Dose-response relationship in cognitive behavioral therapy for depression: A nonlinear metaregression analysis.

OBJECTIVE: Evidence on the optimal "dose" of cognitive behavioral therapy (CBT) for treating major depressive disorder is sparse. This analysis aimed to evaluate the dose-response curve in CBT using a nonlinear approach, whereby "dose" was defined as number of treatment sessions. The dose-response curve of CBT was compared to other psychotherapies and pharmacological treatments for depression. METHOD: A systematic review and metaregression analysis of randomized controlled trials (RCTs) examining the efficacy of CBT in adults with acute depression was conducted. Treatment arms examining other psychosocial or pharmacological interventions were also analyzed. Cubic spline metaregression techniques were used to model nonlinear dose-response curves. RESULTS: Seventy-two studies and 7,377 participants were included. Modeling the dose-response curve between change of depression symptom severity and the number of CBT sessions resulted in a nonlinear curve characterized by a strong improvement in symptom severity from baseline within the first eight sessions. Symptom reduction continues in the further course of the treatment, but at a slower pace. A similar pattern of symptom development was found for other therapies as well, although the prominence of early improvement and overall effect sizes vary across treatment arms. CONCLUSION: Results imply a general tendency for the strongest alleviation of depressive symptom severity in early stages of CBT treatment, thus, if aiming at symptom alleviation, speak for short CBT interventions. However, these findings have to be discussed in the light of the limited data regarding the sustainability of treatment effects in short-term therapies and effects beyond symptomatic changes. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Treatment of Locally Advanced Rectal Cancer in the Era of Total Neoadjuvant Therapy: A Systematic Review and Network Meta-Analysis.

Importance: Treatment of locally advanced rectal cancer (LARC) involves neoadjuvant chemoradiotherapy plus total mesorectal excision and adjuvant chemotherapy. However, total neoadjuvant therapy (TNT) protocols (ie, preoperative chemotherapy in addition to radiotherapy) may allow better adherence and early treatment of distant micrometastases and may increase pathological complete response (pCR) rates. Objective: To assess the efficacy and tolerability of TNT protocols for LARC. Data Sources: MEDLINE, Embase, Cochrane Central Register of Controlled Trials (CENTRAL), and Web of Science Core Collection electronic databases and ClinicalTrials.gov for unpublished studies were searched from inception to March 2, 2024. Study Selection: Randomized clinical trials including adults with LARC who underwent rectal resection as a final treatment were included. Studies including nonoperative treatment (watch-and-wait strategy), treatments other than rectal resection, immunotherapy, or antiangiogenic agents were excluded. Among the initially identified studies, 2.9% met the selection criteria. Data Extraction and Synthesis: Two authors independently screened the records and extracted data. Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA)-compliant pairwise and network meta-analyses with a random-effects model were performed in a frequentist framework, and the certainty of evidence was assessed according to the confidence in network meta-analysis approach. Main Outcomes and Measures: The primary outcome was pCR, defined as the absence of residual tumor at pathological assessment after surgery. Secondary outcomes included tolerability, toxic effects, perioperative outcomes, and long-term survival. Results: Of 925 records identified, 27 randomized clinical trials, including 13 413 adults aged 18 years or older (median age, 60.0 years [range, 42.0-63.5 years]; 67.2% male) contributed to the primary network meta-analysis. With regard to pCR, long-course chemoradiotherapy (L-CRT) plus consolidation chemotherapy (relative risk [RR], 1.96; 95% CI, 1.25-3.06), short-course radiotherapy (S-RT) plus consolidation chemotherapy (RR, 1.76; 95% CI, 1.34-2.30), and induction chemotherapy plus L-CRT (RR, 1.57; 95% CI, 1.09-2.25) outperformed standard L-CRT with single-agent fluoropyrimidine-based chemotherapy. Considering 3-year disease-free survival, S-RT plus consolidation chemotherapy (RR, 1.08; 95% CI, 1.01-1.14) and induction chemotherapy plus L-CRT (RR, 1.12; 95% CI, 1.01-1.24) outperformed L-CRT, in spite of an increased 5-year locoregional recurrence rate of S-RT plus consolidation chemotherapy (RR, 1.65; 95% CI, 1.03-2.63). Conclusions and Relevance: In this systematic review and network meta-analysis, 3 TNT protocols were identified to outperform the current standard of care in terms of pCR rates, with good tolerability and optimal postoperative outcomes, suggesting they should be recognized as first-line treatments.

Effect of trauma on asylum seekers and refugees receiving a WHO psychological intervention: a mediation model.

Background: Scalable psychological interventions such as the WHO's Self-Help Plus (SH+) have been developed for clinical and non-clinical populations in need of psychological support. SH+ has been successfully implemented to prevent common mental disorders among asylum seekers and refugees who are growing in number due to increasing levels of forced migration. These populations are often exposed to multiple, severe sources of traumatisation, and evidence of the effect of such events on treatment is insufficient, especially for non-clinical populations.Objective: We aim to study the effect of potentially traumatic experiences (PTEs) and the mediating role of symptoms of posttraumatic stress disorder (PTSD) on the improvement following SH+.Method: Participants allocated to SH+ who received at least three sessions (N = 345) were extracted from two large, randomised, European prevention trials involving asylum seekers and refugees. Measures of distress, depression, functional impairment, and post-traumatic stress symptoms were administered at baseline and 6 months post-intervention, together with measures of well-being and quality of life. Adjusted models were constructed to examine the effect of PTEs on post-intervention improvement. The possible mediating role of PTSD symptoms in this relationship was then tested.Results: Increasing numbers of PTEs decreased the beneficial effect of SH+ for all measures. This relationship was mediated by symptoms of PTSD when analysing measures of well-being and quality of life. However, this did not apply for measures of mental health problems.Conclusions: Exposure to PTEs may largely reduce benefits from SH+. PTSD symptomatology plays a specific, mediating role on psychological well-being and quality of life of participants who experienced PTE. Healthcare professionals and researchers should consider the role of PTEs and PTSD symptoms in the treatment of migrants and refugees and explore possible feasible add-on solutions for cases exposed to multiple PTEs.

