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IntroductionMood instability in bipolar disorder (BD) is poorly understood. Here we examined cognitive and neural mechanisms related to these fluctuations and how they are changed with the mood stabilizer lithium.MethodsWe recruited volunteers with low (n=37) or high (n=40) risk of BD (using the Mood Disorder Questionnaire, MDQ). We also recruited patients with BD who were assigned (randomized, double-blind) to six weeks of lithium (n=19) or placebo (n=16) after a two-week baseline period. Participants completed mood ratings daily over 50 (healthy) or 42 (BD) days, as well as a risky decision-making task and one functional magnetic resonance imaging session. The task measured adaptation of risk taking to past outcomes (increased risk aversion after a previous win, ‘outcome history’).ResultsWhile the low MDQ group was risk averse after a win, this was less evident in the high MDQ group and least so in the patients with BD. Neurally, ‘outcome history’ was linked to medial frontal pole activation at the time of the decision. Corresponding to the behavioural effect, this activation was reduced in the high MDQ vs. the low MDQ group. While lithium did not reverse the pattern of BD in the task, it changed reward processing in the dorsolateral prefrontal cortex.DiscussionHealthy participants’ modulation of risk-taking in response to reward outcomes was reduced by risk of BD and BD. These results provide a model for how reward may prime escalation of risk-related behaviours in bipolar disorder and how mood stabilising treatments may work.

The gabapentinoids, gabapentin, and pregabalin, target the α2δ subunits of voltage-gated calcium channels. Initially licensed for pain and seizures, they have become widely prescribed drugs. Many of these uses are off-label for psychiatric indications, and there is increasing concern about their safety, so it is particularly important to have good evidence to justify this usage. We conducted a systematic review and meta-analysis of the evidence for three of their common psychiatric uses: bipolar disorder, anxiety, and insomnia. Fifty-five double-blind randomised controlled trials (RCTs) and 15 open-label studies were identified. For bipolar disorder, four double-blind RCTs investigating gabapentin, and no double-blind RCTs investigating pregabalin, were identified. A quantitative synthesis could not be performed due to heterogeneity in the study population, design and outcome measures. Across the anxiety spectrum, a consistent but not universal effect in favour of gabapentinoids compared to placebo was seen (standardised mean difference [SMD] ranging between -2.25 and -0.25). Notably, pregabalin (SMD -0.55, 95% CI -0.92 to -0.18) and gabapentin (SMD -0.92, 95% CI -1.32 to -0.52) were more effective than placebo in reducing preoperative anxiety. In insomnia, results were inconclusive. We conclude that there is moderate evidence of the efficacy of gabapentinoids in anxiety states, but minimal evidence in bipolar disorder and insomnia and they should be used for these disorders only with strong justification. This recommendation applies despite the attractive pharmacological and genetic rationale for targeting voltage-gated calcium channels.

