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Several in-person and remote delivery formats of cognitive-behavioural therapy (CBT) for panic disorder are available, but up-to-date and comprehensive evidence on their comparative efficacy and acceptability is lacking. Our aim was to evaluate the comparative efficacy and acceptability of all CBT delivery formats to treat panic disorder. To answer our question we performed a systematic review and network meta-analysis of randomised controlled trials. We searched MEDLINE, Embase, PsycINFO, and CENTRAL, from inception to 1st January 2022. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO. We found a total of 74 trials with 6699 participants. Evidence suggests that face-to-face group [standardised mean differences (s.m.d.) −0.47, 95% confidence interval (CI) −0.87 to −0.07; CINeMA = moderate], face-to-face individual (s.m.d. −0.43, 95% CI −0.70 to −0.15; CINeMA = Moderate), and guided self-help (SMD −0.42, 95% CI −0.77 to −0.07; CINeMA = low), are superior to treatment as usual in terms of efficacy, whilst unguided self-help is not (SMD −0.21, 95% CI −0.58 to −0.16; CINeMA = low). In terms of acceptability (i.e. all-cause discontinuation from the trial) CBT delivery formats did not differ significantly from each other. Our findings are clear in that there are no efficacy differences between CBT delivered as guided self-help, or in the face-to-face individual or group format in the treatment of panic disorder. No CBT delivery format provided high confidence in the evidence at the CINeMA evaluation.

Background Digital interventions for anxiety disorders are a promising solution to address barriers to evidence-based treatment access. Precise and powerful estimates of digital intervention effectiveness for anxiety disorders are necessary for further adoption in practice. The present systematic review and meta-analysis examined the effectiveness of digital interventions across all anxiety disorders and specific to each disorder v. wait-list and care-as-usual controls. Methods A systematic search of bibliographic databases identified 15 030 abstracts from inception to 1 January 2020. Forty-seven randomized controlled trials (53 comparisons; 4958 participants) contributed to the meta-analysis. Subgroup analyses were conducted by an anxiety disorder, risk of bias, treatment support, recruitment, location and treatment adherence. Results A large, pooled effect size of g = 0.80 [95% Confidence Interval: 0.68–0.93] was found in favor of digital interventions. Moderate to large pooled effect sizes favoring digital interventions were found for generalized anxiety disorder (g = 0.62), mixed anxiety samples (g = 0.68), panic disorder with or without agoraphobia (g = 1.08) and social anxiety disorder (g = 0.76) subgroups. No subgroups were significantly different or related to the pooled effect size. Notably, the effects of guided interventions (g = 0.84) and unguided interventions (g = 0.64) were not significantly different. Supplemental analysis comparing digital and face-to-face interventions (9 comparisons; 683 participants) found no significant difference in effect [g = 0.14 favoring digital interventions; Confidence Interval: −0.01 to 0.30]. Conclusion The precise and powerful estimates found further justify the application of digital interventions for anxiety disorders in place of wait-list or usual care.

BACKGROUND Although antipsychotic maintenance treatment is widely recommended to prevent relapse in chronic psychoses, evidence-based guidelines do not provide clear indications on different maintenance treatment strategies, including continuing the antipsychotic at standard doses, reducing the dose, switching to another antipsychotic, or even stopping the antipsychotic. We aimed to compare the effectiveness of these maintenance treatment strategies, hypothesising the superiority of all strategies over stopping, and of continuing at standard doses over both switching and reducing the dose. METHODS We did a systematic review and network meta-analysis of randomized controlled trials (RCTs) that investigated antipsychotics for relapse prevention in adults with schizophrenia-spectrum disorders who were clinically stable, and which compared four treatment strategies: continuing the current antipsychotic at standard doses recommended for acute treatment; reducing the current antipsychotic dose; switching to a different antipsychotic; and stopping the antipsychotic and replacing it with placebo. We excluded RCTs with fewer than 25 individuals, a prerandomisation washout period greater than 4 weeks, a follow-up shorter than 6 weeks, and those recruiting treatment-resistant individuals. We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term treatment for schizophrenia-spectrum disorders. Relative risks (RRs) and standardised mean differences were pooled using random-effects pairwise and network meta-analyses. We assessed risk of bias of each RCT with the Cochrane Risk-of-Bias 2 tool, and confidence of pooled estimates with CINeMA. The primary outcome was relapse prevention. The study protocol was registered in advance in the Open Science Forum registry. FINDINGS Of 3936 records identified, 119 records, reporting on 101 RCTs, were eligible, 98 of which (including 13 988 individuals) provided data that could be meta-analysed for at least one outcome. The mean proportion of female participants per study was 38% (range 0-100; median 39%, IQR 29-50), whereas for male participants it was 62% (range 0-100; median 61%, IQR 50-71), and the overall mean age was 38·8 years (range 23·2-63·9; median 39·3, IQR 35·0-43·9). Of the 98 RCTs meta-analysed, 89·8% were done in high-income and upper-middle-income countries. The ethnic group White or so-called Caucasian was the most represented (mean 56% participants per study), although this information was relatively scarce. All continuation strategies were significantly more effective in preventing relapse than stopping antipsychotic treatment, with a large risk reduction for continuing at standard doses (RR 0·37, 95% CI 0·32-0·43; number-needed-to-treat [NNT] 3·17, 95% CI 2·94-3·51) and antipsychotic switching (RR 0·44, 0·37-0·53; NNT 3·57, 3·17-4·25), and moderate risk reduction for dose reduction (RR 0·68, 0·51-0·90; NNT 6·25, 4·08-20·00). Continuing and switching antipsychotics did not differ significantly (RR 0·84, 0·69-1·02; with lower values favouring continuing), whereas reducing antipsychotic dose was outperformed by both continuing (RR 0·55, 0·42-0·71; NNT 4·44, 3·45-6·90) and switching (RR 0·65, 0·47-0·89; NNT 5·17, 3·77-18·18). Results were supported by moderate confidence of evidence and confirmed by secondary analyses and by several sensitivity and subgroup analyses, including removing studies with abrupt antipsychotic discontinuation or fast tapering (≤4 weeks). No tolerability differences emerged between treatment strategies. According to the Cochrane Risk-of-Bias tool, version 2, 16·8% of included RCTs had an overall high risk of bias for the primary outcome. We found moderate heterogeneity (τ2=0·13; I2=61%) and no overall incoherence for the primary analysis. Results were supported by moderate confidence of evidence and confirmed by secondary analyses. INTERPRETATION Contrary to our original hypothesis, we found that continuing antipsychotic treatment at standard doses or switching to a different antipsychotic are similarly effective treatment strategies, whereas reducing antipsychotic doses below standard doses is associated with higher risk of relapse than the other two maintenance treatment strategies and should therefore be limited to selected cases. Despite limitations, including moderate heterogeneity and moderate certainty of evidence, these results are of pragmatic relevance for clinicians, and should support the update of evidence-based guidelines. FUNDING None.