Increasing numbers of potentially traumatic experiences can decrease the beneficial effect of a manualized group psychotherapeutic intervention in migrants and refugees across multiple countries.In absence of a full threshold diagnosis of post-traumatic stress disorder, post-traumatic stress symptoms still mediate the relation between potentially traumatic experiences and some outcome improvements at follow-up.While the moderating role of number of potentially traumatic experiences applies to all outcomes (depression symptoms, psychological distress, functional impairment, well-being, and quality of life), the mediating role of post-traumatic stress symptoms in this relation only applies to well-being and quality of life.

Efficacy and safety of long-acting injectable versus oral antipsychotics in the treatment of patients with early-phase schizophrenia-spectrum disorders: a systematic review and meta-analysis.

Background: Long-acting injectable antipsychotics (LAIs) have advantages over oral antipsychotics (OAPs) in preventing relapse and hospitalization in chronically ill patients with schizophrenia-spectrum disorders (SSDs), but evidence in patients with first-episode/recent-onset, that is, early-phase-SSDs is less clear. Objectives: To assess the relative medium- and long-term efficacy and safety of LAIs versus OAPs in the maintenance treatment of patients with early-phase SSDs. Method: We searched major electronic databases for head-to-head randomized controlled trials (RCTs) comparing LAIs and OAPs for the maintenance treatment of patients with early-phase-SSDs. Design: Pairwise, random-effects meta-analysis. Relapse/hospitalization and acceptability (all-cause discontinuation) measured at study-endpoint were co-primary outcomes, calculating risk ratios (RRs) with their 95% confidence intervals (CIs). Subgroup analyses sought to identify factors moderating differences in efficacy or acceptability between LAIs and OAPs. Results: Across 11 head-to-head RCTs (n = 2374, median age = 25.2 years, males = 68.4%, median illness duration = 45.8 weeks) lasting 13-104 (median = 78) weeks, no significant differences emerged between LAIs and OAPs for relapse/hospitalization prevention (RR = 0.79, 95%CI = 0.58-1.06, p = 0.13) and acceptability (RR = 0.92, 95%CI = 0.80-1.05, p = 0.20). The included trials were highly heterogeneous regarding methodology and patient populations. LAIs outperformed OAPs in preventing relapse/hospitalization in studies with stable patients (RR = 0.65, 95%CI = 0.45-0.92), pragmatic design (RR = 0.67, 95%CI = 0.54-0.82), and strict intent-to-treat approach (RR = 0.64, 95%CI = 0.52-0.80). Furthermore, LAIs were associated with better acceptability in studies with schizophrenia patients only (RR = 0.87, 95%CI = 0.79-0.95), longer illness duration (RR = 0.88, 95%CI = 0.80-0.97), unstable patients (RR = 0.89, 95%CI = 0.81-0.99) and allowed OAP supplementation of LAIs (RR = 0.90, 95%CI = 0.81-0.99). Conclusion: LAIs and OAPs did not differ significantly regarding relapse prevention/hospitalization and acceptability. However, in nine subgroup analyses, LAIs were superior to OAPs in patients with EP-SSDs with indicators of higher quality and/or pragmatic design regarding relapse/hospitalization prevention (four subgroup analyses) and/or reduced all-cause discontinuation (five subgroup analyses), without any instance of OAP superiority versus LAIs. More high-quality pragmatic trials comparing LAIs with OAPs in EP-SSDs are needed. Trial registration: CRD42023407120 (PROSPERO).

OBJECTIVE: We aimed to uncover whether LAIs or regular antipsychotic pills demonstrate better outcomes over the medium and long term for individuals in the early stages of schizophrenia. METHOD: We scrutinized several studies comparing LAIs to regular pills in treating early-stage schizophrenia. Employing a combined analysis, we assessed factors such as preventing relapses and hospitalizations, as well as patient treatment adherence. DESIGN: We combined different study results in one unique analysis. We delved into whether LAIs surpassed regular pills in preventing relapses and hospitalizations and in patient treatment adherence. RESULTS: In our study of 11 trials involving over 2000 participants, we observed that LAIs and regular antipsychotic pills were generally comparable regarding preventing relapses, hospitalizations, and treatment adherence. However, on closer inspection, LAIs appeared slightly more effective for specific groups in the early stages of schizophrenia. CONCLUSION: While LAIs and regular antipsychotic pills showed similar results for most individuals in the early stages of schizophrenia, our findings hint at the possibility that LAIs might have a slight edge for certain groups. Nevertheless, we emphasize the need for more high-quality studies to gain a clearer understanding. REGISTRATION: This study is registered under CRD42023407120 (PROSPERO).

Comparing long-acting injections and pills for early schizophrenia: a study review and combined analysis Background: We explored whether antipsychotics long-acting injections (LAIs) might outperform regular antipsychotics pills for people dealing with early-stage conditions like schizophrenia. While LAIs have clear benefits for those with long-term challenges, their effectiveness for those just starting to grapple with these issues is less certain.

Scoping Review: Digital Mental Health Interventions for Children and Adolescents Affected by War.