Major depressive disorder is one of the most common, burdensome, and costly psychiatric disorders worldwide in adults. Pharmacological and non-pharmacological treatments are available; however, because of inadequate resources, antidepressants are used more frequently than psychological interventions. Prescription of these agents should be informed by the best available evidence. Therefore, we aimed to update and expand our previous work to compare and rank antidepressants for the acute treatment of adults with unipolar major depressive disorder.We did a systematic review and network meta-analysis. We searched Cochrane Central Register of Controlled Trials, CINAHL, Embase, LILACS database, MEDLINE, MEDLINE In-Process, PsycINFO, the websites of regulatory agencies, and international registers for published and unpublished, double-blind, randomised controlled trials from their inception to Jan 8, 2016. We included placebo-controlled and head-to-head trials of 21 antidepressants used for the acute treatment of adults (≥18 years old and of both sexes) with major depressive disorder diagnosed according to standard operationalised criteria. We excluded quasi-randomised trials and trials that were incomplete or included 20% or more of participants with bipolar disorder, psychotic depression, or treatment-resistant depression; or patients with a serious concomitant medical illness. We extracted data following a predefined hierarchy. In network meta-analysis, we used group-level data. We assessed the studies' risk of bias in accordance to the Cochrane Handbook for Systematic Reviews of Interventions, and certainty of evidence using the Grading of Recommendations Assessment, Development and Evaluation framework. Primary outcomes were efficacy (response rate) and acceptability (treatment discontinuations due to any cause). We estimated summary odds ratios (ORs) using pairwise and network meta-analysis with random effects. This study is registered with PROSPERO, number CRD42012002291.We identified 28 552 citations and of these included 522 trials comprising 116 477 participants. In terms of efficacy, all antidepressants were more effective than placebo, with ORs ranging between 2·13 (95% credible interval [CrI] 1·89–2·41) for amitriptyline and 1·37 (1·16–1·63) for reboxetine. For acceptability, only agomelatine (OR 0·84, 95% CrI 0·72–0·97) and fluoxetine (0·88, 0·80–0·96) were associated with fewer dropouts than placebo, whereas clomipramine was worse than placebo (1·30, 1·01–1·68). When all trials were considered, differences in ORs between antidepressants ranged from 1·15 to 1·55 for efficacy and from 0·64 to 0·83 for acceptability, with wide CrIs on most of the comparative analyses. In head-to-head studies, agomelatine, amitriptyline, escitalopram, mirtazapine, paroxetine, venlafaxine, and vortioxetine were more effective than other antidepressants (range of ORs 1·19–1·96), whereas fluoxetine, fluvoxamine, reboxetine, and trazodone were the least efficacious drugs (0·51–0·84). For acceptability, agomelatine, citalopram, escitalopram, fluoxetine, sertraline, and vortioxetine were more tolerable than other antidepressants (range of ORs 0·43–0·77), whereas amitriptyline, clomipramine, duloxetine, fluvoxamine, reboxetine, trazodone, and venlafaxine had the highest dropout rates (1·30–2·32). 46 (9%) of 522 trials were rated as high risk of bias, 380 (73%) trials as moderate, and 96 (18%) as low; and the certainty of evidence was moderate to very low.All antidepressants were more efficacious than placebo in adults with major depressive disorder. Smaller differences between active drugs were found when placebo-controlled trials were included in the analysis, whereas there was more variability in efficacy and acceptability in head-to-head trials. These results should serve evidence-based practice and inform patients, physicians, guideline developers, and policy makers on the relative merits of the different antidepressants.National Institute for Health Research Oxford Health Biomedical Research Centre and the Japan Society for the Promotion of Science., 抗うつ剤の効果を網羅的に比較 --効き目と副作用頻度、臨床試験データを統合--. 京都大学プレスリリース. 2018-02-22.

Objective Previous studies reported effect sizes of antidepressants were larger in two- than in three- or more-armed (“multi-armed”) randomized trials, where the probability to be allocated to placebo is smaller. However, two-armed studies may have been subject to publication bias, did not take account of differences among antidepressants or covariance in multi-armed studies, or examine sponsorship bias. Study design and setting We searched published and unpublished randomized controlled trials that compared placebo with 21 antidepressants for the acute treatment of major depression in adults. We calculated the ratio of odds ratios (ROR) of drug response over placebo in two-armed versus multi-armed trials for each antidepressant, and then synthesized RORs across all the included antidepressants using the multi-variate meta-analysis. Random effects model was used throughout. Results Two hundred fifty eight trials (66 two-armed and 192 multi-armed trials; 80454 patients; 43.0% with unpublished data) were included in the present analyses. The pooled ROR for response of two-armed trials over multi-armed trials was 1.09 (95 %CI: 0.96 to 1.24). The ROR did not materially change between types of antidepressants, publication year or sponsorship. Conclusion The differences between two- versus multi-armed studies were much smaller than were suggested in previous studies and were not significant.

