesity , and child weight status reported . Types of studies All intervention studies were included in the review including : r and omized controlled trials ( RCTs ) ; non‐r and omized controlled trials , longitudinal studies , cohort ( both retrospective and prospect i ve ) , case control and time series studies which had been conducted in a community setting . Types of outcomes This review considered studies that included overweight/obesity related outcomes , eating behavior outcomes , physical activity behaviour outcomes , and sedentary behavior outcomes and constructs . Search strategy A literature search of community‐based parent‐centred intervention studies to promote nutrition and physical activity for the prevention and treatment and of childhood overweight and obesity was performed in eight electronic data bases dating from 1975 to April 2009 . Method ological quality Studies were critically appraised for method ological quality using st and ardized tools . Data collection Data was extracted by one review er using a st and ardized data extraction form developed by the research ers and checked for accuracy and consistency by a second review er . Data synthesis Data in relation to setting , methodology , intervention components and effect on weight , dietary intake and physical activity was extracted , and described in a narrative synthesis . Where possible a meta‐ analysis was undertaken . Results Of the home‐based interventions , five of nine studies reported statistically significant changes in anthropometric outcomes post intervention . Of the 10 studies in the before and after school care setting , seven reported a significant decrease in a weight‐related outcome post intervention , with only one reporting an increase . Conclusions Results from the review support the after‐school setting as the most promising for community intervention setting for targeting parents as agents of change within child obesity prevention and treatment programs . Implication s for practice At this stage , interventions to support parents should target the after‐school environment as opposed to being conducted in the home , summer camps , leisure centers or churches . Targeting a decrease in energy intake and sweetened beverages in parallel with increasing number of daily steps and decreasing screen time use . Implication s for research Future studies of high quality are needed across the full range of community setting s. Given that currently most of the higher quality RCTs and the studies showing positive impacts of weight change are in the after‐school setting , further studies in this area using similar method ologies to those already published will facilitate future meta‐analyses in this area Background Depression is a leading cause of disability worldwide and depressive symptoms are common in later life . Observational evidence suggests that depression is more prevalent among people with high plasma homocysteine ( tHcy ) , but the results of r and omized trials to date have been unable to show that lowering tHcy through the supplementation of vitamins B6 , B12 and folate benefits depressive symptoms . We design ed the B-VITAGE trial to determine whether adjunctive treatment with vitamins B6 , B12 and folate increases the efficacy of st and ard antidepressant treatment . Methods / Design The B-VITAGE trial is a 12-month r and omized , double-blind , placebo-controlled trial of daily citalopram ( 20 to 40 mg ) plus B12(0.4 mg ) , B6 ( 25 mg ) and folic acid ( 2 mg ) or citalopram ( 20 to 40 mg ) plus placebo for the treatment of depression in later life . The trial aims to recruit over 300 older adults with major depression ( DSM-IV ) and has been powered to detect the impact of an intervention associated with moderate effect size . Depressive symptoms will be rated with the Montgomery-Åsberg Depression Rating Scale ( MADRS ) . The trial has two main outcomes of interest : a reduction of 50 % or more in the MADRS total score between baseline and week 12 and the remission of the depressive episode at weeks 12 , 26 and 52 according to DSM-IV criteria . We hypothesize that subjects r and omly allocated to the vitamin arm of the study will be more likely to show a clinical ly significant improvement and achieve and maintain remission of symptoms at 12 , 26 and 52 weeks . Secondary outcomes of interest include compliance with treatment , reduction in the severity of depressive symptoms , switching to different antidepressants , the use of non-pharmacological antidepressant treatments , response to treatment according to MTHFRC677 T genotype , and changes in cognitive function over 52 weeks . Conclusions The results of this trial will clarify whether the systematic use of B-vitamins improves the response of older adults to st and ard antidepressant treatment . We anticipate that our findings will have implication s for clinical practice and health policy development . Trial Registration The trial is registered with the Australian Clinical Trials Registry , trial number ( ())ACTRN12609000256279 Background Depression is a common mental health disorder for which clinical practice guidelines have been developed . Prior systematic review s have identified complex organizational interventions , such as collaborative care , as effective for guideline implementation ; yet , many healthcare delivery organizations are interested in less re source -intensive methods to increase provider adherence to guidelines and guideline -concordant practice s. The objective of this systematic review was to assess the effectiveness of  healthcare provider  interventions that aim to increase adherence to evidence -based treatment of depression in routine clinical practice . Methods We search ed five data bases through August 2017 using a comprehensive search strategy to identify English- language r and omized controlled trials ( RCTs ) in the quality improvement , implementation science , and behavior change literature that evaluated outpatient provider interventions , in the absence of practice re design efforts , to increase adherence to treatment guidelines or guideline -concordant practice s for depression . We used meta- analysis to summarize odds ratios , st and ardized mean differences , and incidence rate ratios , and assessed quality of evidence ( QoE ) using the GRADE approach . Results Twenty-two RCTs promoting adherence to clinical practice guidelines or guideline -concordant practice s met inclusion criteria . Studies evaluated diverse provider interventions , including distributing guidelines to providers , education/training such as academic detailing , and combinations of education with other components such as targeting implementation barriers . Results were heterogeneous and analyses comparing provider interventions with usual clinical practice did not indicate a statistically significant difference in guideline adherence across studies . There was some evidence that provider interventions improved individual outcomes such as medication prescribing and indirect comparisons indicated more complex provider interventions may be associated with more favorable outcomes . We did not identify types of provider interventions that were consistently associated with improvements across