OBJECTIVE: More than 200 million children and adolescents live in countries affected by violent conflict, are likely to have complex mental health needs, and struggle to access traditional mental health services. Digital mental health interventions have the potential to overcome some of the barriers in accessing mental health support. We performed a scoping review to map existing digital mental health interventions relevant for children and adolescents affected by war, to examine the strength of the evidence base, and to inform the development of future interventions. METHOD: Based on a pre-registered strategy, we systematically searched MEDLINE, Embase, Global Health, APA PsychInfo, and Google Scholar from the creation of each database to September 30, 2022, identifying k = 6,843 studies. Our systematic search was complemented by extensive consultation with experts from the GROW Network. RESULTS: The systematic search identified 6 relevant studies: 1 study evaluating digital mental health interventions for children and adolescents affected by war, and 5 studies for those affected by disasters. Experts identified 35 interventions of possible relevance. The interventions spanned from universal prevention to specialist-guided treatment. Most interventions directly targeted young people and parents or carers/caregivers and were self-guided. A quarter of the interventions were tested through randomized controlled trials. Because most interventions were not culturally or linguistically adapted to relevant contexts, their implementation potential was unclear. CONCLUSION: There is very limited evidence for the use of digital mental health interventions for children and adolescents affected by war at present. The review provides a framework to inform the development of new interventions. DIVERSITY & INCLUSION STATEMENT: We actively worked to promote sex and gender balance in our author group. STUDY PREREGISTRATION INFORMATION: Digital mental health interventions for children and young people affected by war: a scoping review; https://osf.io/; hrny9.

Psychological and social interventions for the promotion of mental health in people living in low- and middle-income countries affected by humanitarian crises.

BACKGROUND: Because of wars, conflicts, persecutions, human rights violations, and humanitarian crises, about 84 million people are forcibly displaced around the world; the great majority of them live in low- and middle-income countries (LMICs). People living in humanitarian settings are affected by a constellation of stressors that threaten their mental health. Psychosocial interventions for people affected by humanitarian crises may be helpful to promote positive aspects of mental health, such as mental well-being, psychosocial functioning, coping, and quality of life. Previous reviews have focused on treatment and mixed promotion and prevention interventions. In this review, we focused on promotion of positive aspects of mental health. OBJECTIVES: To assess the effects 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. SEARCH METHODS: We searched CENTRAL, MEDLINE, Embase, and seven other databases to January 2023. We also searched the World Health Organization's (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify unpublished or ongoing studies, and checked the reference lists of relevant studies and reviews. SELECTION CRITERIA: Randomised controlled trials (RCTs) comparing psychosocial interventions versus control conditions (no intervention, intervention as usual, or waiting list) to promote positive aspects of mental health 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 used standard Cochrane methods. Our primary outcomes were mental well-being, functioning, quality of life, resilience, coping, hope, and prosocial behaviour. The secondary outcome was acceptability, defined as the number of participants who dropped out of the trial for any reason. We used GRADE to assess the certainty of evidence for the outcomes of mental well-being, functioning, and prosocial behaviour. MAIN RESULTS: We included 13 RCTs with 7917 participants. Nine RCTs were conducted on children/adolescents, and four on adults. All included interventions were delivered to groups of participants, mainly by paraprofessionals. Paraprofessional is defined as an individual who is not a mental or behavioural health service professional, but works at the first stage of contact with people who are seeking mental health care. Four RCTs were carried out in Lebanon; two in India; and single RCTs in the Democratic Republic of the Congo, Jordan, Haiti, Bosnia and Herzegovina, the occupied Palestinian Territories (oPT), Nepal, and Tanzania. The mean study duration was 18 weeks (minimum 10, maximum 32 weeks). Trials were generally funded by grants from academic institutions or non-governmental organisations. For children and adolescents, there was no clear difference between psychosocial interventions and control conditions in improving mental well-being and prosocial behaviour at study endpoint (mental well-being: standardised mean difference (SMD) 0.06, 95% confidence interval (CI) -0.17 to 0.29; 3 RCTs, 3378 participants; very low-certainty evidence; prosocial behaviour: SMD -0.25, 95% CI -0.60 to 0.10; 5 RCTs, 1633 participants; low-certainty evidence), or at medium-term follow-up (mental well-being: mean difference (MD) -0.70, 95% CI -2.39 to 0.99; 1 RCT, 258 participants; prosocial behaviour: SMD -0.48, 95% CI -1.80 to 0.83; 2 RCT, 483 participants; both very low-certainty evidence). Interventions may improve functioning (MD -2.18, 95% CI -3.86 to -0.50; 1 RCT, 183 participants), with sustained effects at follow-up (MD -3.33, 95% CI -5.03 to -1.63; 1 RCT, 183 participants), but evidence is very uncertain as the data came from one RCT (both very low-certainty evidence). Psychosocial interventions may improve mental well-being slightly in adults at study endpoint (SMD -0.29, 95% CI -0.44 to -0.14; 3 RCTs, 674 participants; low-certainty evidence), but they may have little to no effect at follow-up, as the evidence is uncertain and future RCTs might either confirm or disprove this finding. No RCTs measured the outcomes of functioning and prosocial behaviour in adults. AUTHORS' CONCLUSIONS: To date, there is scant and inconclusive randomised evidence on the potential benefits of psychological and social interventions to promote mental health in people living in LMICs affected by humanitarian crises. Confidence in the findings is hampered by the scarcity of studies included in the review, the small number of participants analysed, the risk of bias in the studies, and the substantial level of heterogeneity. Evidence on the efficacy of interventions on positive mental health outcomes is too scant to determine firm practice and policy implications. This review has identified a large gap between what is known and what still needs to be addressed in the research area of mental health promotion in humanitarian settings.