Objectives: Emotional processing abnormalities have been implicated in bipolar disorder (BD) but studies are typically small and uncontrolled. Here, facial expression recognition was explored in a large and naturalistically recruited cohort of BD patients. Methods: 271 patients with BD completed the facial expression recognition task. The effects of current medication together with the influence of current mood state and diagnostic subtype were assessed whilst controlling for the effects of demographic variables. Results: Patients who were currently receiving treatment with lithium demonstrated significantly poorer accuracy in recognising angry faces, an effect that held in a monotherapy sub-analysis comparing those participants on lithium only and those who were medication-free. Accuracy in recognising angry faces was also lower amongst participants currently taking dopamine antagonists (antipsychotics). Higher levels of current depressive symptoms were linked to poorer accuracy at identifying happy faces. Conclusion: Use of lithium and possibly dopamine antagonists may be associated with reduced processing of anger cues in BD. Findings support the existence of mood-congruent negative biases associated with depressive symptoms in BD. Observational cohort studies provide opportunities to explore the substantial effects of demographic, psychometric and clinical variables on cognitive performance and emotional processing.

The True Colours remote mood monitoring system was developed over a decade ago by researchers, psychiatrists, and software engineers at the University of Oxford to allow patients to report on a range of symptoms via text messages, Web interfaces, or mobile phone apps. The system has evolved to encompass a wide range of measures, including psychiatric symptoms, quality of life, and medication. Patients are prompted to provide data according to an agreed personal schedule: weekly, daily, or at specific times during the day. The system has been applied across a number of different populations, for the reporting of mood, anxiety, substance use, eating and personality disorders, psychosis, self-harm, and inflammatory bowel disease, and it has shown good compliance. Over the past decade, there have been over 36,000 registered True Colours patients and participants in the United Kingdom, with more than 20 deployments of the system supporting clinical service and research delivery. The system has been adopted for routine clinical care in mental health services, supporting more than 3000 adult patients in secondary care, and 27,263 adolescent patients are currently registered within Oxfordshire and Buckinghamshire. The system has also proven to be an invaluable scientific resource as a platform for research into mood instability and as an electronic outcome measure in randomized controlled trials. This paper aimed to report on the existing applications of the system, setting out lessons learned, and to discuss the implications for tailored symptom monitoring, as well as the barriers to implementation at a larger scale.

