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World Health Organization's (WHO) International Clinical Trials Registry Platform and ClinicalTrials.gov to identify unpublished or ongoing studies, and checked the reference lists of relevant studies and reviews.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.

CBT treatment delivery formats for panic disorder: a systematic review and network meta-analysis of randomised controlled trials.

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

Postpartum hemorrhage and postpartum depression: A systematic review and meta-analysis of observational studies.

OBJECTIVE: To assess the postpartum depression (PPD) risk in women with postpartum hemorrhage (PPH) and moderators. METHODS: We identified observational studies of PPD rates in women with versus without PPH in Embase/Medline/PsychInfo/Cinhail in 09/2022. Study quality was evaluated using the Newcastle-Ottawa-Scale. Our primary outcome was the odds ratio (OR, 95% confidence intervals [95%CI]) of PPD in women with versus without PPH. Meta-regression analyses included the effects of age, body mass index, marital status, education, history of depression/anxiety, preeclampsia, antenatal anemia and C-section; subgroup analyses were based on PPH and PPD assessment methods, samples with versus without history of depression/anxiety, from low-/middle- versus high-income countries. We performed sensitivity analyses after excluding poor-quality studies, cross-sectional studies and sequentially each study. RESULTS: One, five and three studies were rated as good-, fair- and poor-quality respectively. In nine studies (k = 10 cohorts, n = 934,432), women with PPH were at increased PPD risk compared to women without PPH (OR = 1.28, 95% CI = 1.13 to 1.44, p < 0.001), with substantial heterogeneity (I2 = 98.9%). Higher PPH-related PPD ORs were estimated in samples with versus without history of depression/anxiety or antidepressant exposure (OR = 1.37, 95%CI = 1.18 to 1.60, k = 6, n = 55,212, versus 1.06, 95%CI = 1.04 to 1.09, k = 3, n = 879,220, p < 0.001) and in cohorts from low-/middle- versus high-income countries (OR = 1.49, 95%CI = 1.37 to 1.61, k = 4, n = 9197, versus 1.13, 95%CI = 1.04 to 1.23, k = 6, n = 925,235, p < 0.001). After excluding low-quality studies the PPD OR dropped (1.14, 95%CI = 1.02 to 1.29, k = 6, n = 929,671, p = 0.02). CONCLUSIONS: Women with PPH had increased PPD risk amplified by history of depression/anxiety, whereas more data from low-/middle-income countries are required.

Risk factors of postpartum depression and depressive symptoms: umbrella review of current evidence from systematic reviews and meta-analyses of observational studies.

BACKGROUND: Evidence on risk factors for postpartum depression (PPD) are fragmented and inconsistent. AIMS: To assess the strength and credibility of evidence on risk factors of PPD, ranking them based on the umbrella review methodology. METHOD: Databases were searched until 1 December 2020, for systematic reviews and meta-analyses of observational studies. Two reviewers assessed quality, credibility of associations according to umbrella review criteria (URC) and evidence certainty according to Grading of Recommendations-Assessment-Development-Evaluations criteria. RESULTS: Including 185 observational studies (n = 3 272 093) from 11 systematic reviews, the association between premenstrual syndrome and PPD was the strongest (highly suggestive: odds ratio 2.20, 95%CI 1.81-2.68), followed by violent experiences (highly suggestive: odds ratio (OR) = 2.07, 95%CI 1.70-2.50) and unintended pregnancy (highly suggestive: OR=1.53, 95%CI 1.35-1.75). Following URC, the association was suggestive for Caesarean section (OR = 1.29, 95%CI 1.17-1.43), gestational diabetes (OR = 1.60, 95%CI 1.25-2.06) and 5-HTTPRL polymorphism (OR = 0.70, 95%CI 0.57-0.86); and weak for preterm delivery (OR = 2.12, 95%CI 1.43-3.14), anaemia during pregnancy (OR = 1.47, 95%CI 1.17-1.84), vitamin D deficiency (OR = 3.67, 95%CI 1.72-7.85) and postpartum anaemia (OR = 1.75, 95%CI 1.18-2.60). No significant associations were found for medically assisted conception and intra-labour epidural analgesia. No association was rated as 'convincing evidence'. According to GRADE, the certainty of the evidence was low for Caesarean section, preterm delivery, 5-HTTLPR polymorphism and anaemia during pregnancy, and 'very low' for remaining factors. CONCLUSIONS: The most robust risk factors of PDD were premenstrual syndrome, violent experiences and unintended pregnancy. These results should be integrated in clinical algorithms to assess the risk of PPD.