Early pharmacological interventions for prevention of post-traumatic stress disorder (PTSD) in individuals experiencing acute traumatic stress symptoms.

BACKGROUND: Acute traumatic stress symptoms may develop in people who have been exposed to a traumatic event. Although they are usually self-limiting in time, some people develop post-traumatic stress disorder (PTSD), a severe and debilitating condition. Pharmacological interventions have been proposed for acute symptoms to act as an indicated prevention measure for PTSD development. As many individuals will spontaneously remit, these interventions should balance efficacy and tolerability. OBJECTIVES: To assess the efficacy and acceptability of early pharmacological interventions for prevention of PTSD in adults experiencing acute traumatic stress symptoms. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Controlled Trial Register (CCMDCTR), CENTRAL, MEDLINE, Embase and two other databases. We checked the reference lists of all included studies and relevant systematic reviews. The search was last updated on 23 January 2023. SELECTION CRITERIA: We included randomised controlled trials on adults exposed to any kind of traumatic event and presenting acute traumatic stress symptoms, without restriction on their severity. We considered comparisons of any medication with placebo, or with another medication. We excluded trials that investigated medications as an augmentation to psychotherapy. DATA COLLECTION AND ANALYSIS: We used standard Cochrane methodological procedures. Using a random-effects model, we analysed dichotomous data as risk ratios (RR) and calculated the number needed to treat for an additional beneficial/harmful outcome (NNTB/NNTH). We analysed continuous data as mean differences (MD) or standardised mean differences (SMD). Our primary outcomes were PTSD severity and dropouts due to adverse events. Secondary outcomes included PTSD rate, functional disability and quality of life. MAIN RESULTS: We included eight studies that considered four interventions (escitalopram, hydrocortisone, intranasal oxytocin, temazepam) and involved a total of 779 participants. The largest trial contributed 353 participants and the next largest, 120 and 118 participants respectively. The trials enrolled participants admitted to trauma centres or emergency departments. The risk of bias in the included studies was generally low except for attrition rate, which we rated as high-risk. We could meta-analyse data for two comparisons: escitalopram versus placebo (but limited to secondary outcomes) and hydrocortisone versus placebo. One study compared escitalopram to placebo at our primary time point of three months after the traumatic event. There was inconclusive evidence of any difference in terms of PTSD severity (mean difference (MD) on the Clinician-Administered PTSD Scale (CAPS, score range 0 to 136) -11.35, 95% confidence interval (CI) -24.56 to 1.86; 1 study, 23 participants; very low-certainty evidence), dropouts due to adverse events (no participant left the study early due to adverse events; 1 study, 31 participants; very low-certainty evidence) and PTSD rates (RR 0.59, 95% CI 0.03 to 13.08; NNTB 37, 95% CI NNTB 15 to NNTH 1; 1 study, 23 participants; very low-certainty evidence). The study did not assess functional disability or quality of life. Three studies compared hydrocortisone to placebo at our primary time point of three months after the traumatic event. We found inconclusive evidence on whether hydrocortisone was more effective in reducing the severity of PTSD symptoms compared to placebo (MD on CAPS -7.53, 95% CI -25.20 to 10.13; I2 = 85%; 3 studies, 136 participants; very low-certainty evidence) and whether it reduced the risk of developing PTSD (RR 0.47, 95% CI 0.09 to 2.38; NNTB 14, 95% CI NNTB 8 to NNTH 5; I2 = 36%; 3 studies, 136 participants; very low-certainty evidence). Evidence on the risk of dropping out due to adverse events is inconclusive (RR 3.19, 95% CI 0.13 to 75.43; 2 studies, 182 participants; low-certainty evidence) and it is unclear whether hydrocortisone might improve quality of life (MD on the SF-36 (score range 0 to 136, higher is better) 19.70, 95% CI -1.10 to 40.50; 1 study, 43 participants; very low-certainty evidence). No study assessed functional disability. AUTHORS' CONCLUSIONS: This review provides uncertain evidence regarding the use of escitalopram, hydrocortisone, intranasal oxytocin and temazepam for people with acute stress symptoms. It is therefore unclear whether these pharmacological interventions exert a positive or negative effect in this population. It is important to note that acute traumatic stress symptoms are often limited in time, and that the lack of data prevents the careful assessment of expected benefits against side effects that is therefore required. To yield stronger conclusions regarding both positive and negative outcomes, larger sample sizes are required. A common operational framework of criteria for inclusion and baseline assessment might help in better understanding who, if anyone, benefits from an intervention. As symptom severity alone does not provide the full picture of the impact of exposure to trauma, assessment of quality of life and functional impairment would provide a more comprehensive picture of the effects of the interventions. The assessment and reporting of side effects may facilitate a more comprehensive understanding of tolerability.

Effectiveness of combining prevention psychological interventions with interventions that address the social determinants of mental health in low and middle-income countries: protocol of a systematic review and meta-analysis.

INTRODUCTION: Common mental health conditions (CMHCs), including depression, anxiety and post-traumatic stress disorder (PTSD), are highly prevalent in low and middle-income countries (LMICs). Preventive strategies combining psychological interventions with interventions addressing the social determinants of mental health may represent a key strategy for effectively preventing CMHCs. However, no systematic reviews have evaluated the effectiveness of these combined intervention strategies for preventing CMHCs. METHODS AND ANALYSIS: This systematic review will include randomised controlled trials (RCTs) focused on the effectiveness of interventions that combine preventive psychological interventions with interventions that address the social determinants of mental health in LMICs. Primary outcome is the frequency of depression, anxiety or PTSD at postintervention as determined by a formal diagnostic tool or any other standardised criteria. We will search Epistemonikos, Cochrane Controlled Trials Register (CENTRAL), MEDLINE, Embase, PsycINFO, CINAHL, Global Index Medicus, ClinicalTrials.gov (Ctgov), International Clinical Trials Registry Platform (ICTRP). Two reviewers will independently extract the data and evaluate the risk of bias of included studies using the Cochrane risk of bias tool 2. Random-effects meta-analyses will be performed, and certainty of evidence will be rated using the Grading of Recommendations Assessment, Development and Evaluation approach. ETHICS AND DISSEMINATION: This study uses data from published studies; therefore, ethical review is not required. Findings will be presented in a published manuscript. TRIAL REGISTRATION NUMBER: CRD42023451072.

