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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 We searched MEDLINE, EMBASE, PsycINFO, CINAHL, CENTRAL, and online trial registers for published and unpublished RCTs from inception to Sept 1, 2021, combining terms describing all available antipsychotics, and terms describing continuation, maintenance, or long-term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.

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.

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.

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.

Backgrounds: individuals with chronic medical conditions are considered highly exposed to COVID-19 pandemic stress, but emerging evidence is demonstrating that resilience is common even among them. We aimed at identifying sustained resilient outcomes and their predictors in chronically ill people during the first year of the pandemic. Methods: this international 4-wave 1-year longitudinal online survey included items on socio-demographic characteristics, economic and living situation, lifestyle and habits, pandemic-related issues, and history of mental disorders. Adherence to and approval of imposed restrictions, trust in governments and in scientific community during the pandemic were also investigated. The following tools were administered: the Patient Health Questionnaire, the Generalized Anxiety Disorder scale, the PTSD Checklist DSM-5, the Oslo Social Support Scale, the Padua Inventory, and the Portrait Values Questionnaire. Results: one thousand fifty-two individuals reporting a chronic condition out of 8011 total participants from 13 countries were included in the study, and 965 had data available for the final model. The estimated probability of being "sustained-resilient" was 34%. Older male individuals, participants employed before and during the pandemic or with perceived social support were more likely to belong to the sustained-resilience group. Loneliness, a previous mental disorder, high hedonism, fear of COVID-19 contamination, concern for the health of loved ones, and non-approving pandemic restrictions were predictors of not-resilient outcomes in our sample. Conclusions: we found similarities and differences from established predictors of resilience and identified some new ones specific to pandemics. Further investigation is warranted and could inform the design of resilience-building interventions in people with chronic diseases., NA

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: 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.

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 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.

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.

A substantial proportion of people with mental health conditions do not adhere to prescribed pharmacological treatments. Poor adherence is probably one of the most critical elements contributing to relapse in people with schizophrenia and other severe mental disorders. In order to tackle this global issue, in November 2017 the Food and Drug Administration approved a tablet formulation of the atypical antipsychotic aripiprazole embedded with a novel digital adherence-assessment device. In this commentary, we critically appraised the potential beneficial and harmful consequences of this new digital formulation of aripiprazole, and we highlighted expected implications for clinical practice.

IntroductionThis article describes two randomised controlled trials that will evaluate the effectiveness and cost-effectiveness of Self-Help Plus (SH+), a group self-help intervention developed by the WHO to reduce distress. In these trials SH+ is being tested as a preventative intervention to lower the incidence of mental disorders in asylum seekers and refugees with psychological distress resettled in Europe and Turkey.Methods and analysisTwo prospective, multicentre, randomised, rater-blinded, parallel-group studies will follow participants over a period of 12 months. One trial will be conducted in Europe and one in Turkey. In each trial, 600 asylum seekers and refugees screening positive on the General Health Questionnaire (≥3), but without a formal diagnosis of any mental disorders according to the Mini International Neuropsychiatric Interview, will be randomly allocated to SH+or to enhanced treatment-as-usual. The primary outcome will be a lower incidence of mental disorders at 6 month follow-up. Secondary outcomes will include the evaluation of psychological symptoms, functioning, well-being, treatment acceptability and indicators of intervention cost-effectiveness.Ethics and disseminationThe two trials received ethical clearance from the local Ethics Committees of the participating sites (seven sites), as well as from the WHO Ethics Committee. All participants will provide informed consent before screening and before study inclusion (a two-step procedure). The results of the trials will be disseminated in agreement with a dissemination plan that includes publication(s) in peer-reviewed journals and presentations at relevant national and international conferences and meetings.Trials registration numbersNCT03571347,NCT03587896.

To assess the efficacy and acceptability of antidepressants in adults with ischemic heart disease (IHD). We gathered all available randomized-controlled trials comparing antidepressants versus placebo or other antidepressants in adults with IHD. The primary outcome was depressive symptoms at the study endpoint, as measured by validated rating scales. We pooled data in a meta-analysis using a random-effects model. The confidence in the estimates (or certainty of the evidence) was assessed using the GRADE approach. Antidepressants appeared to be more effective than placebo in reducing depressive symptoms (11 comparisons; 1685 participants; standardized mean difference -0.71, 95% confidence interval: -1.11 to -0.30; GRADE quality: moderate). This result was confirmed in the subgroup of serotonin selective reuptake inhibitors, and for the single drugs sertraline and citalopram, with a greater magnitude of effect and a higher quality of evidence for the former. No differences between antidepressants and placebo emerged in terms of acceptability and tolerability, quality of life, mortality, and cardiovascular events. Only two small head-to-head studies were identified. Sertraline is a reasonable first-line choice in patients with IHD and depression, whereas the role of citalopram as the first-line agent should be reconsidered.