indicators of adherence and across studies . Effects on patients ’ health in these RCTs were inconsistent across studies and outcomes . Conclusions Existing RCTs describe a range of provider interventions to increase adherence to depression guidelines . Low QoE and lack of replication of specific intervention strategies across studies limited conclusions that can be drawn from the existing research . Continued efforts are needed to identify successful strategies to maximize the impact of provider interventions on increasing adherence to evidence -based treatment for depression . Trial registration PROSPERO record CRD42017060460 on This paper reports the efficacy and tolerability of the nicotinic channel modulator TC-5214 ( dexmecamylamine ) as adjunct therapy for patients with major depressive disorder who have an inadequate response to initial antidepressant treatment in 2 Phase III studies . These double-blind , placebo-controlled studies ( NCT01157078 , D4130C00002 [ Study 002 ] conducted in the US and India ; NCT01180400 , D4130C00003 [ Study 003 ] conducted in Europe ) comprised 8 weeks of open-label antidepressant treatment followed by 8 weeks of active treatment during which patients were r and omized to flexibly-dosed TC-5214 1 - 4 mg twice daily ( BID ) or placebo as an adjunct to ongoing therapy with SSRI/SNRI . The primary efficacy endpoint in both studies was change in Montgomery Åsberg Depression Rating Scale ( MADRS ) total score from r and omization ( week 8) to treatment end ( week 16 ) . Secondary endpoints included change in Sheehan Disability Scale and Hamilton Depression Rating Scale 17-item scores . Study 002 r and omized 319 patients and Study 003 r and omized 295 patients to TC-5214 or placebo . At treatment end , no significant differences were seen for change in MADRS total score with TC-5214 versus placebo . Furthermore , there were no significant differences in any of the secondary endpoints . The most commonly reported ( ≥ 10 % ) adverse events with TC-5214 in these studies were constipation and headache . In these 2 flexibly-dosed studies , no specific therapeutic effects were observed for TC-5214 ( 1 - 4 mg BID ) adjunct to antidepressant in the primary endpoint or any secondary endpoint ; however , TC-5214 was generally well tolerated . In conclusion , no antidepressant effect of TC-5214 was observed in these studies Background There is increasing interest in nonoperative management ( NOM ) for rectal cancer with complete clinical response ( cCR ) after neoadjuvant chemoradiation ( nCRT ) . Objective The aim of this systematic review was to summarize the available data on NOM , with the intention of formulating st and ardized protocol s on which to base future investigations . Methods A systematic review following the Preferred Reporting Items for Systematic Review s and Meta-Analyses ( PRISMA ) guidelines was conducted . A highly sensitive literature search identified all relevant studies published between January 2004 and December 2016 . Data extraction and quality assessment was performed independently by two authors , and resolved by consensus with a third review er . Results In total , 15 studies , including 920 patients , met the inclusion criteria ; 575 ( 62.5 % ) of these patients underwent NOM after cCR , with the remaining patients forming a surgical control group . The weighted mean follow-up was 39.4 ( 12.7 ) months in the NOM group and 39.8 ( 5.1 ) months in the surgery group . The pooled regrowth rate in the NOM group was 21.3 % at a mean of 15.6 ( 7.0 ) months . Surgical salvage was possible and was undertaken in 93.2 % of these patients . Overall survival in the NOM group was 91.7 % , while disease-free survival was 82.7 % . For the comparison proctectomy group , pooled rates of local recurrence , overall survival , and disease-free survival were 8.4 , 92.4 , and 87.5 % , respectively . Conclusion NOM may be a feasible option for surgically eligible rectal cancer patients with cCR after nCRT . Before such a strategy can be widely implemented , further prospect i ve data are required with st and ardized definitions , diagnostic criteria , and management protocol s , with an emphasis on shared patient – provider decision making and patient-centered outcomes Traditional clinical review articles , also known as up date s , differ from systematic review s and meta-analyses . Up date s selectively review the medical literature while discussing a topic broadly . Non-quantitative systematic review s comprehensively examine the medical literature , seeking to identify and synthesize all relevant information to formulate the best approach to diagnosis or treatment . Meta-analyses ( quantitative systematic review s ) seek to answer a focused clinical question , using rigorous statistical analysis of pooled research studies . This article presents guidelines for writing an evidence -based clinical review article for American Family Physician . First , the topic should be of common interest and relevance to family practice . Include a table of the continuing medical education objectives of the review . State how the literature search was done and include several sources of evidence -based review s , such as the Cochrane Collaboration , BMJ 's Clinical Evidence , or the InfoRetriever Web site . Where possible , use evidence based on clinical outcomes relating to morbidity , mortality , or quality of life , and studies of primary care population s. In articles su bmi tted to American Family Physician , rate the level of evidence for key recommendations according to the following scale : level A ( r and omized controlled trial [ RCT ] , meta- analysis ) ; level B ( other evidence ) ; level C ( consensus/expert opinion ) . Finally , provide a table of key summary points Differences in disease prevalence , clinical manifestations , and health outcomes exist between men and women . Sources for this variation range from biological differentiation at the cellular level to behavioral differences influenced by societal gender norms . Typically , biologically based differences between men and women are called sex differences , whereas gender differences describe health differences related , at least in part , to societal constructs of gender ( 13 ) . For example , biological events unique to women , such as pregnancy and menopause , are probably associated with sex differences in occurrence of certain conditions or in response to some medical therapies ( 48 ) . Gender differences probably exist in health-related perceptions and behaviors for women and men with medical conditions that are prevalent for both sexes ( for example , heart disease and chronic pain ) ( 9 –16 ) . Although sex and gender differences are theoretically distinct , they remain difficult to disentangle when differences between men and women in health outcomes and treatment effectiveness are being examined . For this reason , and for brevity , we hereafter refer to sex and gender differences collectively as sex effects . In the past 2 decades , recognition of the importance of sex effects for health outcomes and treatment heterogeneity has been growing . Beginning in 1993 , the National Institutes of Health has issued policies requiring the inclusion of women and minorities