© 2018 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license Background: The benefits and safety of medications for attention-deficit hyperactivity disorder (ADHD) remain controversial, and guidelines are inconsistent on which medications are preferred across different age groups. We aimed to estimate the comparative efficacy and tolerability of oral medications for ADHD in children, adolescents, and adults. Methods: We did a literature search for published and unpublished double-blind randomised controlled trials comparing amphetamines (including lisdexamfetamine), atomoxetine, bupropion, clonidine, guanfacine, methylphenidate, and modafinil with each other or placebo. We systematically contacted study authors and drug manufacturers for additional information. Primary outcomes were efficacy (change in severity of ADHD core symptoms based on teachers' and clinicians' ratings) and tolerability (proportion of patients who dropped out of studies because of side-effects) at timepoints closest to 12 weeks, 26 weeks, and 52 weeks. We estimated summary odds ratios (ORs) and standardised mean differences (SMDs) using pairwise and network meta-analysis with random effects. We assessed the risk of bias of individual studies with the Cochrane risk of bias tool and confidence of estimates with the Grading of Recommendations Assessment, Development, and Evaluation approach for network meta-analyses. This study is registered with PROSPERO, number CRD42014008976. Findings: 133 double-blind randomised controlled trials (81 in children and adolescents, 51 in adults, and one in both) were included. The analysis of efficacy closest to 12 weeks was based on 10 068 children and adolescents and 8131 adults; the analysis of tolerability was based on 11 018 children and adolescents and 5362 adults. The confidence of estimates varied from high or moderate (for some comparisons) to low or very low (for most indirect comparisons). For ADHD core symptoms rated by clinicians in children and adolescents closest to 12 weeks, all included drugs were superior to placebo (eg, SMD −1·02, 95% CI −1·19 to −0·85 for amphetamines, −0·78, −0·93 to −0·62 for methylphenidate, −0·56, −0·66 to −0·45 for atomoxetine). By contrast, for available comparisons based on teachers' ratings, only methylphenidate (SMD −0·82, 95% CI −1·16 to −0·48) and modafinil (−0·76, −1·15 to −0·37) were more efficacious than placebo. In adults (clinicians' ratings), amphetamines (SMD −0·79, 95% CI −0·99 to −0·58), methylphenidate (−0·49, −0·64 to −0·35), bupropion (−0·46, −0·85 to −0·07), and atomoxetine (−0·45, −0·58 to −0·32), but not modafinil (0·16, −0·28 to 0·59), were better than placebo. With respect to tolerability, amphetamines were inferior to placebo in both children and adolescents (odds ratio [OR] 2·30, 95% CI 1·36–3·89) and adults (3·26, 1·54–6·92); guanfacine was inferior to placebo in children and adolescents only (2·64, 1·20–5·81); and atomoxetine (2·33, 1·28–4·25), methylphenidate (2·39, 1·40–4·08), and modafinil (4·01, 1·42–11·33) were less well tolerated than placebo in adults only. In head-to-head comparisons, only differences in efficacy (clinicians' ratings) were found, favouring amphetamines over modafinil, atomoxetine, and methylphenidate in both children and adolescents (SMDs −0·46 to −0·24) and adults (−0·94 to −0·29). We did not find sufficient data for the 26-week and 52-week timepoints. Interpretation: Our findings represent the most comprehensive available evidence base to inform patients, families, clinicians, guideline developers, and policymakers on the choice of ADHD medications across age groups. Taking into account both efficacy and safety, evidence from this meta-analysis supports methylphenidate in children and adolescents, and amphetamines in adults, as preferred first-choice medications for the short-term treatment of ADHD. New research should be funded urgently to assess long-term effects of these drugs. Funding: Stichting Eunethydis (European Network for Hyperkinetic Disorders), and the UK National Institute for Health Research Oxford Health Biomedical Research Centre.

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More than fifteen years ago, it was noted that the failure rate of antidepressant clinical trials was high, and such negative outcomes were thought to be related to the increasing magnitude of placebo response. However, there is considerable debate regarding this phenomenon and its relationship to outcomes in more recent antidepressant clinical trials. To investigate this, we accessed the US Food and Drug Administration (FDA) reviews for sixteen antidepressants (85 trials, 115 trial arms, 23,109 patients) approved between 1987 and 2013. We calculated the magnitude of placebo and antidepressant responses, antidepressant‐placebo differences, as well as the effect sizes and success rates, and compared these measures over time. Exploratory analysis investigated potential changes in trial design and conduct over time. As expected, the magnitude of placebo response has steadily grown in the past 30 years, increasing since 2000 by 6.4% (r=0.46, p

Background Technology and the internet has enabled rapid access to research but most mental health professionals do not have time to keep up with the vast and growing scientific literature. Secondary information sources, such as the National Elf Service (NES), aim to summarise the most important and up-to-date research to improve mental health professionals9 access to information to support evidence-based medicine (EBM). Objective To explore mental health professionals9 attitudes towards evidence-based practice and methods used to keep up-to-date with research. To promote use of a digital evidence-based platform (the National Elf Service), assess its use and explore its potential to impact clinical practice. Methods Baseline and follow-up surveys were distributed among staff of 5 adult mental health community teams and 2 early intervention services (n=331) in Oxford Health Foundation Trust (OHFT) prior to and following an intervention raising awareness of the National Elf Service. Findings Of 133 baseline survey responders, the majority of staff reported their clinical practice was informed by evidence, mostly using existing clinical guidelines and online resources. Few had used the National Elf Service. 122 staff members completed the follow-up survey. Postintervention, 42 staff members indicated they had used the National Elf Service (compared with 13 preintervention) and that it had improved access to research. Lack of time was most often the barrier restricting evidence-based practice. Conclusions Mental health professionals are engaged with EBM and those that used the National Elf Service felt it did, or could have the potential to impact on their clinical practice. Clinical implications Barriers and challenges to implement EBM more widely suggest targeted efforts should be made to embed evidence-based practice into the working culture.