BackgroundCare-as-usual (CAU) is often used as a control condition in psychotherapy research, but it may vary considerably what that entails, ranging from no treatment, to routine treatment in primary care, general medical care, perinatal care, and specialized mental health care.MethodsWe conducted a meta-analysis of trials comparing psychotherapy for depression to CAU, with a focus on the different categories of CAU and countries where the studies were conducted. We used an existing database of randomized trials on psychotherapy for depression that is updated every year.ResultsA total of 140 studies with 15 419 patients were included. We found no significant differences in effects between categories of CAU (effect sizes ranging from g = 0.43 for CAU in primary care to g = 0.73 for no treatment), but heterogeneity was high in all CAU categories. After stratifying effects across specific countries (within CAU categories) we found that heterogeneity was considerably lower and there were several significant differences between countries. Overall, effects were larger in non-Western countries (g = 0.84 to 1.28) compared to those in Western countries (g = 0.52; p for difference = 0.002). Effects were smaller in studies with risk of bias (p = 0.01).ConclusionsThere are no significant differences between major categories of CAU when compared to psychotherapy conditions in randomized trials. However, effects of psychotherapy differ considerably across CAU conditions in specific countries. CAU therefore is a heterogeneous control condition in psychotherapy research.

Background People living in humanitarian settings in low- and middle-income countries (LMICs) are exposed to a constellation of stressors that make them vulnerable to developing mental disorders. Mental disorders with a higher prevalence in these settings include post-traumatic stress disorder (PTSD) and major depressive, anxiety, somatoform (e.g. medically unexplained physical symptoms (MUPS)), and related disorders. A range of psychological therapies are used to manage symptoms of mental disorders in this population. Objectives To compare the effectiveness and acceptability of psychological therapies versus control conditions (wait list, treatment as usual, attention placebo, psychological placebo, or no treatment) aimed at treating people with mental disorders (PTSD and major depressive, anxiety, somatoform, and related disorders) living in LMICs affected by humanitarian crises. Search methods We searched the Cochrane Common Mental Disorders Controlled Trials Register (CCMDCTR), the Cochrane Central Register of Controlled Trials (Wiley), MEDLINE (OVID), Embase (OVID), and PsycINFO (OVID), with results incorporated from searches to 3 February 2016. We also searched the World Health Organization (WHO) trials portal (ICTRP) and ClinicalTrials.gov to identify any unpublished or ongoing studies. We checked the reference lists of relevant studies and reviews. Selection criteria All randomised controlled trials (RCTs) comparing psychological therapies versus control conditions (including no treatment, usual care, wait list, attention placebo, and psychological placebo) to treat adults and children with mental disorders living in LMICs affected by humanitarian crises. Data collection and analysis We used standard Cochrane procedures for collecting data and evaluating risk of bias. 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); at medium term (one to four months after therapy); and at long term (six months or longer). GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) was used to assess the quality of evidence for post-traumatic stress disorder (PTSD), depression, anxiety and withdrawal outcomes. Main results We included 36 studies (33 RCTs) with a total of 3523 participants. Included studies were conducted in sub-Saharan Africa, the Middle East and North Africa, and Asia. Studies were implemented in response to armed conflicts; disasters triggered by natural hazards; and other types of humanitarian crises. Together, the 33 RCTs compared eight psychological treatments against a control comparator. Four studies included children and adolescents between 5 and 18 years of age. Three studies included mixed populations (two studies included participants between 12 and 25 years of age, and one study included participants between 16 and 65 years of age). Remaining studies included adult populations (18 years of age or older). Included trials compared a psychological therapy versus a control intervention (wait list in most studies; no treatment; treatment as usual). Psychological therapies were categorised mainly as cognitive-behavioural therapy (CBT) in 23 comparisons (including seven comparisons focused on narrative exposure therapy (NET), two focused on common