in all clinical research and trial design s with valid analysis of sex effects or differences between racial and ethnic groups ( 17 , 18 ) . Since then , the inclusion of women in clinical trials has increased ( 19 , 20 ) , and sex effects have been identified for medications , such as nicotine replacement therapy , analgesics , and aspirin ( 13 , 14 , 21 ) . Recently , sex effects in adverse reactions led to sex-specific dosage recommendations for a widely used sedative ( 7 ) . Despite this progress , representation of women in clinical studies remains inadequate for many conditions ( 22 ) . Further , published clinical trials infrequently report sex effects or discuss the appropriateness of sex-specific analyses ( 19 , 20 , 23 ) . To advance the clinical evidence base and improve health outcomes for women , clinical research must include adequate numbers of women , appropriately conduct sex-specific analyses , and consistently report sex effects . Systematic review s ( SRs ) are a key source of information for clinicians , research ers , and guideline panels . By synthesizing the overall body of evidence for key clinical and research questions , SRs could potentially make a unique contribution to the evaluation of sex effects . To our knowledge , however , the reporting of sex effects by SRs has not been previously examined . Here , we use evidence mapping to systematic ally evaluate the reporting of sex effects by SRs examining a diverse set of interventions for chronic conditions common to women ( that is , depression , diabetes , and chronic pain ) . Evidence mapping is an emerging approach that describes key characteristics of studies for a broad area of medicine ( 2426 ) . Our evidence map addresses the volume and characteristics of eligible SRs , including the representation of women in primary studies , whether and how review s reported sex effects , and findings about sex effects . Methods This work was part of a larger report for the Veterans Health Administration ( VHA ) Evidence -based Synthesis Program ( ESP ) . The complete technical report is available online ( www.hsrd . research .va.gov/publications/esp ) and includes additional information on our methods . We focused on SRs to determine the reporting of sex effects , provide high-level information about the volume of current clinical evidence , and summarize information about actual sex effects . Prioritization of Conditions for Inclusion We used forced-ranking prioritization ( 27 ) with our VHA stakeholders to determine our conditions of interest . These stakeholders included representatives from the Health Services Research & Development Center for the Study of Healthcare Innovation , Implementation and Policy ; Health Services Research & Development Women 's Health Research Network ; Women 's Health Research in the Office of Research & Development ; Women 's Health Services ; and Mental Health Services . We initially selected 34 conditions ( Appendix Table 1 ) based on disease prevalence in women , disease burden in women , availability and breadth of effective treatments for men or women , and women veterans ' priorities for gender-specific care . Stakeholders ranked this initial set of conditions , discussed the rankings , and reranked conditions that initially received intermediate priority rankings . After 2 rounds of iterative prioritization , the following conditions were selected : depressive disorders , type 2 diabetes mellitus , and chronic pain ( that is , chronic low back pain , fibromyalgia , and chronic knee pain due to osteoarthritis ) . Appendix Table 1 . Conditions Presented to Stakeholders for Prioritization * Data Sources and Search es In collaboration with an expert reference librarian , we search ed PubMed and Cochrane Data base of Systematic Review s to identify eligible SRs published after 1 October 2009 through 31 October 2014 for depression , 13 February 2015 for diabetes , and 27 February 2015 for chronic pain . Search strategies used Medical Subject Headings and free-text terms for the conditions of interest , eligible interventions , and SRs ( Appendix Table 2 ) . We restricted the search to the past 6 years because SRs are typically out date d within 5 years of publication ( 28 ) , and our goal was to describe the current state of the clinical literature . In addition to electronic search ing , we screened published review s of review s for eligible articles . Appendix Table 2 . Search Strategies Study Selection and Quality Assessment Eligible SRs evaluated interventions in several broad categories ( that is , medications , behavioral interventions , supervised exercise , and quality improvement or organizational interventions ) . We also included condition-specific interventions , such as bariatric surgery for diabetes . Review s that evaluated mixed conditions or multiple interventions must have reported results separately for at least 1 eligible condition or intervention . We included review s of interventions in any setting , with any type of active or inactive comparator , and with any duration of follow-up . Detailed inclusion and exclusion criteria are provided in Appendix Table 3 . Appendix Table 3 . Detailed Inclusion and Exclusion Criteria for Review Eligibility Two investigators screened citations for eligibility , and citations that were considered to be relevant by either person were retained for full-text review . Full-text articles were review ed by 2 investigators , and disagreements were resolved through discussion or adjudicated by a third person . Formal assessment of review quality was beyond the scope of this project . However , we noted whether review s originated from organizations known for high- quality review s ( that is , Cochrane Collaboration , Agency for Healthcare Research and Quality Evidence -based Practice Centers , and VHA ESP ) . For review s reporting sex effects , we also assessed industry funding and whether statistical power was considered . Data Abstract ion Data were abstract ed by 1 investigator and review ed by a second person . Disagreements were resolved by discussion or by a third review er . Abstract ed data included the analysis method ( that is , qualitative synthesis , meta- analysis , network meta- analysis , or individual-patient data [ IPD ] meta- analysis ) ; clinical conditions ; interventions ; main outcomes ; number and design of primary studies ( for example , r and omized , controlled trials [ RCTs ] or observational cohorts ) ; proportion of women in the included primary studies ; and if sex effects were part of the study aims , analysis plan , or results . For review s reporting sex effects , we also recorded the number of primary studies used for sex-specific analyses , effect estimates , and the method used ( for example , metaregression , subgroup analysis , or IPD meta- analysis ) . All eligible review s on depressive disorders and chronic pain conditions were fully abstract ed . All diabetes review s of nonpharmacologic interventions were also fully abstract ed . For eligible diabetes medication review s ( n= 120 ) , we applied an additional prioritization procedure before full abstract ion . We prioritized review s that examined multiple classes of medications or evaluated a single class