Antipsychotic-Related DRESS Syndrome: Analysis of Individual Case Safety Reports of the WHO Pharmacovigilance Database.

INTRODUCTION: Drug reaction with eosinophilia and systemic symptoms (DRESS) syndrome is gaining attention in pharmacovigilance, but its association with antipsychotics, other than clozapine, is still unclear. METHODS: We conducted a case/non-case study with disproportionality analysis based on the World Health Organization (WHO) global spontaneous reporting database, VigiBase®. We analyzed individual case safety reports of DRESS syndrome related to antipsychotics compared to (1) all other medications in VigiBase®, (2) carbamazepine (a known positive control), and (3) within classes (typical/atypical) of antipsychotics. We calculated reporting odds ratio (ROR) and Bayesian information component (IC), with 95% confidence intervals (CIs). Disproportionate reporting was prioritized based on clinical importance, according to predefined criteria. Additionally, we compared characteristics of patients reporting with serious/non-serious reactions. RESULTS: A total of 1534 reports describing DRESS syndrome for 19 antipsychotics were identified. The ROR for antipsychotics as a class as compared to all other medications was 1.0 (95% CI 0.9-1.1). We found disproportionate reporting for clozapine (ROR 2.3, 95% CI 2.1-2.5; IC 1.2, 95% CI 1.1-1.3), cyamemazine (ROR 2.3, 95% CI 1.5-3.5; IC 1.2, 95% CI 0.5-1.7), and chlorpromazine (ROR 1.5, 95% CI 1.1-2.1; IC 0.6, 95% CI 0.1-1.0). We found 35.7% of cases with co-reported anticonvulsants, and 25% with multiple concurrent antipsychotics in serious compared to 8.6% in non-serious cases (p = 0.03). Fatal cases were 164 (10.7%). CONCLUSIONS: Apart from the expected association with clozapine, chlorpromazine and cyamemazine (sharing an aromatic heteropolycyclic molecular structure) emerged with a higher-than-expected reporting of DRESS. Better knowledge of the antipsychotic-related DRESS syndrome should increase clinicians' awareness leading to safer prescribing of antipsychotics.

Mapping the evidence on psychosocial interventions for migrant populations: Descriptive analysis of a living database of randomized studies.

Migrant mental health is a pressing public health issue with wide-ranging implications. Many randomized controlled trials (RCTs) have been conducted in this population to assess the effects of psychosocial interventions. However, the available evidence is characterized by controversy and fragmentation, with studies focusing on different migrant populations, interventions, outcomes, delivery modalities and settings. Aiming to promote systematic reviews of the effectiveness of psychosocial interventions in different migrant groups, we have developed a living database of existing RCTs. The development of the database provides an opportunity to map the existing RCT evidence in this population. A total of 135 studies involving 24,859 participants were included in the living database. The distribution of studies by year of publication aligns with the increasing global migrant population in recent years. Most studies focus primarily on adult participants, with a limited representation of children and adolescents, and a prevalence of female participants, which is consistent with epidemiological data, except for older adults, who are underrepresented in research. Studies predominantly focus on refugees and asylum seekers, likely due to their elevated risk of mental health issues, despite the substantial presence of economic migrants worldwide. While studies mainly involve migrants from the Middle East and East Asia, epidemiological data suggest a broader geographic representation, with migrants coming from Eastern Europe, Latin America and South Asia. The present descriptive analysis of RCTs on mental health and psychosocial interventions for migrant populations provides valuable insights into the existing research landscape. It should be used to inform future research efforts, ensuring that studies are more representative of the global migrant population and more responsive to the mental health needs of migrants in different contexts.

Tolerability of vortioxetine compared to selective serotonin reuptake inhibitors in older adults with major depressive disorder (VESPA): a randomised, assessor-blinded and statistician-blinded, multicentre, superiority trial.

Background: Major depressive disorder (MDD) is prevalent and disabling among older adults. Standing on its tolerability profile, vortioxetine might be a promising alternative to selective serotonin reuptake inhibitors (SSRIs) in such a vulnerable population. Methods: We conducted a randomised, assessor- and statistician-blinded, superiority trial including older adults with MDD. The study was conducted between 02/02/2019 and 02/22/2023 in 11 Italian Psychiatric Services. Participants were randomised to vortioxetine or one of the SSRIs, selected according to common practice. Treatment discontinuation due to adverse events after six months was the primary outcome, for which we aimed to detect a 12% difference in favour of vortioxetine. The study was registered in the online repository clinicaltrials.gov (NCT03779789). Findings: The intention-to-treat population included 179 individuals randomised to vortioxetine and 178 to SSRIs. Mean age was 73.7 years (standard deviation 6.1), and 264 participants (69%) were female. Of those on vortioxetine, 78 (44%) discontinued the treatment due to adverse events at six months, compared to 59 (33%) of those on SSRIs (odds ratio 1.56; 95% confidence interval 1.01-2.39). Adjusted and per-protocol analyses confirmed point estimates in favour of SSRIs, but without a significant difference. With the exception of the unadjusted survival analysis showing SSRIs to outperform vortioxetine, secondary outcomes provided results consistent with a lack of substantial safety and tolerability differences between the two arms. Overall, no significant differences emerged in terms of response rates, depressive symptoms and quality of life, while SSRIs outperformed vortioxetine in terms of cognitive performance. Interpretation: As opposed to what was previously hypothesised, vortioxetine did not show a better tolerability profile compared to SSRIs in older adults with MDD in this study. Additionally, hypothetical advantages of vortioxetine on depression-related cognitive symptoms might be questioned. The study's statistical power and highly pragmatic design allow for generalisability to real-world practice. Funding: The study was funded by the Italian Medicines Agency within the "2016 Call for Independent Drug Research".