elements treatment approach (CETA), and one focused on brief behavioural activation treatment (BA)); eye movement desensitisation and reprocessing (EMDR) in two comparisons; interpersonal psychotherapy (IPT) in three comparisons; thought field therapy (TFT) in three comparisons; and trauma or general supportive counselling in two comparisons. Although interventions were described under these categories, several psychotherapeutic elements were common to a range of therapies (i.e. psychoeducation, coping skills). In adults, psychological therapies may substantially reduce endpoint PTSD symptoms compared to control conditions (standardised mean difference (SMD) -1.07, 95% confidence interval (CI) -1.34 to -0.79; 1272 participants; 16 studies; low-quality evidence). The effect is smaller at one to four months (SMD -0.49, 95% CI -0.68 to -0.31; 1660 participants; 18 studies) and at six months (SMD -0.37, 95% CI -0.61 to -0.14; 400 participants; five studies). Psychological therapies may also substantially reduce endpoint depression symptoms compared to control conditions (SMD -0.86, 95% CI -1.06 to -0.67; 1254 participants; 14 studies; low-quality evidence). Similar to PTSD symptoms, follow-up data at one to four months showed a smaller effect on depression (SMD -0.42, 95% CI -0.63 to -0.21; 1386 participants; 16 studies). Psychological therapies may moderately reduce anxiety at endpoint (SMD -0.74, 95% CI -0.98 to -0.49; 694 participants; five studies; low-quality evidence) and at one to four months' follow-up after treatment (SMD -0.53, 95% CI -0.66 to -0.39; 969 participants; seven studies). Dropout rates are probably similar between study conditions (19.5% with control versus 19.1% with psychological therapy (RR 0.98 95% CI 0.82 to 1.16; 2930 participants; 23 studies, moderate quality evidence)). In children and adolescents, we found very low quality evidence for lower endpoint PTSD symptoms scores in psychotherapy conditions (CBT) compared to control conditions, although the confidence interval is wide (SMD -1.56, 95% CI -3.13 to 0.01; 130 participants; three studies;). No RCTs provided data on major depression or anxiety in children. The effect on withdrawal was uncertain (RR 1.87 95% CI 0.47 to 7.47; 138 participants; 3 studies, low quality evidence). We did not identify any studies that evaluated psychological treatments on (symptoms of) somatoform disorders or MUPS in LMIC humanitarian settings. Authors' conclusions There is low quality evidence that psychological therapies have large or moderate effects in reducing PTSD, depressive, and anxiety symptoms in adults living in humanitarian settings in LMICs. By one to four month and six month follow-up assessments treatment effects were smaller. Fewer trials were focused on children and adolescents and they provide very low quality evidence of a beneficial effect of psychological therapies in reducing PTSD symptoms at endpoint. Confidence in these findings is influenced by the risk of bias in the studies and by substantial levels of heterogeneity. More research evidence is needed, particularly for children and adolescents over longer periods of follow-up.

To investigate the extent to which exposure to first-generation and second-generation antipsychotics (APs) is associated with an increased risk of fractures, with a particular focus on hip fractures, and to ascertain the risk associated with exposure to individual drugs. We included observational studies that reported data on fractures in individuals exposed to APs compared with unexposed individuals or individuals with previous exposure. We extracted information on study design, source of data, population characteristics, outcomes of interest, matching and confounding factors, and used a modified version of the Newcastle-Ottawa Scale to judge study risk of bias. We pooled adjusted estimates of relative effects to generate pooled odds ratios (ORs) and their 95% confidence interval (CI) using a random-effects model. We rated the quality of evidence using the GRADE approach. Of 36 observational studies, 29 proved to have a low risk of bias and seven were found to have a high risk of bias. The risk of hip fracture (OR: 1.57, 95% CI: 1.42-1.74, low quality of evidence) and of any fracture (OR: 1.17, 95% CI: 1.04-1.31, very low quality of evidence) increased with exposure to APs, with similar increases in risk in the first generation and second generation. The risk was similar among different diagnostic categories. The few studies that provided data were insufficient to allow inferences on individual drugs. AP exposure in unselected populations was associated with a 57% increase in the risk of hip fractures and a 17% increase in the risk of any fractures. Between-study heterogeneity limits the confidence in this estimate.