Background Effects of Selective Serotonin Reuptake Inhibitors (SSRI) for symptoms of autism spectrum disorder (ASD) or comorbid conditions are uncertain. We conducted a systematic review and meta-analyses to determine the efficacy and safety of SSRIs in children with ASD on restricted repetitive behaviors, obsessive-compulsive, anxiety and depressive symptoms, disruptive behaviors, global functioning, and quality of life. Methods We searched MEDLINE, EMBASE, CENTRAL, CINAHL, PsycINFO, WHO ICTRP, Clinical.Trials.gov. to retrieve RCT of SSRIs versus placebo in children with ASD that evaluated the outcomes of interest with a validated measurement instrument. Two authors independently extracted data, assessed risk of bias and rated the certainty of evidence. Results Seven RCTs with a total of 606 participants were included. The evidence is very uncertain on the effect of SSRIs on restricted-repetitive behaviors and anxiety symptoms in children with ASD, there is low certainty of the evidence suggesting that SSRIs result in little to no effect on obsessive-compulsive symptoms and disruptive behaviors and there is moderate certainty of the evidence that SSRIs likely result in little to no difference in global functioning and a slight increase in adverse events. No studies evaluated depressive symptoms. Conclusions The number of studies on this population remains limited, and there is a lack of commonly accepted outcome measures able to identify relevant changes for patients and families. Protocol registration number:PROSPERO-CRD42020169836

Background: Over the past 16 years, we have developed a ‘Meta-analytic Research Domain’ (MARD) of all randomized trials of psychological treatments of depression. A MARD is a living systematic review of a research field, that cannot be otherwise covered by one (network) meta-analysis and includes multiple PICOs. In this paper we give an overview of the findings of this MARD. Methods: A narrative review of the results of the 118 meta-analyses on psychotherapies for depression that were published within our MARD. Results: Most research has been conducted on cognitive-behavioral therapy (CBT), but several other psychotherapies are also effective, with few differences between therapies. They can be effectively delivered in individual, group, telephone and guided self-help format and are effective in many different target groups and across different age groups, although the effects are significantly smaller in children and adolescents. Psychotherapies have comparable effects as pharmacotherapy at the short term but are probably more effective at the longer term. Combined treatment is more effective than either psychotherapy or pharmacotherapy alone at the short, but also at the longer term. Limitations: We did not summarize all published meta-analyses (protocols, methodological studies) and have not compared our results to those found in other meta-analyses on comparable subjects. Conclusion: Psychotherapies can contribute considerably to a reduction of the disease burden of depression. MARDs are an important next step in the aggregation of knowledge from randomized controlled trials in psychological treatments of depression as well as in other healthcare sectors.

Evidence on long-acting antipsychotics (LAIs) in unselected populations with severe mental illness is scant. In this mirror-image study, we compared multiple clinical outcomes 1 year before and after a first LAI prescription in adults with severe mental illness, describing clinical trajectories of LAI continuers and discontinuers. We compared LAI continuers and discontinuers through Mann–Whitney U test, Kaplan–Meier survival curves, regression for interval-censored data, and a maximum-likelihood mixed-model with individual random-effect and time as predictor. Of the 261 participants analyzed, 71.3% had schizophrenia-spectrum disorders, and 29.5% discontinued the LAI before 1 year. At baseline, LAI discontinuers had a shorter illness duration, lower attitude and adherence scores. The mirror-image analysis showed reduced hospital admissions only for LAI continuers. Over time, continuers spent less days hospitalized, but had more adverse events and more antipsychotics prescribed, with higher overall doses. In conclusion, this study shows that LAIs might be beneficial in unselected patient populations, provided that adherence is maintained. LAI continuers spent less time hospitalized, but received more antipsychotics and suffered from more cumulative adverse events over time. Therefore, the choice of initiating and maintaining a LAI should be carefully weighed on a case-by-case basis.

BackgroundPsychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence.AimsTo examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-analysis.MethodWe conducted a systematic review and network meta-analysis of randomised controlled trials (RCTs) to examine the most effective and accepted psychotherapy for the acute phase of panic disorder. We searched MEDLINE, Embase, PsycInfo and CENTRAL, from inception to 1 Jan 2021 for RCTs. Cochrane and PRISMA guidelines were used. Pairwise and network meta-analyses were conducted using a random-effects model. Confidence in the evidence was assessed using Confidence in Network Meta-Analysis (CINeMA). The protocol was published in a peer-reviewed journal and in PROSPERO (CRD42020206258).ResultsWe included 136 RCTs in the systematic review. Taking into consideration efficacy (7352 participants), acceptability (6862 participants) and the CINeMA confidence in evidence appraisal, the best interventions in comparison with treatment as usual (TAU) were cognitive–behavioural therapy (CBT) (for efficacy: standardised mean differences s.m.d. = −0.67, 95% CI −0.95 to −0.39; CINeMA: moderate; for acceptability: relative risk RR = 1.21, 95% CI −0.94 to 1.56; CINeMA: moderate) and short-term psychodynamic therapy (for efficacy: s.m.d. = −0.61, 95% CI −1.15 to −0.07; CINeMA: low; for acceptability: RR = 0.92, 95% CI 0.54–1.54; CINeMA: moderate). After removing RCTs at high risk of bias only CBT remained more efficacious than TAU.ConclusionsCBT and short-term psychodynamic therapy are reasonable first-line choices. Studies with high risk of bias tend to inflate the overall efficacy of treatments. Results from this systematic review and network meta-analysis should inform clinicians and guidelines.