SUMMARYPerforming an effective literature search to obtain the best available evidence is the basis of any evidence-based discipline, in particular evidence-based medicine. However, with a vast and growing volume of published research available, searching the literature can be challenging. Even when journals are indexed in electronic databases, it can be difficult to identify all relevant studies without an effective search strategy. It is also important to search unpublished literature to reduce publication bias, which occurs from a tendency for authors and journals to preferentially publish statistically significant studies. This article is intended for clinicians and researchers who are approaching the field of evidence synthesis and would like to perform a literature search. It aims to provide advice on how to develop the search protocol and the strategy to identify the most relevant evidence for a given research or clinical question. It will also focus on how to search not only the published but also the unpublished literature using a number of online resources.LEARNING OBJECTIVES•Understand the purpose of conducting a literature search and its integral part of the literature review process•Become aware of the range of sources that are available, including electronic databases of published data and trial registries to identify unpublished data•Understand how to develop a search strategy and apply appropriate search terms to interrogate electronic databases or trial registriesDECLARATION OF INTERESTNone.

Contains fulltext : 169930.pdf (Publisher’s version ) (Open Access) INTRODUCTION: Attention-deficit/hyperactivity disorder (ADHD) is a major public health issue. Pharmacological treatments play an important role in the multimodal treatment of ADHD. Currently, there is a lack of up-to-date and comprehensive evidence on how available ADHD drugs compare and rank in terms of efficacy and tolerability, in children or adolescents as well as in adults. We will conduct a network meta-analysis (NMA), integrating direct and indirect comparisons from randomised controlled trials (RCTs), to rank pharmacological treatments for ADHD according to their efficacy and tolerability profiles. METHODS AND ANALYSIS: We will search a broad range of electronic databases, including PubMed, MEDLINE, EMBASE, PsycINFO, ERIC and Web of Science, with no date or language restrictions. We will also search for unpublished studies using international clinical trial registries and contacting relevant drug companies. We will identify and include available parallel-group, cross-over and cluster randomised trials that compare methylphenidate, dexmethylphenidate, amphetamine derivatives (including lisdexamfetamine), atomoxetine, clonidine, guanfacine, bupropion or modafinil (as oral therapy) either with each other or to placebo, in children, adolescents or adults with ADHD. Primary outcomes will be efficacy (indicated by reduction in severity of ADHD core symptoms measured on a standardised scale) and tolerability (the proportion of patients who left a study early due to side effects). Secondary outcomes will be global functioning, acceptability (proportion of patients who left the study early by any cause) and changes in blood pressure and body weight. NMA will be conducted in STATA within a frequentist framework. The quality of RCTs will be evaluated using the Cochrane risk of bias tool, and the quality of the evidence will be assessed using the GRADE approach. Subgroup and sensitivity analyses will be conducted to assess the robustness of the findings. ETHICS AND DISSEMINATION: No ethical issues are foreseen. Results from this study will be published in a peer-reviewed journal and possibly presented at relevant national and international conferences. TRIAL REGISTRATION NUMBER: CRD42014008976.