of medications when 6 or fewer eligible review s were identified . For SRs evaluating a single class ( > 6 eligible review s were identified ) , we used additional prioritization criteria ( for example , the most recent review published in a high-impact journal or work done by an organization known for high- quality review s ) . The remaining unselected but eligible review s ( n= 58 ) had a keyword text search for sex effects and were fully abstract ed only when this search yielded positive results ( n= 13 ) . Data Synthesis and Analysis of SRs We grouped eligible review s by intervention category and described the overall volume of clinical literature for interventions addressing each condition of interest . We also determined the number of review s reporting sex effects and summarized these results . Time trends for the proportion of these review s were examined for depression and diabetes . Examination of Primary RCTs for Selected Interventions We anticipated that some interventions for each condition would have few or no eligible SRs that addressed sex effects . Thus , for a subset of interventions for each condition , we evaluated primary RCTs to determine the feasibility of conducting a future review to evaluate sex effects . Specifically , we examined  quality improvement interventions and psychotherapy for depression ; diet , physical activity , and culturally tailored psychoeducation for diabetes ; behavioral interventions for chronic low back pain ; and exercise interventions BACKGROUND An expert panel convened by the American Dental Association ( ADA ) Council on Scientific Affairs and the Center for Evidence -Based Dentistry conducted a systematic review and formulated clinical recommendations to inform primary care clinicians about the potential use of adjuncts as triage tools for the evaluation of lesions , including potentially malignant disorders ( PMDs ) , in the oral cavity . TYPES OF STUDIES REVIEW ED This is an up date of the ADA 's 2010 recommendations on the early diagnosis of PMDs and oral squamous cell carcinoma . The authors conducted a systematic search of the literature in MEDLINE and Embase via Ovid and the Cochrane Central Register of Controlled Trials to identify r and omized controlled trials and diagnostic test accuracy studies . The authors used the Grading of Recommendations Assessment , Development and Evaluation approach to assess the certainty in the evidence and to move from the evidence to the decisions . RESULTS The panel formulated 1 good practice statement and 6 clinical recommendations that concluded that no available adjuncts demonstrated sufficient diagnostic test accuracy to support their routine use as triage tools during the evaluation of lesions in the oral cavity . For patients seeking care for suspicious lesions , immediate performance of a biopsy or referral to a specialist remains the single most important recommendation for clinical practice . In exceptional cases , when patients decline a biopsy or live in rural areas with limited access to care , the panel suggested that cytologic testing may be used to initiate the diagnostic process until a biopsy can be performed ( conditional recommendation , low- quality evidence ) . CONCLUSIONS AND PRACTICAL IMPLICATION S The authors urge clinicians to remain alert and take diligent action when they identify a PMD . The authors emphasize the need for counseling because patients may delay diagnosis because of anxiety and denial Although lithium augmentation is the foremost and most well-documented treatment strategy for treatment resistant depression , knowledge of factors related to response remains scanty . Findings with the combined dexamethasone/corticotropin-releasing hormone ( DEX/CRH ) test are associated with response to treatment with a tricyclic antidepressant . This study investigated the potential predictive value of the DEX/CRH test for lithium augmentation response in major depressive disorder . The DEX/CRH test was conducted prior to lithium augmentation in 30 patients with a major depressive episode who had not responded to an antidepressant monotherapy trial of at least 4 weeks . Response status was assessed weekly using the Hamilton Rating Scale for Depression . For multivariate prediction , a logistic regression analysis was performed . Eleven ( 37 % ) patients responded to lithium augmentation within 4 weeks . Responders showed higher ACTH response and lower cortisol response in the DEX/CRH test , but results were not statistically significant . However , non-responders had a statistically significant higher cortisol/ACTH peak ratio ( 3.43+/-1.75 ) compared to responders ( 2.18+/-1.38 ) ( P=0.027 ) . This ratio is an indicator for the sensitivity of the adrenal cortex to ACTH . A cortisol/ACTH peak ratio of 1.8 was identified as the best cutoff point to differentiate responders from non-responders . In conclusion , results suggest a more sensitive adrenal cortex in non-responders to lithium augmentation . The findings would be in line with the assumption of a more chronic course of depression with more pronounced biological alterations in the non-responder group , because chronic depression is known to cause enlargement of the adrenal gl and with a subsequent hypersensitivity to ACTH . Results of this study should be confirmed in a larger study group Objective The aim of this article is to summarize the relevant findings that inform the 2017 International Consultation on Incontinence pathway for surgical treatment of pelvic organ prolapse ( POP ) . Methods We conducted an evidence -based review of the English- language peer- review ed literature relating to POP surgery published prior to December 2016 . Level 1 evidence ( r and omized controlled trials [ RCTs ] or systematic review s of RCTs ) was preferred ; however , level 2 ( poor- quality RCT , prospect i ve cohort studies ) or 3 evidence ( case series or retrospective studies ) has been included if level 1 data were lacking . The committee evaluated the literature and made recommendations based on the Oxford grading system summarized as follows : grade A recommendation usually depends on consistent level 1 evidence ; grade B recommendation usually depends on consistent level 2 and /or 3 studies , or “ majority evidence ” from RCTs ; grade C recommendation usually depends on level 3 studies or “ majority evidence ” from level 2/3 studies or Delphi-processed expert opinion ; grade D , “ no recommendation possible , ” would be used where the evidence is inadequate or conflicting . Results The recommendations from each chapter of the review are presented and serve to inform an evidence -based pathway for the surgical treatment of prolapse . A Web-based interactive application of the pathway is presented . Conclusions The 2017 International Consultation on Incontinence pathway on surgery for POP is design ed as an adjunct to transparent consultation and consent relating to POP surgery . The final decision regarding surgical intervention can be made only after a shared decision-making process between the patient and the clinician that will evaluate a variety of individual factors that can not be assessed in the pathway OBJECTIVES To evaluate the efficacy and safety of adjunctive aripiprazole compared with st and ard antidepressant therapy ( ADT ) for older patients with major depressive disorder ( MDD ) who demonstrated an incomplete response to st and ard antidepressant monotherapy .  