Aim: to assess the efficacy of psychosocial interventions delivered through task-sharing approaches for preventing perinatal common mental disorders among women in low- and middle-income countries. Methods: We conducted a systematic review of randomized controlled trials following a prespecified protocol registered in the Open Science Framework (osf.io/qt4y3). We searched MEDLINE, Web of Science, PsycINFO, and Cochrane Central Register of Controlled Trials (CENTRAL) through June 2022. Two reviewers independently extracted the data and evaluated the risk of bias of included studies using the Cochrane risk of bias tool. We performed random-effects meta-analyses and rated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach. Results: We included 23 studies with 24,442 participants. At post-intervention, task-shared psychosocial interventions, were effective in preventing the development of mental disorders in general (RR 0.57, 95% CI [0.35, 0.91]), and specifically depression (RR 0.51, 95% CI [0.35, 0.75]), but not anxiety disorders (RR 0.46, 95% CI [0.06, 3.33]). Similarly, psychosocial interventions reduced psychological distress (SMD −1.32, 95% CI [−2.28, −0.35]), and depressive symptoms (SMD −0.50, 95% CI [−0.80, −0.16]), and increased parenting self-efficacy (SMD −0.76, 95% CI [−1.13, −0.38]) and social support (SMD −0.72, 95% CI [−1.22, −0.22]). No effect was detected for anxiety symptoms at post-intervention. At follow-up the beneficial effects of interventions progressively decreased. Conclusions: Psychosocial interventions delivered through the task-sharing modality are effective in preventing perinatal common mental disorders and fostering positive mental health among women in low- and middle-income countries. However, our findings are tentative, due to the low number of preventative intervention strategies considering outcomes as the incidence of mental disorders, especially in the long-term. This evidence supports calls to implement and scale up psychosocial prevention interventions for perinatal common mental disorders in low- and middle-income countries.

OBJECTIVE This study compared relapse prevention and acceptability of long-acting injectable (LAI) antipsychotics in the maintenance treatment of adults with nonaffective psychoses. METHODS The authors searched MEDLINE, Embase, PsycINFO, CINAHL, CENTRAL, and online registers for randomized controlled trials published until June 2020. Relative risks and standardized mean differences were pooled using random-effects pairwise and network meta-analysis. The primary outcomes were relapse rate and all-cause discontinuation ("acceptability"). The quality of included studies was rated with the Cochrane Risk of Bias tool, and the certainty of pooled estimates was measured with GRADE (Grading of Recommendations Assessment, Development, and Evaluation). RESULTS Of 86 eligible trials, 78 (N=11,505) were included in the meta-analysis. Regarding relapse prevention, most of the 12 LAIs included outperformed placebo. The largest point estimates and best rankings of LAIs compared with placebo were found for paliperidone (3-month formulation) and aripiprazole. Moderate to high GRADE certainty for superior relapse prevention compared with placebo was also found for (in descending ranking order) risperidone, pipothiazine, olanzapine, and paliperidone (1-month formulation). In head-to-head comparisons of LAIs, only haloperidol was inferior to aripiprazole, fluphenazine, and paliperidone. For acceptability, most LAIs outperformed placebo, with moderate to high GRADE certainty for (in descending ranking order) zuclopenthixol, aripiprazole, paliperidone (3-month formulation), olanzapine, flupenthixol, fluphenazine, and paliperidone (1-month formulation). In head-to-head comparisons, only LAI aripiprazole had superior acceptability to other LAIs (bromperidol, fluphenazine, paliperidone [1-month formulation], pipothiazine, and risperidone). CONCLUSIONS LAI formulations of paliperidone (3-month formulation), aripiprazole, olanzapine, and paliperidone (1-month formulation) showed the highest effect sizes and certainty of evidence for both relapse prevention and acceptability. Results from this network meta-analysis should inform frontline clinicians and guidelines.

Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. To assess the efficacy of psychosocial interventions aimed at promoting mental health versus control conditions (no intervention, intervention as usual, or waiting list) in people living in LMICs affected by humanitarian crises.

To evaluate the efficacy of physical exercise in improving depressive symptoms in Parkinson disease (PD).We conducted a systematic review of randomized controlled trials (RCTs) following a prespecified protocol guidance (PROSPERO CRD42021243142). Two independent authors searched for studies in MEDLINE, Cochrane Register of Controlled Trials, Physiotherapy Evidence Database, Embase, PsycINFO, and Sports Discus from database inception to June 2022.Two independent authors extracted the data and evaluated the risk of bias using the revised Cochrane risk of bias tool. We performed random-effects meta-analyses and rated the certainty of evidence using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach.A total of 36 RCTs met the inclusion criteria, 14 of which were pooled in the quantitative synthesis. Depression symptomatology significantly decreased in the exercise group compared with usual care (standardized mean difference [SMD], -0.49; 95% confidence interval [CI], -0.74 to -0.24; very low quality of evidence; 14 RCTs; 961 participants). Physical exercise also improved patients' quality of life (SMD, -0.51; 95% CI, -0.81 to -0.21; 7 RCTs; 485 participants). As for acceptability, we did not find any difference between exercise and usual care (relative risk, 1.01; 95% CI, 0.97 to 1.05; 12 RCTs; 1048 participants). We judged all the studies except 2 to be at high risk of bias.Results from our systematic review identify physical activity as a viable option to reduce depressive symptoms in PD. Future clinical practice guidelines should consider physical exercise in their recommendations for depression symptomatology reduction in people with PD.

In this prospective study, we assessed the effectiveness and acceptability of paliperidone palmitate 1-month (PP1M) and aripiprazole monohydrate (AM) over 1-year follow-up. We included 195 subjects (117 treated with PP1M and 78 with AM) with schizophrenia spectrum disorders from real-world settings. We estimated no differences in hospitalization (Odds Ratio=1.59; p = 0.12), symptoms improvement (p = 0.90 adjusted for baseline severity), and discontinuation (Hazard Ratio=0.72; p = 0.20) at study endpoint. Although current evidence suggests the possible superiority of AM over PP1M, our findings showed comparable effectiveness between these drugs. Additional studies in real-world settings with direct comparisons between these two LAIs are needed.