BackgroundMobile technology enables high frequency mood monitoring and automated passive collection of data (e.g. actigraphy) from patients more efficiently and less intrusively than has previously been possible. Such techniques are increasingly being deployed in research and clinical settings however little is known about how such approaches are experienced by patients. Here, we explored the experiences of individuals with bipolar disorder engaging in a study involving mood and activity monitoring with a range of portable and wearable technologies.MethodPatients were recruited from a wider sample of 50 individuals with Bipolar Disorder taking part in the Automated Monitoring of Symptom Severity (AMoSS) study in Oxford. A sub-set of 21 patients participated in a qualitative interview that followed a semi-structured approach.ResultsMonitoring was associated with benefits including increased illness insight, behavioural change. Concerns were raised about the potential preoccupation with, and paranoia about, monitoring. Patients emphasized the need for personalization, flexibility, and the importance of context, when monitoring mood.ConclusionsMobile and electronic health approaches have potential to lend new insights into mental health and transform healthcare. Capitalizing on the perceived utility of these approaches from the patients’ perspective, while addressing their concerns, will be essential for the promise of new technologies to be realised.

Major depressive disorder (MDD) is associated with key regions of the brain involved in emotional processing. The present meta-analysis revealed widespread structural reductions in limbic and prefrontal regions that occur in MDD, with no regions of increased grey matter volume. Functional impairments involve many of the same regions with dysregulated interactions between limbic and cortical structures. Longitudinal treatment studies have predominantly investigated pharmacological therapies, and there have been fewer studies of psychological treatments. Reports of increased hippocampal volume and reductions in amygdala activation following treatment suggest implications for the course of illness and the impact of pharmacological as well as psychological therapies. Measures of regional brain volume and activity during an acute depressive episode prior to or early in the course of treatment offer the potential to develop predictors of clinical response. High predictive accuracy at the level of the individual is essential for translation of these findings to clinical use. Development of such biomarkers may help to guide treatment strategies, particularly for individuals who may not benefit from current first-line therapeutic options, in order to preclude a potential series of ineffective treatment trials.

BackgroundAberrant emotional biases have been reported in bipolar disorder (BD), but results are inconsistent. Despite the clinical relevance of chronic mood variability in BD, there is no previous research investigating how the extent of symptom fluctuations in bipolar disorder might relate to emotional biases. This exploratory study investigated, in a large cohort of bipolar patients, whether instability in weekly mood episode symptoms and other clinical and demographic factors were related to emotional bias as measured in a simple laboratory task.MethodParticipants (N = 271, BDI = 206, BDII = 121) completed an ‘emotional categorization and memory’ task. Weekly self-reported symptoms of depression and mania were collected prospectively. In linear regression analyses, associations between cognitive bias and mood variability were explored together with the influence of demographic and clinical factors, including current medication.ResultsGreater accuracy in the classification of negative words relative to positive words was associated with greater instability in depressive symptoms. Furthermore, greater negative bias in free recall was associated with higher instability in manic symptoms. Participants diagnosed with BDII, compared with BDI, showed overall better word recognition and recall. Current antipsychotic use was associated with reduced instability in manic symptoms but this did not impact on emotional processing performance.ConclusionsEmotional processing biases in bipolar disorder are related to instability in mood. These findings prompt further investigation into the underpinnings as well as clinical significance of mood instability.

Background: Psychoeducation is an effective adjunct to medications in bipolar disorder (BD). Brief psychoeducational approaches have been shown to improve early identification of relapse. However, the optimal method of delivery of psychoeducation remains uncertain. Here, our objective was to compare a short therapist-facilitated vs. self-directed psychoeducational intervention for BD. Methods: BD outpatients who were receiving medication-based treatment were randomly assigned to 5 psychoeducation sessions administered by a therapist (Facilitated Integrated Mood Management; FIMM; n=60), or self-administered psychoeducation (Manualized Integrated Mood Management; MIMM; n=61). Follow-up was based on patients' weekly responses to an electronic mood monitoring programme over 12 months. Results: Over follow-up, there were no group differences in weekly self-rated depression symptoms or relapse/readmission rates. However, knowledge of BD (assessed with the Oxford Bipolar Knowledge questionnaire (OBQ)) was greater in the FIMM than the MIMM group at 3 months. Greater illness knowledge at 3 months was related to a higher proportion of weeks well over 12 months. Limitations: Features of the trial may have reduced the sensitivity to our psychoeducation approach, including that BD participants had been previously engaged in self-monitoring. Conclusions: Improved OBQ score, while accelerated by a short course of therapist-administered psychoeducation (FIMM), was seen after both treatments. It was associated with better outcome assessed as weeks well. When developing and testing a new psychosocial intervention, studies should consider proximal outcomes (e.g., acquired knowledge) and their short-term impact on illness course in bipolar disorder.