Comparative efficacy and acceptability of psychotherapies for panic disorder with or without agoraphobia: systematic review and network meta-analysis of randomised controlled trials.

BACKGROUND: Psychotherapies are the treatment of choice for panic disorder, but which should be considered as first-line treatment is yet to be substantiated by evidence. AIMS: To examine the most effective and accepted psychotherapy for the acute phase of panic disorder with or without agoraphobia via a network meta-analysis. METHOD: We 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). RESULTS: We 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. CONCLUSIONS: CBT 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.

Post-Marketing Safety Concerns with Esketamine: A Disproportionality Analysis of Spontaneous Reports Submitted to the FDA Adverse Event Reporting System.

INTRODUCTION: Esketamine nasal spray received approval for treatment-resistant depression in March 2019. OBJECTIVE: Using the FDA Adverse Event Reporting System (FAERS) database (March 2019-March 2020), we analysed esketamine-related adverse events (AEs) to detect and characterize relevant safety signals. METHODS: We used the consolidated case/non-case approach to estimate the reporting odds ratio (ROR) and information component (IC) with relevant confidence intervals (95% CI) for esketamine-related AEs with ≥4 counts. Comparisons between serious and non-serious AEs were performed using non-parametric tests. RESULTS: The FAERS database contained 962 cases of esketamine-related AEs, with signals detected for several AEs, such as dissociation (ROR = 1,612.64, 95% CI = 1,354.63, 1,919.79; IC = 8.19, 95% CI = 7.96, 8.35), sedation (ROR = 238.46, 95% CI = 202.98, 280.15; IC = 7, 95% CI = 6.75, 7.18), feeling drunk (ROR = 96.17, 95% CI = 61.42, 150.57; IC = 4.84, 95% CI = 4.09, 5.36), suicidal ideation (ROR = 24.03, 95% CI = 18.72, 30.84; IC = 4.31, 95% CI = 3.9, 4.61), and completed suicide (ROR = 5.75, 95% CI = 3.18, 10.41; IC = 2.25, 95% CI = 1.23, 2.94). Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine. Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, benzodiazepines, or somatic medications were more likely to suffer from serious versus non-serious AEs (χ2 = 125.29, p < 0.001, χ2 = 9.08, p = 0.003, χ2 = 8.14, p = 0.004, χ2 = 19.48, p < 0.001, χ2 = 25.62, p < 0.001, and χ2 = 16.79, p < 0.001, respectively). CONCLUSIONS: Esketamine may carry a clear potential for serious AEs, which deserves urgent clarification by means of further prospective studies.

Effectiveness of Self-Help Plus in Preventing Mental Disorders in Refugees and Asylum Seekers in Western Europe: A Multinational Randomized Controlled Trial.

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.

A systematic review and pooled, patient-level analysis of predictors of mortality in neuroleptic malignant syndrome.

