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".

Antidepressants for the treatment of depression in people with cancer.

BACKGROUND: Major depression and other depressive conditions are common in people with cancer. These conditions are not easily detectable in clinical practice, due to the overlap between medical and psychiatric symptoms, as described by diagnostic manuals such as the Diagnostic and Statistical Manual of Mental Disorders (DSM) and International Classification of Diseases (ICD). Moreover, it is particularly challenging to distinguish between pathological and normal reactions to such a severe illness. Depressive symptoms, even in subthreshold manifestations, have a negative impact in terms of quality of life, compliance with anticancer treatment, suicide risk and possibly the mortality rate for the cancer itself. Randomised controlled trials (RCTs) on the efficacy, tolerability and acceptability of antidepressants in this population are few and often report conflicting results. OBJECTIVES: To evaluate the efficacy, tolerability and acceptability of antidepressants for treating depressive symptoms in adults (aged 18 years or older) with cancer (any site and stage). SEARCH METHODS: We used standard, extensive Cochrane search methods. The latest search date was November 2022. SELECTION CRITERIA: We included RCTs comparing antidepressants versus placebo, or antidepressants versus other antidepressants, in adults (aged 18 years or above) with any primary diagnosis of cancer and depression (including major depressive disorder, adjustment disorder, dysthymic disorder or depressive symptoms in the absence of a formal diagnosis). DATA COLLECTION AND ANALYSIS: We used standard Cochrane methods. Our primary outcome was 1. efficacy as a continuous outcome. Our secondary outcomes were 2. efficacy as a dichotomous outcome, 3. Social adjustment, 4. health-related quality of life and 5. dropouts. We used GRADE to assess certainty of evidence for each outcome. MAIN RESULTS: We identified 14 studies (1364 participants), 10 of which contributed to the meta-analysis for the primary outcome. Six of these compared antidepressants and placebo, three compared two antidepressants, and one three-armed study compared two antidepressants and placebo. In this update, we included four additional studies, three of which contributed data for the primary outcome. For acute-phase treatment response (six to 12 weeks), antidepressants may reduce depressive symptoms when compared with placebo, even though the evidence is very uncertain. This was true when depressive symptoms were measured as a continuous outcome (standardised mean difference (SMD) -0.52, 95% confidence interval (CI) -0.92 to -0.12; 7 studies, 511 participants; very low-certainty evidence) and when measured as a proportion of people who had depression at the end of the study (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; 5 studies, 662 participants; very low-certainty evidence). No studies reported data on follow-up response (more than 12 weeks). In head-to-head comparisons, we retrieved data for selective serotonin reuptake inhibitors (SSRIs) versus tricyclic antidepressants (TCAs) and for mirtazapine versus TCAs. There was no difference between the various classes of antidepressants (continuous outcome: SSRI versus TCA: SMD -0.08, 95% CI -0.34 to 0.18; 3 studies, 237 participants; very low-certainty evidence; mirtazapine versus TCA: SMD -4.80, 95% CI -9.70 to 0.10; 1 study, 25 participants). There was a potential beneficial effect of antidepressants versus placebo for the secondary efficacy outcomes (continuous outcome, response at one to four weeks; very low-certainty evidence). There were no differences for these outcomes when comparing two different classes of antidepressants, even though the evidence was very uncertain. In terms of dropouts due to any cause, we found no difference between antidepressants compared with placebo (RR 0.85, 95% CI 0.52 to 1.38; 9 studies, 889 participants; very low-certainty evidence), and between SSRIs and TCAs (RR 0.83, 95% CI 0.53 to 1.22; 3 studies, 237 participants). We downgraded the certainty of the evidence because of the heterogeneous quality of the studies, imprecision arising from small sample sizes and wide CIs, and inconsistency due to statistical or clinical heterogeneity. AUTHORS' CONCLUSIONS: Despite the impact of depression on people with cancer, the available studies were few and of low quality. This review found a potential beneficial effect of antidepressants against placebo in depressed participants with cancer. However, the certainty of evidence is very low and, on the basis of these results, it is difficult to draw clear implications for practice. The use of antidepressants in people with cancer should be considered on an individual basis and, considering the lack of head-to-head data, the choice of which drug to prescribe may be based on the data on antidepressant efficacy in the general population of people with major depression, also taking into account that data on people with other serious medical conditions suggest a positive safety profile for the SSRIs. Furthermore, this update shows that the usage of the newly US Food and Drug Administration-approved antidepressant esketamine in its intravenous formulation might represent a potential treatment for this specific population of people, since it can be used both as an anaesthetic and an antidepressant. However, data are too inconclusive and further studies are needed. We conclude that to better inform clinical practice, there is an urgent need for large, simple, randomised, pragmatic trials comparing commonly used antidepressants versus placebo in people with cancer who have depressive symptoms, with or without a formal diagnosis of a depressive disorder.

Effectiveness of a stepped-care programme of WHO psychological interventions in migrant populations resettled in Italy: Study protocol for the RESPOND randomized controlled trial.

Introduction: Migrant populations, including workers, undocumented migrants, asylum seekers, refugees, internationally displaced persons, and other populations on the move, are exposed to a variety of stressors and potentially traumatic events before, during, and after the migration process. In recent years, the COVID-19 pandemic has represented an additional stressor, especially for migrants on the move. As a consequence, migration may increase vulnerability of individuals toward a worsening of subjective wellbeing, quality of life, and mental health, which, in turn, may increase the risk of developing mental health conditions. Against this background, we designed a stepped-care programme consisting of two scalable psychological interventions developed by the World Health Organization and locally adapted for migrant populations. The effectiveness and cost-effectiveness of this stepped-care programme will be assessed in terms of mental health outcomes, resilience, wellbeing, and costs to healthcare systems. Methods and analysis: We present the study protocol for a pragmatic randomized study with a parallel-group design that will enroll participants with a migrant background and elevated level of psychological distress. Participants will be randomized to care as usual only or to care a usual plus a guided self-help stress management guide (Doing What Matters in Times of Stress, DWM) and a five-session cognitive behavioral intervention (Problem Management Plus, PM+). Participants will self-report all measures at baseline before random allocation, 2 weeks after DWM delivery, 1 week after PM+ delivery and 2 months after PM+ delivery. All participants will receive a single-session of a support intervention, namely Psychological First Aid. We will include 212 participants. An intention-to-treat analysis using linear mixed models will be conducted to explore the programme's effect on anxiety and depression symptoms, as measured by the Patient Health Questionnaire-Anxiety and Depression Scale summary score 2 months after PM+ delivery. Secondary outcomes include post-traumatic stress disorder symptoms, resilience, quality of life, resource utilization, cost, and cost-effectiveness. Discussion: This study is the first randomized controlled trial that combines two World Health Organization psychological interventions tailored for migrant populations with an elevated level of psychological distress. The present study will make available DWM/PM+ packages adapted for remote delivery following a task-shifting approach, and will generate evidence to inform policy responses based on a more efficient use of resources for improving resilience, wellbeing and mental health. Clinical trial registration: ClinicalTrials.gov, identifier: NCT04993534.