METHODS Data from three similar 14-week studies ( an 8-week prospect i ve ADT treatment phase and a 6-week r and omized , double-blind phase ) of aripiprazole augmentation were pooled for this post hoc analysis . Two age groups were defined : younger patients ( aged 18 - 49 years ) and older patients ( aged 50 - 67 years ) . The older patient group was further divided into three subgroups : 50 - 55 , 56 - 60 , and 61 - 67 years . The efficacy endpoint was the mean change in Montgomery-Åsberg Depression Rating Scale ( MADRS ) total score from end of the prospect i ve phase ( Week 8) to endpoint ( Week 14 , last observation carried forward ( LOCF ) ) . Remission was defined as MADRS total score ≤10 at endpoint . RESULTS Four hundred and nine older patients ( placebo , n = 198 ; aripiprazole , n = 211 ) and 679 younger patients ( placebo , n = 341 ; aripiprazole , n = 338 ) were included in this analysis . Older patients  receiving aripiprazole demonstrated significantly greater improvement in MADRS total score  versus placebo at Week 14 ( -10.0 vs. -6.4 ; p < 0.001 ; LOCF ) , similar to the improvement seen in younger patients . Remission rates were significantly higher with aripiprazole versus placebo in older ( 32.5 % vs. 17.1 % ; p < 0.001 ) and younger ( 26.9 % vs. 16.4 % ; p < 0.001 ) patients . Akathisia was the most common adverse event in both the older ( 17.1 % ) and younger ( 26.0 % ) patient groups . CONCLUSIONS Adjunctive aripiprazole was effective in improving depressive symptoms in older patients , 50 - 67 years , with MDD who have had an inadequate response to st and ard antidepressant medication BACKGROUND Patients with major depressive disorder ( MDD ) who fail to achieve complete remission with antidepressant therapy  may benefit from augmentation therapy with an atypical antipsychotic . METHOD A pooled analysis was performed on 2 identical 14-week studies ( 8-week prospect i ve antidepressant therapy treatment phase followed by 6-week r and omized double-blind phase ) evaluating the efficacy of adjunctive aripiprazole ( 2 - 20 mg/day ) in DSM-IV-TR-defined MDD patients with an inadequate response to antidepressant therapy . Primary efficacy endpoint was the mean change in Montgomery-Asberg Depression Rating Scale ( MADRS ) total score from end of the prospect i ve phase ( week 8) to end of r and omized phase ( week 14 , last observation carried forward ) . Subgroup analyses were performed . The key secondary endpoint was mean change in Sheehan Disability Scale ( SDS ) mean score . RESULTS At endpoint , mean change in MADRS total score was significantly greater with adjunctive aripiprazole ( -8.7 ) than with adjunctive placebo ( -5.7 ; p < .001 ) . Except for a differential treatment-by-sex interaction , change in MADRS total scores were consistently greater with adjunctive aripiprazole than with adjunctive placebo , regardless of race , age , episode duration , prior antidepressant therapy response , number of historical treatment failures , severity of depressive symptoms , and antidepressant . At endpoint , MADRS remission rates were significantly greater with adjunctive aripiprazole than with placebo ( 25.7 % vs. 15.4 % ; p < .001 ) . Adjunctive aripiprazole also demonstrated significantly greater improvements in mean change from baseline in SDS total score than adjunctive placebo ( -1.2 vs. -0.6 ; p = .001 ) . CONCLUSION Augmentation of antidepressant therapy with the atypical antipsychotic aripiprazole result ed in significant efficacy benefits across a range of subgroups of patients with MDD . Further study of a treatment-by-sex interaction is needed . TRIAL REGISTRATION www . clinical trials.gov Identifiers : NCT00095823 and NCT00095758 Background Systematic review s of behaviour change interventions for  smoking cessation  vary in scope , quality , and applicability . The current review aims to generate more accurate and useful findings by ( 1 ) a detailed analysis of intervention elements that change behaviour ( i.e. behaviour change techniques ( BCTs ) ) and potential moderators of behaviour change ( i.e. other intervention and sample characteristics ) and ( 2 ) assessing and controlling for variability in support provided to comparison groups in smoking cessation trials . Methods A systematic review will be conducted of r and omized controlled trials of behaviour change interventions for smoking cessation in adults ( with or without pharmacological support ) , with a minimum follow-up of 6 months , published after 1995 . Eligible articles will be identified through the Cochrane Tobacco Addiction Group Specialized Register . Study authors will be asked for detailed descriptions of smoking cessation support provided to intervention and comparison groups . All data will be independently coded by two research ers . The BCT taxonomy v1 ( tailored to smoking cessation interventions ) and template for intervention description and replication criteria will be used to code intervention characteristics . Data collection will further include sample and trial characteristics and outcome data ( smoking cessation rates ) . Multilevel mixed-effects meta-regression models will be used to examine which BCTs and /or BCT clusters delivered to intervention and comparison groups explain smoking cessation rates in treatment arms ( and effect sizes ) and what key moderators of behaviour change are . Predicted effect sizes of each intervention will be computed assuming all interventions are compared against comparison groups receiving the same levels of behavioural support ( i.e. low , medium , and high levels ) . Multi-disciplinary advisory board members ( policymakers , health care providers , and (ex-)smokers ) will provide strategic input throughout the project to ensure the review ’s applicability to policy and practice . Discussion By capturing BCTs in intervention and comparison groups , this systematic review will provide more accurate estimates of the effectiveness of smoking cessation interventions , the most promising BCTs and /or BCT clusters associated with smoking cessation rates in intervention and comparison arms , and important moderators of behaviour change . The results could set new st and ards for conducting meta-analyses of behaviour change interventions and improve research , service delivery , and training in the area of smoking cessation . Systematic review registration PROSPERO Background Depression is a common comorbidity in individuals with cognitive impairment . Those with cognitive impairments face unique challenges in receiving the benefits of many conventional therapies for depression , and may have poorer outcomes in areas such as recovery and quality of life . However , the stigmatization of mental health disorders , cost barriers and physical disabilities may prevent these individuals from seeking mental health care . An online , self-help intervention specifically developed for adults with cognitive deficits and depression may be particularly beneficial to this population . We aim to inform the design of such an intervention through