IntroductionSeveral evidence-based treatments are effective for post-traumatic stress disorder (PTSD), yet a substantial proportion of patients do not respond or dropout of treatment. We describe the protocol for a systematic review and individual participant data meta-analysis (IPD-MA) aimed at assessing the effectiveness and adverse effects of psychotherapy and pharmacotherapy interventions for treating PTSD. Additionally, we seek to examine moderators and predictors of treatment outcomes.Method and analysisThis IPD-MA includes randomised controlled trials comparing psychotherapy and pharmacotherapy interventions for PTSD. PubMed, Embase, PsycINFO, PTSDpubs and CENTRAL will be screened up till the 11th of January 2021. The target population is adults with above-threshold baseline PTSD symptoms on any standardised self-report measure. Trials will only be eligible if at least 70% of the study sample have been diagnosed with PTSD by means of a structured clinical interview. The primary outcomes of this IPD-MA are PTSD symptom severity, and response rate. Secondary outcomes include treatment dropout and adverse effects. Two independent reviewers will screen major bibliographic databases and past reviews. Authors will be contacted to contribute their participant-level datasets. Datasets will be merged into a master dataset. A one-stage IPD-MA will be conducted focusing on the effects of psychological and pharmacological interventions on PTSD symptom severity, response rate, treatment dropout and adverse effects. Subsequent analyses will focus on examining the effect of moderators and predictors of treatment outcomes. These will include sociodemographic, treatment-related, symptom-related, resilience, intervention, trauma and combat-related characteristics. By determining the individual factors that influence the effectiveness of specific PTSD treatments, we will gain insight into personalised treatment options for PTSD.Ethics and disseminationSpecific ethics approval for an IPD-MA is not required as this study entails secondary analysis of existing anonymised data. The results of this study will be published in peer-reviewed scientific journals and presentations.

BackgroundMental health conditions are leading causes of disability worldwide. Psychosocial interventions for these conditions might have a key role in their treatment, although applicability of findings to poor-resource settings might be a challenge. We aimed to evaluate the strength and credibility of evidence generated in low-income and middle-income countries (LMICs) on the efficacy of psychosocial interventions for various mental health outcomes.MethodsWe did an umbrella review of meta-analyses of randomised studies done in LMICs. Literature searches were done in Medline, Embase, PsychINFO, CINAHL, Cochrane Library, and Epistemonikos from Jan 1, 2010, until May 31, 2019. Systematic reviews of randomised studies investigating the efficacy of psychosocial interventions for mental health conditions in LMICs were included. Systematic reviews of promotion, prevention, and protection interventions were excluded, because the focus was on treatment interventions only. Information on first author, year of publication, outcomes, number of included studies, and reported summary meta-analytic estimates was extracted from included meta-analyses. Summary effects were recalculated using a common metric and random-effects models. We assessed between-study heterogeneity, predictive intervals, publication bias, small-study effects, and whether the results of the observed positive studies were more than expected by chance. On the basis of these calculations, strength of associations was assessed using quantitative umbrella review criteria, and credibility of evidence using the GRADE approach. This study is registered with PROSPERO, number CRD42019135711.Findings123 primary studies from ten systematic reviews were included. The evidence on the efficacy of psychosocial interventions in adults with depression in humanitarian settings (standardised mean difference 0·87, 95% CI 0·67–1·07; highly suggestive association, GRADE: moderate) and in adults with common mental disorders (0·49, 0·36–0·62; highly suggestive association, GRADE: moderate) was supported by the most robust evidence. Highly suggestive strength of association was found for psychosocial interventions in adults with schizophrenia for functional outcomes, in adults with depression, and in adults with post-traumatic stress disorder in humanitarian settings. In children in humanitarian settings, and in children with disruptive behaviour, psychosocial interventions were supported by suggestive evidence of efficacy.InterpretationA relatively large amount of evidence suggests the benefit of psychosocial interventions on various mental health outcomes in LMICs. However, strength of associations and credibility of evidence were quite variable, depending on the target mental health condition, type of population and setting, and outcome of interest. This varied evidence should be considered in the development of clinical, policy, and implementation programmes in LMICs and should prompt further studies to improve the strength and credibility of the evidence base.

International audience; Objectives: This is a protocol for a Cochrane Review (intervention). The objectives are as follows:. The main aim of this Cochrane review is to assess the efficacy and tolerability of esketamine for treatment-resistant depression. Secondary aims are to assess the risk of specific adverse events during esketamine treatment, and its acceptability. Copyright © 2022 The Cochrane Collaboration. Published by John Wiley and Sons, Ltd.

According to current evidence and guidelines, continued antipsychotic treatment is key for preventing relapse in people with schizophrenia‐spectrum disorders, but evidence‐based recommendations for the choice of the individual antipsychotic for maintenance treatment are lacking. Although oral antipsychotics are often prescribed first line for practical reasons, long‐acting injectable antipsychotics (LAIs) are a valuable resource to tackle adherence issues since the earliest phase of disease. Medline, EMBASE, PsycINFO, CENTRAL and CINAHL databases and online registers were searched to identify randomized controlled trials comparing LAIs or oral antipsychotics head‐to‐head or against placebo, published until June 2021. Relative risks and standardized mean differences were pooled using random‐effects pairwise and network meta‐analysis. The primary outcomes were relapse and dropout due to adverse events. We used the Cochrane Risk of Bias tool to assess study quality, and the CINeMA approach to assess the confidence of pooled estimates. Of 100 eligible trials, 92 (N=22,645) provided usable data for meta‐analyses. Regarding relapse prevention, the vast majority of the 31 included treatments outperformed placebo. Compared to placebo, “high” confidence in the results was found for (in descending order of effect magnitude) amisulpride‐oral (OS), olanzapine‐OS, aripiprazole‐LAI, olanzapine‐LAI, aripiprazole‐OS, paliperidone‐OS, and ziprasidone‐OS. “Moderate” confidence in the results was found for paliperidone‐LAI 1‐monthly, iloperidone‐OS, fluphenazine‐OS, brexpiprazole‐OS, paliperidone‐LAI 1‐monthly, asenapine‐OS, haloperidol‐OS, quetiapine‐OS, cariprazine‐OS, and lurasidone‐OS. Regarding tolerability, none of the antipsychotics was significantly worse than placebo, but confidence was poor, with only aripiprazole (both LAI and OS) showing “moderate” confidence levels. Based on these findings, olanzapine, aripiprazole and paliperidone are the best choices for the maintenance treatment of schizophrenia‐spectrum disorders, considering that both LAI and oral formulations of these antipsychotics are among the best‐performing treatments and have the highest confidence of evidence for relapse prevention. This finding is of particular relevance for low‐ and middle‐income countries and constrained‐resource settings, where few medications may be selected. Results from this network meta‐analysis can inform clinical guidelines and national and international drug regulation policies.