BackgroundResults from studies evaluating the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in humanitarian settings in low-income and middle-income countries have been inconsistent, showing varying results by setting and subgroup (eg, age or gender). We aimed to assess the effectiveness of these interventions, and to explore which children are likely to benefit most.MethodsWe did a systematic review and meta-analysis of individual participant data (IPD) from 3143 children recruited to 11 randomised controlled trials of focused psychosocial support interventions versus waiting list. We searched the Cochrane Central Register of Controlled Trials, MEDLINE, PubMed, PsycArticles, Web of Science, and the main local low-income and middle-income countries (LMICs) databases according to the list of databases relevant to LMIC developed collaboratively by Cochrane and WHO Library, up to November, 2016. We included randomised controlled trials that assessed the effectiveness of focused psychosocial support interventions in children exposed to traumatic events in LMICs, compared with waiting lists (eg, inactive controls). We excluded quasi-randomised trials, studies that did not focus on psychosocial support interventions, and studies that compared two active interventions without control conditions. We requested anonymised data from each trial for each of the prespecified variables for each child who was randomly assigned. The main outcomes considered were continuous scores in post-traumatic stress disorder (PTSD) symptoms, depressive symptoms, and anxiety symptoms assessed with rating scales administered immediately (0–4 weeks) after the intervention. We harmonised all individual items from rating scales using item response theory methods. This study is registered with PROSPERO, number CRD42013006960.FindingsWe identified a beneficial effect of focused psychosocial support interventions on PTSD symptoms (standardised mean difference [SMD] −0·33, 95% CI −0·52 to −0·14) that was maintained at follow-up (–0·21, −0·42 to −0·01). We also identified benefits at the endpoint for functional impairment (–0·29, −0·43 to −0·15) and for strengths: coping (–0·22, −0·43 to −0·02), hope (–0·29, −0·48 to −0·09), and social support (–0·27, −0·52 to −0·02). In IPD meta-analyses focused on age, gender, displacement status, region, and household size we found a stronger improvement in PTSD symptoms in children aged 15–18 years (–0·43, −0·63 to −0·23), in non-displaced children (–0·40, −0·52 to −0·27), and in children living in smaller households (InterpretationOverall, focused psychosocial interventions are effective in reducing PTSD and functional impairment, and in increasing hope, coping, and social support. Future studies should focus on strengthening interventions for younger children, displaced children, and children living in larger households.

IntroductionMany studies have indicated the impact of bias in dissemination and publication in medical research. Existence of such bias among clinical trials has been repeatedly pointed out, but it has not been well studied in the field of systematic reviews (SRs). We therefore aim to investigate whether or not time lag bias and publication bias in SRs based on statistical significance in results exist. In addition, we will examine at what stage of paper publication process such bias, if any, creeps in.Method and analysisThe present study is a meta-epidemiological study. We will include all SRs of interventions registered in the international prospective register of SRs (PROSPERO) before December 2014 if the SR has completed its analysis irrespective of its publication status. All contact authors of eligible SRs will be asked to participate in a survey administered through the Internet. Our primary outcome is time from protocol registration to full publication of SR as a journal article, defined as time from the registration date to the acceptance date among all the relevant SRs. We will examine the impact of statistically significant findings on the primary outcomes through time to event analyses.Ethics and disseminationEthics approval will be obtained from the Ethical Committee of the Kyoto University Graduate School of Medicine. This protocol has been registered in the University Hospital Medical Information Network Clinical Trials Registry. We will publish our findings in a peer-reviewed journal and also may present them at conferences. Trial registration number:UMIN000028325