a systematic review by answering the following research question : among adults with cognitive impairment ( including those with acquired brain injuries or neurodegenerative diseases ) , which technology-amenable interventions have been shown to effectively decrease symptoms of depression ? Specifically , psychotherapeutic and /or behavioural interventions that could be delivered in a self-guided , online system will be included . Methods Comprehensive electronic search es will be conducted in MEDLINE , EMBASE , PsycINFO and CINAHL . Additional studies will be obtained through manually search ing the references of relevant systematic review s , contacting primary authors of select articles and tracking conference proceedings and trial registries . Article titles and abstract s will be screened using predefined eligibility criteria , and then judged for their amenability to the proposed self-help , technology-based intervention . The full text of those articles with selected interventions will then be screened to determine final eligibility for inclusion . Included articles will be categorized by intervention type and assessed for risk of bias using the Cochrane Effective Practice and Organization of Care Risk of Bias tool for non-r and omized trials , controlled before-after studies and interrupted time series . The primary outcome will be a change in score on a vali date d depression scale , and adverse events will be documented as a secondary outcome . After data extraction from selected articles , pooling of data and meta- analysis will be conducted if a sufficient pool of studies with comparable methodology and quality are identified . Alternatively , plain language summaries will be developed . The quality of evidence will be assessed using the Grading of Recommendations Assessment , Development and Evaluation ( GRADE ) system . Systematic review registration PROSPERO There is a growing recognition that insufficient attention has been paid to the selection of the outcomes to measure in clinical trials and clinical audit . Outcomes need to be relevant to patients , clinicians , purchasers and policy-makers if the findings of research are to influence practice and future research . In addition , st and ardization of outcomes is needed to combine data from different studies to allow evidence synthesis and to compare data sets . Inconsistent choice of outcome measures means that many meta-analyses are unable to include data from all the relevant studies . For example , the five most accessed Cochrane review s in 2009 , together with the top cited review in that year , all described inconsistencies in the outcomes reported in eligible trials . A call for the st and ardization of outcomes is a regular conclusion of systematic review s. Furthermore , outcome reporting bias , defined as the bias arising from selecting outcomes for publication based on the results , affects many r and omized trials and ‘ is an under-recognized problem that affects the conclusions in a substantial proportion of Cochrane review s ’ . That bias is likely to affect systematic review s more widely as well as affecting individual studies when considered on their own . Similar problems occur with clinical audit , highlighting the importance of establishing national audits that use and report the same outcomes for all participants . All these issues could be addressed with the development and application of agreed st and ardized sets of outcomes that have been termed ‘ core outcome sets ’ . These should be measured and reported , as a minimum , in all relevant clinical trials and national clinical audits for a specific condition . Adopting a core outcome set does not imply that a particular study , review or audit should be restricted to only those outcomes . Rather , the expectation is that , as a minimum , core outcomes will always be collected and reported to allow the results of trials to be compared , contrasted and combined as appropriate . The adoption of core outcomes would have implication s across all areas of research in health and health care , reduce heterogeneity between trials , and lead to research that is more likely to have measured relevant outcomes . Importantly , they would enhance the value of evidence synthesis by reducing the risk of outcome reporting bias and ensuring that all trials contribute usable information . In addition , they will increase the efficiency and value of research . An important rationale for core outcome sets is that outcomes currently reported for trials do not consistently reflect endpoints that are meaningful for patients . Examples exist where trials failed to include all outcomes important to patients and where involvement of patients has identified an outcome that might not have been considered by practitioners on their own . Despite increasing recognition of the importance of incorporating patients ’ opinions , their involvement has been limited . Recent regulatory guidance in the USA requires documented evidence of patient input during the development of instruments to measure  patient reported outcomes ( PROs ) . However , measurement of PROs in clinical trials is hampered by the multiplicity and heterogeneity of tools currently available . Many generic , disease and domain-specific instruments have been developed and vali date d , each containing multiple scales and items . As a result , synthesis of PRO data from trials is difficult and review s aim ing to summarize treatment effect according to PROs may fail . There is synergy between the development of core outcome sets for trials and work to select up to seven outcomes that are important to patients for inclusion in Summary of Findings tables in systematic review s. Developed by the GRADE group ( http://www . grade workinggroup.org ) , Cochrane review s have featured such tables since 2008 , and they play a key role in presenting research in guidelines , such as those produced by the World Health Organization ( WHO ) . The development of core outcome sets needs to be accelerated and undertaken in ways that maximize efficiency . The COMET ( Core Outcome Measures in Effectiveness Trials , http://www.comet-initiative.org ) Initiative in the UK brings together research ers interested in the development and application of core outcome sets . These include key participants in a collaboration of research ers in rheumatology who have done the most notable work to date in this area . The COMET Initiative was launched in January 2010 , with a second meeting in July 2011 . Attendees included trialists , systematic review ers , patients , clinicians , journal editors , research funders , policy-makers , people responsible for trials registries and regulators . Data on individual studies , both published and ongoing , are being included in a free , publically available internet-based re source . This will be up date d periodically , to minimize the risk of duplication . Seventy-eight published or ongoing studies have already been entered into the repository . In addition , published review s of outcomes used in clinical trials or studies examining patients ’ views , will be entered Background In spite of the large body of evidence available in the literature , definition and treatment