Umbrella Systematic Review and Meta-Analysis: Physical Activity as an Effective Therapeutic Strategy for Improving Psychosocial Outcomes in Children and Adolescents.

OBJECTIVE: Physical activity (PA) interventions are part of many interdisciplinary programs for the management of children and adolescents with or without physical or psychological conditions or disabilities. Aiming to summarize the available evidence, we conducted an umbrella review of meta-analyses of PA interventions that included psychosocial outcomes in populations of children and adolescents. METHOD: Literature searches were conducted in PubMed, Cochrane Central, Web of Science, Medline, SPORTDiscus, and PsychInfo from January 1, 2010, to May 6, 2022. Meta-analyses of randomized and quasi-randomized studies investigating the efficacy of PA interventions for psychosocial outcomes in children and adolescents were included. Summary effects were recalculated using 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 greater than expected due to chance. On the basis of these calculations, strength of associations was assessed using quantitative umbrella review criteria, and credibility of evidence was assessed using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Quality was assessed using the AMSTAR 2 tool. This study is registered with the Open Science Framework, https://osf.io/ap8qu. RESULTS: A total of 112 studies from 18 meta-analyses generating 12 new meta-analyses comprising 21,232 children and adolescents in population groups including attention-deficit/hyperactivity disorder, cancer, cerebral palsy, chronic respiratory diseases, depression, neuromotor impairment, and obesity and in general populations were included. PA interventions were efficacious in reducing psychological symptoms in all meta-analyses across the different population groups using random-effects models. However, umbrella review criteria suggested a weak strength of association for this outcome, and GRADE credibility of evidence ranged from moderate to very low. For psychological well-being, 3 out of 5 meta-analyses identified significant effects, but the strength of these associations was weak, and GRADE credibility of evidence ranged from moderate to very low. Similarly, for social outcomes, meta-analyses reported a significant summary effect, but the strength of association was weak, and GRADE credibility of evidence ranged from moderate to very low. For self-esteem, one meta-analysis in children with obesity failed to show any effect. CONCLUSION: Even though existing meta-analyses suggested a beneficial effect of PA interventions on psychosocial outcomes across different population groups, the strength of associations was weak, and the credibility of evidence was variable depending on the target population, outcome, and condition or disability. Randomized studies of PA interventions in children and adolescents with and without different physical and psychological conditions or disabilities should always include psychosocial outcomes as an important dimension of social and mental health. STUDY PREREGISTRATION INFORMATION: Prenatal Maternal Infection and Adverse Neurodevelopment: A Structural Equation Modelling Approach to Downstream Environmental Hits; https://osf.io/; ap8qu.

Psychotherapies for Generalized Anxiety Disorder in Adults: A Systematic Review and Network Meta-Analysis of Randomized Clinical Trials.

Importance: Generalized anxiety disorder (GAD) is one of the most common mental disorders in adults. Psychotherapies are among the most recommended treatments for GAD, but which should be considered as first-line treatment needs to be clarified. Objective: To use a network meta-analysis to examine the short- and long-term associations of different psychotherapies with outcomes of effectiveness and acceptability in adults with GAD. Data Sources: MEDLINE, Embase, PsycINFO, and the Cochrane Register of Controlled Trials were searched from database inception to January 1, 2023, to identify randomized clinical trials (RCTs) of psychotherapies for adults with GAD. Study Selection: RCTs comparing any type of psychotherapy against another or with a control condition for the treatment of adults (≥18 years, both sexes) with a primary diagnosis of GAD were eligible for inclusion. Data Extraction and Synthesis: This study followed Cochrane standards for extracting data and assessing data quality and used the PRISMA guideline for reporting. Risk of bias of individual studies was assessed using the second version of the Cochrane risk of bias tool, and the Confidence in Network Meta-Analysis was used to rate the certainty of evidence for meta-analytical results. Main Outcomes and Measures: Eight psychotherapies were compared against one another and with 2 control conditions. Primary outcomes were severity of GAD symptoms and acceptability of the psychotherapies. Random-effects model pairwise and network meta-analyses were conducted. For effectiveness, standardized mean differences (SMDs) were pooled, and for acceptability, relative risks with 95% CIs were calculated. Results: Data from 65 RCTs were included. Effect size estimates on data from 5048 participants (mean [SD], 70.9% [11.9%] women; mean [SD] age, 42.2 [12.5] years) suggested that third-wave cognitive behavior therapies (CBTs) (SMD, -0.76 [95% CI, -1.15 to -0.36]; certainty, moderate), CBT (SMD, -0.74 [95% CI, -1.09 to -0.38]; certainty, moderate), and relaxation therapy (SMD, -0.59 [95% CI, -1.07 to -0.11]; certainty, low) were associated with reduced GAD symptoms vs treatment as usual. Relative risks for all-cause discontinuation (indication of acceptability) signaled no differences compared with treatment as usual for all psychotherapies (eg, relative risk, 1.04 [95% CI, 0.64-1.67] for CBT vs treatment as usual). When excluding studies at high risk of bias, relaxation therapy lost its superiority over treatment as usual (SMD, -0.47; 95% CI, -1.18 to 0.23). When considering anxiety severity at 3 to 12 months after completion of the intervention, only CBT remained significantly associated with greater effectiveness than treatment as usual (SMD, -0.60; 95% CI, -0.99 to -0.21). Conclusions and Relevance: Given the evidence in this systematic review and network meta-analysis for its associations with both acute and long-term effectiveness, CBT may represent the first-line therapy of GAD. Third-wave CBTs and relaxation therapy were associated with short-term effectiveness and may also be offered.