Objective To estimate the benefits and harms of using corticosteroids as an adjunct treatment for sore throat. Design Systematic review and meta-analysis of randomised control trials. Data sources Medline, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), trial registries up to May 2017, reference lists of eligible trials, related reviews. Study selection Randomised controlled trials of the addition of corticosteroids to standard clinical care for patients aged 5 or older in emergency department and primary care settings with clinical signs of acute tonsillitis, pharyngitis, or the clinical syndrome of sore throat. Trials were included irrespective of language or publication status. Review methods Reviewers identified studies, extracted data, and assessed the quality of the evidence, independently and in duplicate. A parallel guideline committee ( BMJ Rapid Recommendation) provided input on the design and interpretation of the systematic review, including the selection of outcomes important to patients. Random effects model was used for meta-analyses. Quality of evidence was assessed with the GRADE approach. Results 10 eligible trials enrolled 1426 individuals. Patients who received single low dose corticosteroids (the most common intervention was oral dexamethasone with a maximum dose of 10 mg) were twice as likely to experience pain relief after 24 hours (relative risk 2.2, 95% confidence interval 1.2 to 4.3; risk difference 12.4%; moderate quality evidence) and 1.5 times more likely to have no pain at 48 hours (1.5, 1.3 to 1.8; risk difference 18.3%; high quality). The mean time to onset of pain relief in patients treated with corticosteroids was 4.8 hours earlier (95% confidence interval −1.9 to −7.8; moderate quality) and the mean time to complete resolution of pain was 11.1 hours earlier (−0.4 to −21.8; low quality) than in those treated with placebo. The absolute pain reduction at 24 hours (visual analogue scale 0-10) was greater in patients treated with corticosteroids (mean difference 1.3, 95% confidence interval 0.7 to 1.9; moderate quality). Nine of the 10 trials sought information regarding adverse events. Six studies reported no adverse effects, and three studies reported few adverse events, which were mostly complications related to disease, with a similar incidence in both groups. Conclusion Single low dose corticosteroids can provide pain relief in patients with sore throat, with no increase in serious adverse effects. Included trials did not assess the potential risks of larger cumulative doses in patients with recurrent episodes of acute sore throat. Systematic review registration PROSPERO CRD42017067808.

In the treatment of resistant schizophrenia, a number of meta-analyses attempted to quantify the efficacy and tolerability of antipsychotic (AP) polypharmacy v. monotherapy with contradictory results. Recently, a systematic review and meta-analysis of randomised controlled trials investigated the efficacy and tolerability of AP combination v. monotherapy in schizophrenia. It included 31 studies: 21 double-blind (considered high-quality studies) and 10 open-label (considered low-quality studies). The meta-analysis showed that, overall, the combination of two APs was more effective than monotherapy in terms of symptom reduction (standardised mean difference (SMD) = −0.53, 95% confidence interval (CI) −0.87 to −0.19); however, this result was confirmed only in the subgroup of low-quality studies. Negative symptoms improved when combining a D2 antagonist with a D2 partial agonist (SMD = −0.41, 95% CI −0.79 to −0.03) both in double-blind and open-label studies. In the present commentary, the results of this systematic review are critically discussed in terms of their clinical and research implications.

Three-month long-acting paliperidone is a new, recently marketed, formulation of paliperidone, characterised by the longest available dosing interval among long-acting antipsychotics. The clinical profile of 3-month long-acting paliperidone was recently summarised by the European Medicines Agency (EMA) in a public assessment report, released in April 2016. In this commentary, the main strengths and limitations of the EMA assessment report were appraised and discussed, in order to highlight possible implications for clinical practice, future research and regulatory practices for drug approval.

Patients experiencing psychoses and in need of antipsychotic agents may be exposed to a higher risk of myocardial infarction (MI) than the general population. As there have been no randomised studies investigating this association, a recent systematic review and meta-analysis included all observational studies that compared the incidence of MI among patients receiving antipsychoticsv. no treatment. It found nine studies and calculated that the odds (risk) for developing MI were 1.88-fold higher in antipsychotic users compared with individuals who had not taken antipsychotic drugs. In this commentary, the results of this systematic review are discussed in view of their clinical implications for everyday clinical practice.

Objective This study aimed at investigating whether dose is a mediator of treatment effect in fluoxetine-randomized trials. Specifically, we investigated whether dose was higher in trials in which the aim was to demonstrate fluoxetine efficacy in comparison with older antidepressants and lower in trials in which the aim was to demonstrate a new drug's efficacy against fluoxetine. Method We applied the model developed by Baron and Kenny to investigate the mediational role of drug dose on treatment effect. We included all randomized controlled trials comparing fluoxetine with other antidepressants as monotherapy in the acute-phase treatment of unipolar major depression. Results A total of 173 studies were included. In 76 comparisons (44%), fluoxetine was the experimental antidepressant. A metaregression analysis indicated that after adjusting for possible confounders, studies where fluoxetine was the experimental agent were associated with a significant advantage for fluoxetine. However, the Baron and Kenny model revealed no mediational role of drug dose in influencing treatment effect. Conclusion The outcome of fluoxetine-randomized trials changed according to whether this drug was used as a new compound or as a reference. This finding cannot be attributed to antidepressants dose, as dose failed to emerge as mediator of treatment effect in the Baron and Kenny approach.