of  Post-Herpetic Neuralgia ( PHN )  are still lacking a consistent and universally recognized st and ardization . Furthermore , many issues concerning diagnosis , prediction and prevention of PHN need to be clarified in view of recent contributions . Objectives To assess whether PHN may be better defined , predicted , treated and prevented in light of recent data , and whether available alternative or adjunctive therapies may improve pain relief in treatment recalcitrant PHN . Methods Systematic review s , meta-analyses , r and omized controlled trials , cohort studies and protocol s were search ed ; the search sources included PubMed , Cochrane Library , NICE , and DARE . More than 130 papers were selected and evaluated . Results Diagnosis of PHN is essentially clinical , but it can be improved by resorting to the many tools available , including some practical and accessible question naires . Prediction of PHN can be now much more accurate , taking into consideration a few well vali date d clinical and anamnestic variables . Treatment of PHN is presently based on a well characterized array of drugs and drug associations , including , among others , tricyclic antidepressants , gabapentinoids , opioids and many topical formulations . It is still unsatisfactory , however , in a substantial proportion of patients , especially those with many comorbidities and intense pain at herpes zoster ( HZ ) presentation , so that this frequent complication of HZ still strongly impacts on the quality of life of affected patients . Conclusion Further efforts are needed to improve the management of PHN . Potentially relevant interventions may include early antiviral therapy of acute HZ , prevention of HZ by adult vaccination , as well as new therapeutic approaches for patients experiencing PHN Depressive disorders are a major health care issue and one of the foremost causes of disability in adults around the world , result ing in significant costs to society and health care systems ( 1 ) . The estimated economic burden associated with depression was $ 83.1 billion in 2000 and is probably higher today ( 2 ) . Depressive disorders include major depressive disorder ( MDD ) ; dysthymia ; and subsyndromal depression , including minor depression . Major depressive disorder is the most prevalent depressive disorder , with an estimated lifetime prevalence of 16 % in the United States ( 3 ) . An average of 8 million ambulatory care visits per year result in a primary diagnosis of MDD ( 4 ) . The American Psychiatric Association ( 5 ) defines MDD as depressed mood or loss of pleasure or interest along with other symptoms , including significant change in weight or appetite , insomnia or hypersomnia , psychomotor agitation or retardation nearly every day , fatigue or loss of energy , feelings of worthlessness or excessive or inappropriate guilt , indecisiveness or decreased ability to concentrate , and recurrent thoughts of death or suicide , that last for at least 2 weeks and affect normal functioning . Dysthymia is less severe , but symptoms last for 2 or more years . In contrast , subsyndromal depression is associated with less severe symptoms of depression that do not qualify for MDD or dysthymia diagnoses . The treatment of depression can be characterized by 3 phases ( Figure 1 ) : acute ( 6 to 12 weeks ) , continuation ( 4 to 9 months ) , and maintenance ( 1 year ) ( 7 ) . Relapse is defined as the return of depressive symptoms during the acute or continuation phases and is therefore considered part of the same depressive episode , whereas recurrence is defined as the return of depressive symptoms during the maintenance phase and is considered a new , distinct episode . Response to treatment ( typically defined as 50 % reduction in measured severity ) can be quantified using various tools , such as the Patient Health Question naire-9 ( PHQ-9 ) ( 7 ) or the Hamilton Depression Rating Scale ( HAM-D ) ( 8) . Figure 1 . Phases of treatment of major depression . Adapted from reference 6 . TX = treatment . Various treatment approaches can be used to manage MDD , such as psychotherapy , complementary and alternative medicine ( CAM ) , exercise , and pharmacotherapy . The psychological interventions used to treat depression include acceptance and commitment therapy , cognitive therapy , cognitive behavioral therapy ( CBT ) , interpersonal therapy , and psychodynamic therapies ( Table 1 ) . The CAM treatments include acupuncture , meditation , -3 fatty acids , S-adenosyl-l-methionine ( SAMe ) , St. John 's wort , and yoga . Exercise includes a broad range of activities that can be done for varying duration s , in classes , individually , or in informal groups . For pharmacologic therapy , the scope of this guideline is limited to second-generation antidepressants ( SGAs ) ( selective serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , and selective serotonin norepinephrine reuptake inhibitors ) . First-generation antidepressants ( tricyclic antidepressants and monoamine oxidase inhibitors ) are very rarely used because SGAs have lower toxicity in overdose than first-generation antidepressants and similar efficacy . Table 1 . Common Psychological Interventions to Treat Depression Guideline Focus and Target Population The purpose of this guideline from the American College of Physicians ( ACP ) is to summarize and grade the evidence on the comparative effectiveness and safety of nonpharmacologic treatments and SGAs ( including serotonin reuptake inhibitors , serotonin norepinephrine reuptake inhibitors , bupropion , mirtazapine , nefazodone , and trazodone ) , alone or in combination , for MDD . The target audience for this guideline includes all clinicians , and the target patient population includes all adults with MDD . These recommendations are based on a background evidence article ( 9 ) and a systematic evidence review sponsored by the Agency for Healthcare Research and Quality ( AHRQ ) ( 6 ) . Methods Systematic Review of the Evidence The systematic evidence review was conducted by the AHRQ 's RTI InternationalUniversity of North Carolina at Chapel Hill Evidence -based Practice Center ( 6 ) . Additional method ological details can be found in the Appendix ) , accompanying background evidence article ( 9 ) , and full report ( 6 ) . Review ers search ed several data bases for studies published in English , German , or Italian from 1 January 1990 through September 2015 . Studies on efficacy were limited to r and omized , controlled trials and systematic review s and meta-analyses , although evidence on harms included observational studies . Review ers combined data when possible using meta- analysis and assessed the risk of bias and quality of studies according to established methods . The study population included adult out patients ( aged 18 years ) with MDD during either an initial or a second treatment attempt who did not remit after an initial adequate trial with an SGA . The review evaluated the following classes of interventions : depression-focused psychotherapy , CAM , exercise , and SGAs . Outcomes assessed included benefits in response ( often defined as 50 % improvement in HAM-D scores ) , remission ( often defined as a HAM-D score 7 ) , speed of response , speed of