BackgroundResearch on psychosocial interventions has been focused on the effectiveness of psychosocial interventions on mental health outcomes, without exploring how interventions achieve beneficial effects. Identifying the potential pathways through which interventions work would potentially allow further strengthening of interventions by emphasizing specific components connected with such pathways.MethodsWe conducted a preplanned mediation analysis using individual participant data from a dataset of 11 randomized controlled trials (RCTs) which compared focused psychosocial support interventions versus control conditions for children living in low‐ and middle‐income countries (LMICs) affected by humanitarian crises. Based on an ecological resilience framework, we hypothesized that (a) coping, (b) hope, (c) social support, and (d) functional impairment mediate the relationship between intervention and outcome PTSD symptoms. A systematic search on the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, PubMed, PyscARTICLES, Web of Science, and the main local LMICs databases was conducted up to August 2018. The hypotheses were tested by using individual participant data obtained from study authors of all the studies included in the systematic review.ResultsWe included 3,143 children from 11 studies (100% of data from included studies), of which 1,877 from six studies contributed to the mediation analysis. Functional impairment was the strongest mediator for focused psychosocial interventions on PTSD (mediation coefficient −0.087, standard error 0.040). The estimated proportion of effect mediated by functional impairment, and adjusted for confounders, was 31%.ConclusionsFindings did not support the proposed mediation hypotheses for coping, hope, and social support. The mediation through functional impairment may represent unmeasured proxy measures or point to a broader mechanism that impacts self‐efficacy and agency.

Objectives The objective of the study was to investigate time-lag bias based on statistical significance in findings in non-Cochrane systematic reviews (SRs) and explore barriers to publication for review authors. Study Design and Setting We included SRs of randomized controlled trials with completed analyses for protocols registered in the international prospective register of systematic reviews (PROSPERO) by the end of 2014. To obtain unpublished information, we sent questionnaires regarding barriers to publication of SRs to all authors between May and November 2018 and examined the association between the statistical significance of SR findings and time to acceptance. Results Among the 241 SR authors contacted, 141 (58%) responded, of whom 103 met the eligibility criteria and agreed to participate. Ninety-three (90%) of the protocols had been published as journal articles and 11 (11%) remained unpublished. Statistical significance was not significantly associated with time to acceptance (adjusted hazard ratio, 1.36; 95% confidence interval, 0.84 to 2.19). The authors reported lack of time (52%), rejection by journals (42%), duplication of similar topics (42%), and nonsignificant results (29%) as barriers to publication of SRs. Conclusion We found no convincing evidence of time-lag bias based on statistical significance in the findings among non-Cochrane SRs registered in the PROSPERO.

Background: Long-acting injectable (LAI) antipsychotics are efficacious in managing psychotic symptoms in people affected by severe mental disorders, such as schizophrenia and bipolar disorder. The present study aimed to investigate whether attitude toward treatment and treatment adherence represent predictors of symptoms changes over time.Methods: The STAR Network “Depot Study” was a naturalistic, multicenter, observational, prospective study that enrolled people initiating a LAI without restrictions on diagnosis, clinical severity or setting. Participants from 32 Italian centers were assessed at three time points: baseline, 6-month, and 12-month follow-up. Psychopathological symptoms, attitude toward medication and treatment adherence were measured using the Brief Psychiatric Rating Scale (BPRS), the Drug Attitude Inventory (DAI-10) and the Kemp's 7-point scale, respectively. Linear mixed-effects models were used to evaluate whether attitude toward medication and treatment adherence independently predicted symptoms changes over time. Analyses were conducted on the overall sample and then stratified according to the baseline severity (BPRS < 41 or BPRS ≥ 41).Results: We included 461 participants of which 276 were males. The majority of participants had received a primary diagnosis of a schizophrenia spectrum disorder (71.80%) and initiated a treatment with a second-generation LAI (69.63%). BPRS, DAI-10, and Kemp's scale scores improved over time. Six linear regressions—conducted considering the outcome and predictors at baseline, 6-month, and 12-month follow-up independently—showed that both DAI-10 and Kemp's scale negatively associated with BPRS scores at the three considered time points. Linear mixed-effects models conducted on the overall sample did not show any significant association between attitude toward medication or treatment adherence and changes in psychiatric symptoms over time. However, after stratification according to baseline severity, we found that both DAI-10 and Kemp's scale negatively predicted changes in BPRS scores at 12-month follow-up regardless of baseline severity. The association at 6-month follow-up was confirmed only in the group with moderate or severe symptoms at baseline.Conclusion: Our findings corroborate the importance of improving the quality of relationship between clinicians and patients. Shared decision making and thorough discussions about benefits and side effects may improve the outcome in patients with severe mental disorders.