Background Paroxetine is the most potent inhibitor of the reuptake of serotonin of all selective serotonin reuptake inhibitors (SSRIs) and has been studied in many randomised controlled trials (RCTs). However, these comparative studies provided contrasting findings and systematic reviews of RCTs have always considered the SSRIs as a group, and evidence applicable to this group of drugs might not be applicable to paroxetine alone. The present systematic review assessed the efficacy and tolerability profile of paroxetine in comparison with tricyclics (TCAs), SSRIs and newer or non-conventional agents. Objectives 1. To determine the efficacy of paroxetine in comparison with other anti-depressive agents in alleviating the acute symptoms of Major Depressive Disorder. 2. To review acceptability of treatment with paroxetine in comparison with other anti-depressive agents. 3. To investigate the adverse effects of paroxetine in comparison with other anti-depressive agents. Search methods We searched the Cochrane Depression, Anxiety and Neurosis Review Group's Specialized Register (CCDANCTR, to 30 September 2012), which includes relevant randomised controlled trials from the following bibliographic databases: The Cochrane Library (all years), EMBASE (1974 to date), MEDLINE (1950 to date) and PsycINFO (1967 to date). Reference lists of relevant papers and previous systematic reviews were handsearched. Pharmaceutical companies marketing paroxetine and experts in this field were contacted for supplemental data. Selection criteria All randomised controlled trials allocating participants with major depression to paroxetine versus any other antidepressants (ADs), both conventional (such as TCAs, SSRIs) and newer or non-conventional (such as hypericum). For trials which had a cross-over design, only results from the first randomisation period were considered. Data collection and analysis Two review authors independently checked eligibility and extracted data using a standard form. Data were then entered in RevMan 5.2 with a double-entry procedure. Information extracted included study and participant characteristics, intervention details, settings and efficacy, acceptability and tolerability measures. Main results A total of 115 randomised controlled trials (26,134 participants) were included. In 54 studies paroxetine was compared with older ADs, in 21 studies with another SSRI, and in 40 studies with a newer or non-conventional antidepressant other than SSRIs. For the primary outcome (patients who responded to treatment), paroxetine was more effective than reboxetine at increasing patients who responded early to treatment (Odds Ratio (OR): 0.66, 95% Confidence Interval (CI) 0.50 to 0.87, number needed to treat to provide benefit (NNTb) = 16, 95% CI 10 to 50, at one to four weeks, 3 RCTs, 1375 participants, moderate quality of evidence), and less effective than mirtazapine (OR: 2.39, 95% CI 1.42 to 4.02, NNTb = 8, 95% CI 5 to 14, at one to four weeks, 3 RCTs, 726 participants, moderate quality of evidence). Paroxetine was less effective than citalopram in improving response to treatment (OR: 1.54, 95% CI 1.04 to 2.28, NNTb = 9, 95% CI 5 to 102, at six to 12 weeks, 1 RCT, 406 participants, moderate quality of evidence). We found no clear evidence that paroxetine was more or less effective compared with other antidepressants at increasing response to treatment at acute (six to 12 weeks), early (one to four weeks), or longer term follow-up (four to six months). Paroxetine was associated with a lower rate of adverse events than amitriptyline, imipramine and older ADs as a class, but was less well tolerated than agomelatine and hypericum. Included studies were generally at unclear or high risk of bias due to poor reporting of allocation concealment and blinding of outcome assessment, and incomplete reporting of outcomes. Authors' conclusions Some possibly clinically meaningful differences between paroxetine and other ADs exist, but no definitive conclusions can be drawn from these findings. In terms of response, there was a moderate quality of evidence that citalopram was better than paroxetine in the acute phase (six to 12 weeks), although only one study contributed data. In terms of early response to treatment (one to four weeks) there was moderate quality of evidence that mirtazapine was better than paroxetine and that paroxetine was better than reboxetine. However there was no clear evidence that paroxetine was better or worse compared with other antidepressants at increasing response to treatment at any time point. Even if some differences were identified, the findings from this review are better thought as hypothesis forming rather than hypothesis testing and it would be reassuring to see the conclusions replicated in future trials. Finally, most of included studies were at unclear or high risk of bias, and were sponsored by the drug industry. The potential for overestimation of treatment effect due to sponsorship bias should be borne in mind.