INTRODUCTION Many antidepressants are indicated for the treatment of major depression. Two network meta-analyses have provided the most comprehensive assessments to date, accounting for both direct and indirect comparisons; however, these reported conflicting interpretation of results. Here, we present a protocol for a systematic review and network meta-analysis aimed at updating the evidence base and comparing all second-generation as well as selected first-generation antidepressants in terms of efficacy and acceptability in the acute treatment of major depression. METHODS AND ANALYSIS We will include all randomised controlled trials reported as double-blind and comparing one active drug with another or with placebo in the acute phase treatment of major depression in adults. We are interested in comparing the following active agents: agomelatine, amitriptyline, bupropion, citalopram, clomipramine, desvenlafaxine, duloxetine, escitalopram, fluoxetine, fluvoxamine, levomilnacipran, milnacipran, mirtazapine, nefazodone, paroxetine, reboxetine, sertraline, trazodone, venlafaxine, vilazodone and vortioxetine. The main outcomes will be the proportion of patients who responded to or dropped out of the allocated treatment. Published and unpublished studies will be sought through relevant database searches, trial registries and websites; all reference selection and data extraction will be conducted by at least two independent reviewers. We will conduct a random effects network meta-analysis to synthesise all evidence for each outcome and obtain a comprehensive ranking of all treatments. To rank the various treatments for each outcome, we will use the surface under the cumulative ranking curve and the mean ranks. We will employ local as well as global methods to evaluate consistency. We will fit our model in a Bayesian framework using OpenBUGS, and produce results and various checks in Stata and R. We will also assess the quality of evidence contributing to network estimates of the main outcomes with the GRADE framework. ETHICS AND DISSEMINATION This review does not require ethical approval. PROSPERO REGISTRATION NUMBER CRD42012002291.

Summary Background Previous studies have shown that placebo response rates in antidepressant trials have been increasing since the 1970s. However, these studies have been based on outdated or limited datasets and have used inappropriate statistical methods. We did a systematic review of placebo-controlled randomised controlled trials of antidepressants to examine associations between placebo-response rates and study and patient characteristics. Methods In this systematic review, we searched for published and unpublished double-blind randomised placebo-controlled trials of first-generation and second-generation antidepressants for acute treatment of major depression in adults (update: Jan 8, 2016). The log-transformed proportions of placebo response, defined as 50% or greater reduction in depression severity score from baseline, were meta-analytically synthesised for each year. We then looked for a structural break point in the secular changes in these characteristics through the years and examined the influence of the study year and other trial and patient characteristics on the response rates through meta-regression. Findings We identified 252 placebo-controlled trials (26 324 patients on placebo) done between 1978 and 2015. There was a structural break in 1991, and since then, the average placebo response rates in antidepressant trials have remained constant in the range between 35% and 40% (relative risk [RR] 1·00, 95% CI 0·97–1·03, p=0·99, for every 5-year increase). The length of the study and the number of study centres were significant factors (RR 1·03, 95% CI 1·01–1·05 for 1 more week in trial length; 1·32, 1·11–1·57 for multicentre vs single-centre trials). Interpretation Contrary to the widely held belief, the average placebo response rates in antidepressant trials have been stable for more than 25 years. This new evidence should have an effect on the interpretation of the scientific literature and the future of psychopharmacology, both from a clinical and methodological point of view. Funding Japan Society for Promotion of Science, Great Britain Sasakawa Foundation.