Because of the rapidly increasing number of randomised controlled trials (RCTs) and meta-analyses in many fields, there is an urgent need to step up from meta-analyses to higher levels of aggregation of outcomes of RCTs. Network meta-analyses and umbrella reviews allow higher levels of aggregation of RCT outcomes, but cannot adequately cover the evidence for a whole field. The ‘Meta-Analytic Research Domain’ (MARD) may be a new methodology to aggregate RCT data of a whole field. A MARD is a living systematic review of a research domain that cannot be covered by one PICO. For example, a MARD of psychotherapy for depression covers all RCTs comparing the effects of all types of psychotherapy to control conditions, to each other, to pharmacotherapy and combined treatment. It also covers all RCTs comparing treatment formats, the effects in different target groups, subtypes of depression and secondary outcomes. Although the time and resources needed to build a MARD are considerable, they offer many advantages, including a comprehensive and consistent overview of a research field and important meta-analytic studies that cannot be conducted with conventional methods. MARDs are a promising method to step up the aggregation of RCTs to a next level and it is highly relevant to work out the methods of this approach in a more detailed way.

Background: little is known about changes of mental health during the COVID-19 pandemic in potentially disadvantaged groups. We investigated changes in anxiety and depression symptoms during the first year of the pandemic in six European countries and Australia by prior mental disorders and migration status. Methods: overall, 4674 adults answered a web-based survey in May-June 2020 and were followed by three repeated surveys up to February 2021. Information on psychosocial, financial and demographic, living conditions, prior mental disorders, depression and anxiety symptoms during the pandemic and migration status was collected. Weighted general estimation equations modelling was used to investigate the association between prior mental disorders, migration status, and symptoms over time. Results: most participants were, European Union (EU); Horizon 2020; Research and Innovation Programme Societal Challenges

Introduction: Self-Help Plus (SH+) is a group-based psychological intervention developed by the World Health Organization for managing stress. Objective: to assess the effectiveness of SH+ in preventing mental disorders in refugees and asylum seekers in Western Europe. Methods: we conducted a randomized controlled trial in 5 European countries. Refugees and asylum seekers with psychological distress (General Health Questionnaire score >= 3), but without a Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5) or ICD/10 diagnosis of mental disorder, as assessed with the Mini International Neuropsychiatric Interview (MINI), were randomized to SH+ or enhanced treatment as usual (ETAU). The primary outcome was the frequency of mental disorders with the MINI at 6 months. Secondary outcomes included the frequency of mental disorders at postintervention, self-identified problems, psychological symptoms, and other outcomes. Results: four hundred fifty-nine individuals were randomly assigned to SH+ or ETAU. For the primary outcome, we found no difference in the frequency of mental disorders at 6 months (Cramer V = 0.007, p = 0.90, RR = 0.96; 95% CI 0.52-1.78), while the difference significantly favored SH+ at after the intervention (secondary outcome, measured within 2 weeks from the last session; Cramer V = 0.13, p = 0.01, RR = 0.50; 95% CI 0.29-0.87). Conclusions: this is the first randomized indicated prevention study with the aim of preventing the onset of mental disorders in asylum seekers and refugees in Western Europe. As a prevention effect of SH+ was not observed at 6 months, but rather after the intervention only, modalities to maintain its beneficial effect in the long term need to be identified., European Union (EU); Horizon 2020; European Commission (EC); RE-DEFINE: Refugee Emergency: DEFining and Implementing Novel Evidence-based Psychosocial Interventions

Objective To quantify the risk of hip fracture, thromboembolism, stroke, myocardial infarction, pneumonia and sudden cardiac death associated with exposure to antipsychotics. Methods Systematic searches were conducted in Medline, Embase and PsycINFO from inception until 30/07/2018 for systematic reviews of observational studies. AMSTAR-2 was used for the quality assessment of systematic reviews, while the strength of associations was measured using GRADE and quantitative umbrella review criteria (URC). Results Sixty-eight observational studies from six systematic reviews were included. The association between antipsychotic exposure and pneumonia was the strongest [URC = class I; GRADE = low quality; odds ratio (OR) = 1.84, 95% confidence interval (CI) = 1.62-2.09; participants = 28 726; age = 76.2 ± 12.3 years], followed by the association with hip fracture (URC = class II; GRADE = low quality; OR = 1.57, 95% CI = 1.42-1.74; participants = 5 288 118; age = 55.4 ± 12.5 years), and thromboembolism (URC = class II; GRADE = very low quality; OR = 1.55, 95% CI = 1.31-1.83; participants = 31 417 175; age = 55.5 ± 3.2 years). The association was weak for stroke (URC = class III; GRADE = very low quality; OR = 1.45, 95% CI = 1.24-1.70; participants = 65 700; age = 68.7 ± 13.8 years), sudden cardiac death (URC = class III; GRADE = very low quality; OR = 2.24, 95% CI = 1.45-3.46; participants = 77 488; age = 52.2 ± 6.2 years) and myocardial infarction (URC = class III; GRADE = very low quality; OR = 2.21, 95% CI = 1.41-3.46; participants = 399 868; age = 74.1 ± 9.3 years). Conclusion The most robust results were found for the risk of pneumonia, followed by the risk of hip fracture and thromboembolism. For stroke, sudden cardiac death and myocardial infarction, the strength of association was weak. The observational nature of the primary studies may represent a source of bias.

ObjectivesThis is a protocol for a Cochrane Review (intervention). The objectives are as follows:To assess the effectiveness of delivery by primary workers of interventions for promotion of mental health and for prevention of mental disorders or symptoms of mental illness in LMICsTo examine the impact of intervention delivery by primary workers on resource use and costs associated with provision of mental health care in LMICs

IntroductionPanic disorder is among the most prevalent anxiety diseases. Although psychotherapy is recommended as first-line treatment for panic disorder, little is known about the relative efficacy of different types of psychotherapies. Moreover, there is little evidence concerning the effectiveness of different formats of major psychotherapeutic types, such as cognitive–behavioural therapy (CBT). In this protocol, we present an overarching project consisting of two systematic reviews and network meta-analyses (NMA) to shed light on which psychotherapy (NMA-1), and specifically, which CBT delivery format (NMA-2) should be considered most effective for adults suffering from panic disorder with or without agoraphobia.Methods and analysesStarting from a common pool of data, we will conduct two systematic reviews and NMA of randomised controlled trials examining panic disorder. A comprehensive search will be performed in electronic databases MEDLINE, Embase, PsycINFO and the Cochrane Register of Controlled Trials—CENTRAL from database inception to 1 January 2021 to identify relevant studies. A systematic approach to searching, screening, reviewing and data extraction will be applied. Titles, abstract and—whenever necessary—full texts will be examined independently by at least two reviewers. The quality of the included studies will be assessed using the revised Cochrane risk of bias tool V.2. The primary efficacy outcome will be anxiety symptoms at study endpoint. The primary acceptability outcome will be all-cause discontinuation, as measured by the proportion of patients who had discontinued treatment for any reason at endpoint. Data will be pooled using a random-effects model. Pairwise and NMA will be conducted.Ethics and disseminationNo ethical approval is necessary for these two studies, as there will be no collection of primary data. The results will be disseminated through peer-reviewed publications and presentations at national and international conferences and meetings.