The WHO Mental Health Gap Action Programme for mental, neurological, and substance use conditions: the new and updated guideline recommendations.

The WHO Mental Health Gap Action Programme (mhGAP) guideline update reflects 15 years of investment in reducing the treatment gap and scaling up care for people with mental, neurological, and substance use (MNS) conditions. It was produced by a guideline development group and steering group, with support from topic experts, using quantitative and qualitative evidence and a systematic review of use of mhGAP. 90 recommendations from the 2015 guideline update were validated and endorsed for use in their current format. These are joined by 30 revised recommendations and 18 new recommendations, including a new module on anxiety. Psychological interventions are emphasised as treatments and digitally delivered interventions feature across many modules, as well as updated recommendations for psychotropic medicines. Research gaps identified include the need for evidence from low-resource settings and on the views of people with lived experience of MNS conditions. The revised recommendations ensure that mhGAP continues to offer high-quality, timely, transparent, and evidence-based guidance to support non-specialist health workers in low-income and middle-income countries in providing care to individuals with MNS conditions.

Implementation outcomes in psychosocial intervention studies for children and adolescents living in low- and middle-income countries: A systematic review.

Psychosocial interventions play a key role in addressing mental health and substance use needs for children and adolescents living in low- and middle-income countries (LMICs). While research efforts have primarily focused on their effectiveness, implementation outcomes also require examining. We conducted a systematic review of qualitative, quantitative, and mixed-methods studies (PROSPERO: CRD42022335997) to synthesize the literature on implementation outcomes for psychosocial interventions for children and adolescents in LMICs. We searched Cochrane Central Register of Controlled Trials (CENTRAL), PubMed, Web of Science, PsychINFO, and Global Health through April 2023. Data were extracted and quality appraised through the Mixed Methods Appraisal Tool (MMAT) independently by two reviewers. A total of 13,380 records were screened, and 87 studies met inclusion criteria. Feasibility was the most reported implementation outcome (69, 79%), followed by acceptability (60, 69%), and fidelity (32, 37%). Appropriateness was assessed in 11 studies (13%), implementation costs in 10 (11%), and sustainability in one (1%). None of the included studies reported on penetration or adoption. Despite a growing body of evidence for implementation research in child and adolescent global mental health, most research focused on earlier-stage implementation outcomes, assessing them in research-controlled settings. To overcome this, future efforts should focus on assessing interventions in routine care, assessing later-stage implementation outcomes through standardized tools.

Effectiveness of a scalable, remotely delivered stepped-care intervention to reduce symptoms of psychological distress among Polish migrant workers in the Netherlands: study protocol for the RESPOND randomised controlled trial.

BACKGROUND: The COVID-19 pandemic has negatively affected the mental health of international migrant workers (IMWs). IMWs experience multiple barriers to accessing mental health care. Two scalable interventions developed by the World Health Organization (WHO) were adapted to address some of these barriers: Doing What Matters in times of stress (DWM), a guided self-help web application, and Problem Management Plus (PM +), a brief facilitator-led program to enhance coping skills. This study examines whether DWM and PM + remotely delivered as a stepped-care programme (DWM/PM +) is effective and cost-effective in reducing psychological distress, among Polish migrant workers with psychological distress living in the Netherlands. METHODS: The stepped-care DWM/PM + intervention will be tested in a two-arm, parallel-group, randomized controlled trial (RCT) among adult Polish migrant workers with self-reported psychological distress (Kessler Psychological Distress Scale; K10 > 15.9). Participants (n = 212) will be randomized into either the intervention group that receives DWM/PM + with psychological first aid (PFA) and care-as-usual (enhanced care-as-usual or eCAU), or into the control group that receives PFA and eCAU-only (1:1 allocation ratio). Baseline, 1-week post-DWM (week 7), 1-week post-PM + (week 13), and follow-up (week 21) self-reported assessments will be conducted. The primary outcome is psychological distress, assessed with the Patient Health Questionnaire Anxiety and Depression Scale (PHQ-ADS). Secondary outcomes are self-reported symptoms of depression, anxiety, posttraumatic stress disorder (PTSD), resilience, quality of life, and cost-effectiveness. In a process evaluation, stakeholders' views on barriers and facilitators to the implementation of DWM/PM + will be evaluated. DISCUSSION: To our knowledge, this is one of the first RCTs that combines two scalable, psychosocial WHO interventions into a stepped-care programme for migrant populations. If proven to be effective, this may bridge the mental health treatment gap IMWs experience. TRIAL REGISTRATION: Dutch trial register NL9630, 20/07/2021, https://www.onderzoekmetmensen.nl/en/trial/27052.

Pharmacological treatments in panic disorder in adults: a network meta-analysis.