remission , relapse , quality of life , functional capacity ( as assessed by various scales ) , reduction of suicidality , or reduction of hospitalization . Harms assessed included overall adverse events , withdrawals because of adverse events , serious adverse events , and specific adverse events . Quality of life , functional status , suicidality , and hospitalizations were rarely reported . Grading the Evidence and Developing Recommendations This guideline was developed by the ACP Clinical Guidelines Committee according to the ACP guideline development process , which has been described ( 10 ) . The Clinical Guidelines Committee used the evidence tables in the accompanying systematic review and full report ( 9 ) when reporting the evidence and grade d the recommendations using ACP 's guideline grading system ( Table 2 ) . Table 2 . The American College of Physicians ' Guideline Grading System * Peer Review The AHRQ evidence review was sent to invited peer review ers and posted on the AHRQ Web site for public comments . The guideline was peer- review ed through the journal and was posted online for comments from ACP Governors and Regents . Comparative Benefits of Pharmacologic Versus Nonpharmacologic Treatment Options for Initial Management Refer to Appendix Table 1 and the accompanying systematic review ( 9 ) for additional details of the evidence . Appendix Table 1 . First-Line Treatment for MDD : SGAs Versus Nonpharmacologic Therapies * SGA Versus Psychological Interventions SGA Versus CBT Monotherapy . Moderate- quality evidence from 5 trials ( 1115 ) showed no difference in response when comparing SGAs ( fluoxetine , fluvoxamine , paroxetine , or sertraline ) with CBT in patients with MDD after 8 to 52 weeks of treatment . Low- quality evidence from 3 trials ( 11 , 14 , 15 ) showed no difference between remission rates ( fluoxetine , fluvoxamine , and paroxetine ) and functional capacity ( 14 ) ( fluvoxamine and paroxetine ) for SGAs compared with CBT . Combination Therapy . Low- quality evidence from 2 trials ( 14 , 16 ) showed no difference in response or remission when comparing monotherapy using SGAs ( escitalopram , fluvoxamine , or paroxetine ) with combination therapy using SGAs plus CBT ( problem-solving therapy or telephone-based CBT ) in patients with MDD after 12 to 52 weeks of treatment . Low- quality evidence from 2 trials ( 14 , 16 ) assessed function , and 1 trial showed that patients who received the combination therapy reported more improvement on 3 of 5 work-functioning measures than those who received SGA monotherapy , although clinical ly important differences on these measures are uncertain . SGA Versus Interpersonal Therapy Monotherapy . Low- quality evidence showed no difference in response ( 1 trial ; escitalopram ) ( 17 ) or remission ( 2 trials ; citalopram , escitalopram , or sertraline ) ( 17 , 18 ) for SGAs compared with interpersonal therapy for patients with MDD after 12 weeks of treatment . Combination Therapy . Low- quality evidence from 1 trial ( 19 ) showed increased remission for SGA monotherapy compared with SGA combined with interpersonal therapy ( with nefazodone ) in patients with MDD after 12 weeks of treatment . SGA Versus Psychodynamic Therapies Monotherapy . Low- quality evidence from 1 trial ( 20 ) showed no difference in remission for fluoxetine compared with psychodynamic monotherapy in patients with MDD after 16 weeks of treatment . Low- quality evidence from 2 trials ( 20 , 21 ) showed few differences in functional capacity between the treatments . Combination Therapy . Low- quality evidence from 1 trial ( 21 ) showed no difference in functional capacity for SGA monotherapy compared with SGA plus psychodynamic combination therapy . SGA Versus CAM Interventions SGA Versus Acupuncture Monotherapy . Low- quality evidence from 2 trials ( 22 , 23 ) showed no difference in treatment response when comparing fluoxetine with acupuncture monotherapy for patients with MDD after 6 weeks of treatment . Combination Therapy . Low- quality evidence from 2 trials ( 24 , 25 ) showed that combination therapy of SGAs with acupuncture improved treatment response compared with monotherapy with SGAs ( fluoxetine or paroxetine ) in patients with MDD after 6 weeks of treatment . However , low- quality evidence from 1 trial ( 24 ) showed no difference in remission when comparing paroxetine monotherapy with paroxetine plus acupuncture combination therapy . SGA Versus -3 Fatty Acids Monotherapy . Low- quality evidence from network meta- analysis showed that SGAs ( fluoxetine ) were associated with a greater response than -3 fatty acids in patients with MDD .  SGA Versus SAMe Monotherapy . Low- quality evidence from network meta- analysis showed no difference in response between treatment with escitalopram Objectives . To evaluate the neuronal nicotinic channel modulator TC-5214 ( dexmecamylamine ) as adjunct therapy in patients with major depressive disorder ( MDD ) and inadequate response to prior antidepressant treatment . Methods . Study 004 ( D4130C00004 ) and Study 005 ( D4130C00005 ) comprised an 8-week open-label antidepressant ( SSRI/SNRI ) treatment period followed by an 8-week r and omised , active treatment with twice-daily TC-5214 ( 0.5 , 2 or 4 mg in Study 004 ; 0.1 , 1 or 4 mg in Study 005 ) or placebo , adjunct to ongoing SSRI/SNRI . Primary efficacy endpoint was change in MADRS total score from r and omisation ( Week 8) to treatment end ( Week 16 ) . Secondary endpoints included MADRS response and remission , and changes in SDS and HAM-D-17-item scores . Safety and tolerability were monitored throughout . Results . Studies 004 and 005 r and omised 640 and 696 patients , respectively , to TC-5214 or placebo . No statistically significant improvements in MADRS total score or any secondary endpoints were seen with TC-5214 versus placebo in either study at treatment end . The most commonly reported adverse events ( > 10 % ) with TC-5214 were constipation , dizziness and dry mouth . Conclusions . TC-5214 adjunct to antidepressant was generally well tolerated . However , the studies were not supportive of an antidepressant effect for TC-5214 in patients with MDD and inadequate response to prior antidepressant therapy
Mixed results were found for zinc , folic acid , vitamin C , and tryptophan , with nonsignificant results for inositol .
No major adverse effects were noted in the studies ( aside from minor digestive disturbance ) .
A meta- analysis of adjunctive omega-3 versus placebo revealed a significant and moderate to strong effect in favor of omega-3 .
Conversely , a meta- analysis of folic acid revealed a nonsignificant difference from placebo .
Current evidence supports adjunctive use of SAMe , methylfolate , omega-3 , and vitamin D with antidepressants to reduce depressive symptoms
OBJECTIVE There is burgeoning interest in augmentation strategies for improving inadequate response to antidepressants .
The adjunctive use of st and ardized pharmaceutical- grade nutrients , known as nutraceuticals , has the potential to modulate several neurochemical pathways implicated in depression .
While many studies have been conducted in this area , to date no specialized systematic review ( or meta- analysis ) has been conducted .