Background The novel coronavirus pandemic calls for a rapid adaptation of conventional medical practices to meet the evolving needs of such vulnerable patients. People with coronavirus disease (COVID-19) may frequently require treatment with psychotropic medications, but are at the same time at higher risk for safety issues because of the complex underlying medical condition and the potential interaction with medical treatments. Methods In order to produce evidence-based practical recommendations on the optimal management of psychotropic medications in people with COVID-19, an international, multi-disciplinary working group was established. The methodology of the WHO Rapid Advice Guidelines in the context of a public health emergency and the principles of the AGREE statement were followed. Available evidence informing on the risk of respiratory, cardiovascular, infective, hemostatic, and consciousness alterations related to the use of psychotropic medications, and drug–drug interactions between psychotropic and medical treatments used in people with COVID-19, was reviewed and discussed by the working group. Results All classes of psychotropic medications showed potentially relevant safety risks for people with COVID-19. A set of practical recommendations was drawn in order to inform frontline clinicians on the assessment of the anticipated risk of psychotropic-related unfavorable events, and the possible actions to take in order to effectively manage this risk, such as when it is appropriate to avoid, withdraw, switch, or adjust the dose of the medication. Conclusions The present evidence-based recommendations will improve the quality of psychiatric care in people with COVID-19, allowing an appropriate management of the medical condition without worsening the psychiatric condition and vice versa.

Background People living in 'humanitarian settings' in low‐ and middle‐income countries (LMICs) are exposed to a constellation of physical and psychological stressors that make them vulnerable to developing mental disorders. A range of psychological and social interventions have been implemented with the aim to prevent the onset of mental disorders and/or lower psychological distress in populations at risk, and it is not known whether interventions are effective. Objectives To compare the efficacy and acceptability of psychological and social interventions versus control conditions (wait list, treatment as usual, attention placebo, psychological placebo, or no treatment) aimed at preventing the onset of non‐psychotic mental disorders in people living in LMICs affected by humanitarian crises. Search methods We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMD‐CTR), the Cochrane Drugs and Alcohol Review Group (CDAG) Specialized Register, Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (OVID), Embase (OVID), PsycINFO (OVID), and ProQuest PILOTS database with results incorporated from searches to February 2020. We also searched the World Health Organization's (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify unpublished or ongoing studies. We checked the reference lists of relevant studies and reviews. Selection criteria All randomised controlled trials (RCTs) comparing psychological and social interventions versus control conditions to prevent the onset of mental disorders in adults and children living in LMICs affected by humanitarian crises. We excluded studies that enrolled participants based on a positive diagnosis of mental disorder (or based on a proxy of scoring above a cut‐off score on a screening measure). Data collection and analysis We calculated standardised mean differences for continuous outcomes and risk ratios for dichotomous data, using a random‐effects model. We analysed data at endpoint (zero to four weeks after therapy) and at medium term (one to four months after intervention). No data were available at long term (six months or longer). We used GRADE to assess the quality of evidence. Main results In the present review we included seven RCTs with a total of 2398 participants, coming from both children/adolescents (five RCTs), and adults (two RCTs). Together, the seven RCTs compared six different psychosocial interventions against a control comparator (waiting list in all studies). All the interventions were delivered by paraprofessionals and, with the exception of one study, delivered at a group level. None of the included studies provided data on the efficacy of interventions to prevent the onset of mental disorders (incidence). For the primary outcome of acceptability, there may be no evidence of a difference between psychological and social interventions and control at endpoint for children and adolescents (RR 0.93, 95% CI 0.78 to 1.10; 5 studies, 1372 participants; low‐quality evidence) or adults (RR 0.96, 95% CI 0.61 to 1.50; 2 studies, 767 participants; very low quality evidence). No information on adverse events related to the interventions was available. For children's and adolescents' secondary outcomes of prevention interventions, there may be no evidence of a difference between psychological and social intervention groups and control groups for reducing PTSD symptoms (standardised mean difference (SMD) −0.16, 95% CI −0.50 to 0.18; 3 studies, 590 participants; very low quality evidence), depressive symptoms (SMD −0.01, 95% CI −0.29 to 0.31; 4 RCTs, 746 participants; very low quality evidence) and anxiety symptoms (SMD 0.11, 95% CI −0.09 to 0.31; 3 studies, 632 participants; very low quality evidence) at study endpoint. In adults' secondary outcomes of prevention interventions, psychological counselling may be effective for reducing depressive symptoms (MD −7.50, 95% CI −9.19 to −5.81; 1 study, 258 participants; very low quality evidence) and anxiety symptoms (MD −6.10, 95% CI −7.57 to −4.63; 1 study, 258 participants; very low quality evidence) at endpoint. No data were available for PTSD symptoms in the adult population. Owing to the small number of RCTs included in the present review, it was not possible to carry out neither sensitivity nor subgroup analyses. Authors' conclusions Of the seven prevention studies included in this review, none assessed whether prevention interventions reduced the incidence of mental disorders and there may be no evidence for any differences in acceptability. Additionally, for both child and adolescent populations and adult populations, a very small number of RCTs with low quality evidence on the review's secondary outcomes (changes in symptomatology at endpoint) did not suggest any beneficial effect for the studied prevention interventions. Confidence in the findings is hampered by the scarcity of prevention studies eligible for inclusion in the review, by risk of bias in the studies, and by substantial levels of heterogeneity. Moreover, it is possible that random error had a role in distorting results, and that a more thorough picture of the efficacy of prevention interventions will be provided by future studies. For this reason, prevention studies are urgently needed to assess the impact of interventions on the incidence of mental disorders in children and adults, with extended periods of follow‐up., Plain language summary Do psychological and social interventions prevent mental health disorders in low‐ and middle‐income countries affected by humanitarian crises? Mental health during a humanitarian crisis A humanitarian crisis is an event, or series of events, that threaten the health, safety, security or well‐being of a community or large group of people, usually over a wide area. Examples include: wars, famine, and natural disasters such as earthquakes, hurricanes and floods. People living through a humanitarian crisis may experience physical and mental distress that make them vulnerable to developing mental health disorders. These include post‐traumatic stress disorder, depression and anxiety. What are psychological and social interventions? Psychological interventions of a preventive nature usually offer people support and practical help to develop ways of coping, a sense of hope, and focus on building resilience. Social interventions of a preventive nature usually aim to strengthen social support systems and help people to feel more connected. Why we did this Cochrane Review We wanted to know if psychological and social interventions (psychosocial interventions) could help to stop mental health disorders developing in people living through humanitarian crises in low‐ and middle‐income countries. We were interested in: 1)·how many people developed a mental health disorder after taking part in an intervention; and 2) how many people dropped out of a programme or had unwanted effects related to the intervention. What did we do? We searched for studies that looked at the preventive effects of psychosocial interventions on people's mental health in low‐ and middle‐income countries affected by humanitarian crises. We looked for randomised controlled studies, in which the interventions people received were decided at random. This type of study usually gives the most reliable evidence about the effects of an intervention. Search date We included evidence published up to February 2020. What we found We found seven prevention studies with a total of 2398 participants. Five studies were in children and adolescents (aged 7 to 18 years), and two were in adults (aged over 18 years). Two studies were done in Nepal, and one study each in Democratic Republic of Congo, Haiti, Syria, Uganda and Sri Lanka. Six different psychosocial interventions were studied. The studies measured symptoms of depression, anxiety and post‐traumatic stress disorder in children and adolescents, and anxiety and depression symptoms in adults, at the beginning of the study, the end of the intervention, and after four weeks and up to four months later. They compared the results with symptoms measured in people on a waiting list to take part in the intervention. What are the results of our review? None of the studies measured how many people developed a mental disorder after taking part in a psychosocial intervention, and none measured any unwanted effects of the interventions. There may be little to no difference in how many children and adolescents dropped out of an intervention while taking part, compared with being on a waiting list (5 studies). We were uncertain if there was any difference in the number of adults who dropped out (2 studies). In children and adolescents, only very small differences in symptoms of post‐traumatic stress disorder, depression and anxiety were seen at the end of an intervention, compared with being on a waiting list, suggesting no evidence of a difference. However, we are not confident that these results are reliable: the results are likely to change when further evidence is available. In adults, results from one prevention study showed that psychological counselling may lower depression and anxiety symptoms; but this result is from only one study and we are not confident the result is reliable. This result will probably change when more evidence becomes available. Conclusions We did not find any randomized evidence whether psychosocial interventions can stop mental health disorders developing in people living through humanitarian crises in low‐ to middle‐income countries. We did not find enough reliable evidence about the benefits of these interventions in reducing mental health symptoms. Larger, well‐conducted studies are needed to give more reliable evidence about the short‐ and long‐term effects of psychosocial interventions to prevent mental disorders in people living in low‐ and middle‐income countries affected by humanitarian crises.