BACKGROUND: A panic attack is a discrete period of fear or anxiety that has a rapid onset and reaches a peak within 10 minutes. The main symptoms involve bodily systems, such as racing heart, chest pain, sweating, shaking, dizziness, flushing, churning stomach, faintness and breathlessness. Other recognised panic attack symptoms involve fearful cognitions, such as the fear of collapse, going mad or dying, and derealisation (the sensation that the world is unreal). Panic disorder is common in the general population with a prevalence of 1% to 4%. The treatment of panic disorder includes psychological and pharmacological interventions, including antidepressants and benzodiazepines. OBJECTIVES: To compare, via network meta-analysis, individual drugs (antidepressants and benzodiazepines) or placebo in terms of efficacy and acceptability in the acute treatment of panic disorder, with or without agoraphobia. To rank individual active drugs for panic disorder (antidepressants, benzodiazepines and placebo) according to their effectiveness and acceptability. To rank drug classes for panic disorder (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants (TCAs), mono-amine oxidase inhibitors (MAOIs) and benzodiazepines (BDZs) and placebo) according to their effectiveness and acceptability. To explore heterogeneity and inconsistency between direct and indirect evidence in a network meta-analysis. SEARCH METHODS: We searched the Cochrane Common Mental Disorders Specialised Register, CENTRAL, CDSR, MEDLINE, Ovid Embase and PsycINFO to 26 May 2022. SELECTION CRITERIA: We included randomised controlled trials (RCTs) of people aged 18 years or older of either sex and any ethnicity with clinically diagnosed panic disorder, with or without agoraphobia. We included trials that compared the effectiveness of antidepressants and benzodiazepines with each other or with a placebo. DATA COLLECTION AND ANALYSIS: Two authors independently screened titles/abstracts and full texts, extracted data and assessed risk of bias. We analysed dichotomous data and continuous data as risk ratios (RRs), mean differences (MD) or standardised mean differences (SMD): response to treatment (i.e. substantial improvement from baseline as defined by the original investigators: dichotomous outcome), total number of dropouts due to any reason (as a proxy measure of treatment acceptability: dichotomous outcome), remission (i.e. satisfactory end state as defined by global judgement of the original investigators: dichotomous outcome), panic symptom scales and global judgement (continuous outcome), frequency of panic attacks (as recorded, for example, by a panic diary; continuous outcome), agoraphobia (dichotomous outcome). We assessed the certainty of evidence using threshold analyses. MAIN RESULTS: Overall, we included 70 trials in this review. Sample sizes ranged between 5 and 445 participants in each arm, and the total sample size per study ranged from 10 to 1168. Thirty-five studies included sample sizes of over 100 participants. There is evidence from 48 RCTs (N = 10,118) that most medications are more effective in the response outcome than placebo. In particular, diazepam, alprazolam, clonazepam, paroxetine, venlafaxine, clomipramine, fluoxetine and adinazolam showed the strongest effect, with diazepam, alprazolam and clonazepam ranking as the most effective. We found heterogeneity in most of the comparisons, but our threshold analyses suggest that this is unlikely to impact the findings of the network meta-analysis. Results from 64 RCTs (N = 12,310) suggest that most medications are associated with either a reduced or similar risk of dropouts to placebo. Alprazolam and diazepam were associated with a lower dropout rate compared to placebo and were ranked as the most tolerated of all the medications examined. Thirty-two RCTs (N = 8569) were included in the remission outcome. Most medications were more effective than placebo, namely desipramine, fluoxetine, clonazepam, diazepam, fluvoxamine, imipramine, venlafaxine and paroxetine, and their effects were clinically meaningful. Amongst these medications, desipramine and alprazolam were ranked highest. Thirty-five RCTs (N = 8826) are included in the continuous outcome reduction in panic scale scores. Brofaromine, clonazepam and reboxetine had the strongest reductions in panic symptoms compared to placebo, but results were based on either one trial or very small trials. Forty-one RCTs (N = 7853) are included in the frequency of panic attack outcome. Only clonazepam and alprazolam showed a strong reduction in the frequency of panic attacks compared to placebo, and were ranked highest. Twenty-six RCTs (N = 7044) provided data for agoraphobia. The strongest reductions in agoraphobia symptoms were found for citalopram, reboxetine, escitalopram, clomipramine and diazepam, compared to placebo. For the pooled intervention classes, we examined the two primary outcomes (response and dropout). The classes of medication were: SSRIs, SNRIs, TCAs, MAOIs and BDZs. For the response outcome, all classes of medications examined were more effective than placebo. TCAs as a class ranked as the most effective, followed by BDZs and MAOIs. SSRIs as a class ranked fifth on average, while SNRIs were ranked lowest. When we compared classes of medication with each other for the response outcome, we found no difference between classes. Comparisons between MAOIs and TCAs and between BDZs and TCAs also suggested no differences between these medications, but the results were imprecise. For the dropout outcome, BDZs were the only class associated with a lower dropout compared to placebo and were ranked first in terms of tolerability. The other classes did not show any difference in dropouts compared to placebo. In terms of ranking, TCAs are on average second to BDZs, followed by SNRIs, then by SSRIs and lastly by MAOIs. BDZs were associated with lower dropout rates compared to SSRIs, SNRIs and TCAs. The quality of the studies comparing antidepressants with placebo was moderate, while the quality of the studies comparing BDZs with placebo and antidepressants was low. AUTHORS' CONCLUSIONS: In terms of efficacy, SSRIs, SNRIs (venlafaxine), TCAs, MAOIs and BDZs may be effective, with little difference between classes. However, it is important to note that the reliability of these findings may be limited due to the overall low quality of the studies, with all having unclear or high risk of bias across multiple domains. Within classes, some differences emerged. For example, amongst the SSRIs paroxetine and fluoxetine seem to have stronger evidence of efficacy than sertraline. Benzodiazepines appear to have a small but significant advantage in terms of tolerability (incidence of dropouts) over other classes.