OBJECTIVE: Neuroleptic malignant syndrome (NMS) is a potentially fatal, idiosyncratic reaction to antipsychotics. Due to low incidence of NMS, research on risk factors of mortality associated with NMS is limited. METHODS: Two authors independently searched Medline/Embase/Cochrane/CINAHL/PsychINFO databases for case reports with author-defined NMS published in English until 05/30/2020. Demographic, clinical, treatment, and outcome data were independently extracted following PRISMA guidelines. NMS severity was rated using the Francis-Yacoub scale. Mortality risk factors were identified using a multivariable regression analysis including all characteristics that were significantly different between NMS cases resulting vs. not resulting in death. RESULTS: 683 cases with NMS were analyzed (median age = 36 years, males = 62.1%). In a multivariable model, independent predictors of NMS mortality were lack of antipsychotic discontinuation (odds ratio (OR) = 4.39 95% confidence interval (CI) = 2.14-8.99; p < 0.0001), respiratory problems (OR = 3.54 95%CI = 1.71-7.32; p = 0.0004), severity of hyperthermia (Unit-OR = 1.30, 95%CI = 1.16-1.46; p < 0.0001), and older age (Unit-OR = 1.05, 95%CI = 1.02-1.07; p = 0.0014). Even in univariate, patient-level analyses, antipsychotic formulation was not related to death (oral antipsychotic (OAP): n = 39/554 (7.0%) vs. long-acting injectable (LAI): n = 13/129 (10.1%); p = 0.2413). Similarly, death with NMS was not related to antipsychotic class (first-generation antipsychotic: n = 38/433 (8.8%) vs. second-generation antipsychotic: n = 8/180 (4.4%); p = 0.0638). Non-antipsychotic co-treatments were not associated with NMS mortality. CONCLUSION: Despite reliance on case reports, these findings indicate that presence of respiratory alterations, severity of hyperthermia, and older age should alert clinicians to a higher NMS mortality risk, and that antipsychotics should be stopped to reduce mortality, yet when NMS arises on LAIs, mortality is not increased vs. OAPs.

Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations.

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.

Correction to: Safety of psychotropic medications in people with COVID-19: evidence review and practical recommendations.

An amendment to this paper has been published and can be accessed via the original article.

Mediators of focused psychosocial support interventions for children in low-resource humanitarian settings: analysis from an Individual Participant Dataset with 3,143 participants.

BACKGROUND: Research 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. METHODS: We 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. RESULTS: We 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%. CONCLUSIONS: Findings 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.

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

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.

Psychological therapies for the treatment of mental disorders in low- and middle-income countries affected by humanitarian crises.

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.

Paroxetine versus other anti-depressive agents for depression.

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.

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.

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.

Post-traumatic stress disorder as a risk factor for major adverse cardiovascular events: a cohort study of a South African medical insurance scheme.

AIMS: Prior research, largely focused on US male veterans, indicates an increased risk of cardiovascular disease among individuals with post-traumatic stress disorder (PTSD). Data from other settings and populations are scarce. The objective of this study is to examine PTSD as a risk factor for incident major adverse cardiovascular events (MACEs) in South Africa. METHODS: We analysed reimbursement claims (2011-2020) of a cohort of South African medical insurance scheme beneficiaries aged 18 years or older. We calculated adjusted hazard ratios (aHRs) for associations between PTSD and MACEs using Cox proportional hazard models and calculated the effect of PTSD on MACEs using longitudinal targeted maximum likelihood estimation. RESULTS: We followed 1,009,113 beneficiaries over a median of 3.0 years (IQR 1.1-6.0). During follow-up, 12,662 (1.3%) persons were diagnosed with PTSD and 39,255 (3.9%) had a MACE. After adjustment for sex, HIV status, age, population group, substance use disorders, psychotic disorders, major depressive disorder, sleep disorders and the use of antipsychotic medication, PTSD was associated with a 16% increase in the risk of MACEs (aHR 1.16, 95% confidence interval (CI) 1.05-1.28). The risk ratio for the effect of PTSD on MACEs decreased from 1.59 (95% CI 1.49-1.68) after 1 year of follow-up to 1.14 (95% CI 1.11-1.16) after 8 years of follow-up. CONCLUSION: Our study provides empirical support for an increased risk of MACEs in males and females with PTSD from a general population sample in South Africa. These findings highlight the importance of monitoring cardiovascular risk among individuals diagnosed with PTSD.

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".