Introduction Depression is a highly prevalent condition in the elderly, with a vast impact on quality of life, life expectancy, and medical outcomes. Selective serotonin reuptake inhibitors (SSRIs) are the most commonly prescribed agents in this condition and, although generally safe, tolerability issues cannot be overlooked. Vortioxetine is an antidepressant with a novel mechanism of action. Based on studies to date, it may have a promising tolerability profile in the elderly, as it does not adversely affect psychomotor or cognitive performance and does not alter cardiovascular and endocrine parameters. The present study aims to assess the tolerability profile of vortioxetine in comparison with the SSRIs considered as a single group in elderly participants with depression. The rate of participants withdrawing from treatment due to adverse events after 6 months of follow up will be the primary outcome. Methods and analysis This is a pragmatic, multicentre, open-label, parallel-group, superiority, randomized trial funded by the Italian Medicines Agency (AIFA - Agenzia Italiana del Farmaco). Thirteen Italian Community Psychiatric Services will consecutively enrol elderly participants suffering from an episode of major depression over a period of 12 months. Participants will be assessed at baseline and after 1, 3 and 6 months of follow up. At each time point, the following validated rating scales will be administered: Montgomery–Åsberg Depression Rating Scale (MADRS), Antidepressant Side-Effect Checklist (ASEC), EuroQual 5 Dimensions (EQ-5D), Short Blessed Test (SBT), and Charlson Age-Comorbidity Index (CACI). Outcome assessors and the statistician will be masked to treatment allocation. A total of 358 participants (179 in each group) will be enrolled. Ethics and dissemination This study will fully adhere to the ICH E6 Guideline for Good Clinical Practice. Participants’ data will be managed and safeguarded according to the European Data Protection Regulation 2016/679. An external Ethical Advisory Board will help guarantee high ethical standards. Trial registration Clinicaltrials.gov: NCT03779789, Registered on 19 December 2018. Submitted on 19 December. EudraCT number: 2018–001444-66. Trial status Protocol version 1.5; 09/06/2018. Recruitment started In February 2019 and it is ongoing. It is expected to end approximately on 30 September 2021.

In March 2019, the US Food and Drug Administration (FDA) approved a nasal spray formulation of esketamine for the treatment of resistant depression in adults. Esketamine is the S-enantiomer of ketamine, an FDA-approved anaesthetic, known to cause dissociation and, occasionally, hallucinations. While ketamine has not been approved for depression in the USA or in any other country, it has been used off-label in cases of severe depression. This commentary critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science.

Maju et al. provided clarifications on important and controversial issues related to esketamine clinical trial data, in response to a vivid debate triggered by the marketing authorisation recently granted by this new medicine. In this commentary, we reply to their comments attempting to critically discuss the evidence base needed to obtain regulatory approval.