Hugh McGuire

Treatment and prevention of mental disorders in low-income and middle-income countries

We review the evidence on effectiveness of interventions for the treatment and prevention of selected mental disorders in low-income and middle-income countries. Depression can be treated effectively in such countries with low-cost antidepressants or with psychological interventions (such as cognitive-behaviour therapy and interpersonal therapies). Stepped-care and collaborative models provide a framework for integration of drug and psychological treatments and help to improve rates of adherence to treatment. First-generation antipsychotic drugs are effective and cost effective for the treatment of schizophrenia; their benefits can be enhanced by psychosocial treatments, such as community-based models of care. Brief interventions delivered by primary-care professionals are effective for management of hazardous alcohol use, and pharmacological and psychosocial interventions have some benefits for people with alcohol dependence. Policies designed to reduce consumption, such as increased taxes and other control strategies, can reduce the population burden of alcohol abuse. Evidence about the efficacy of interventions for developmental disabilities is inadequate, but community-based rehabilitation models provide a low-cost, integrative framework for care of children and adults with chronic mental disabilities. Evidence for mental health interventions for people who are exposed to conflict and other disasters is still weak-especially for interventions in the midst of emergencies. Some trials of interventions for prevention of depression and developmental delays in low-income and middle-income countries show beneficial effects. Interventions for depression, delivered in primary care, are as cost effective as antiretroviral drugs for HIV/AIDS. The process and effectiveness of scaling up mental health interventions has not been adequately assessed. Such research is needed to inform the continuing process of service reform and innovation. However, we recommend that policymakers should act on the available evidence to scale up effective and cost-effective treatments and preventive interventions for mental disorders.

Safety Reporting and Adverse-Event Profile of Mirtazapine Described in Randomized Controlled Trials in Comparison with Other Classes of Antidepressants in the Acute-Phase Treatment of Adults with Depression Systematic Review and Meta-Analysis

Background: Mirtazapine has a unique mechanism of antidepressant action, and thus is thought to have a different profile of adverse events from that of other antidepressants.Objective: To present a methodologically rigorous systematic review of the adverse event profile of mirtazapine and point to possible problems with safety reporting in randomized controlled trials (RCTs) of the acute-phase treatment of major depression in adults with mirtazapine in comparison with other types of antidepressant.Methods: The Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials Register was electronically searched using the following search terms: ‘depress*rs’, ‘dysthymi*’, ‘adjustment disorder*’, ‘mood disorder*’, ‘affective disorder’, ‘affective symptoms’ and ‘mirtazapine’. Pharmaceutical companies and experts in this field were contacted, and the reference lists of the relevant RCTs were checked, for additional data. No language restriction was imposed. Two authors independently assessed the quality of trials for inclusion in the review. Disagreements were resolved by consensus. Two authors independently extracted data on adverse events. Disagreements were resolved by consensus. The adequacy of safety reporting was assessed by one author.Regarding the adequacy of safety reporting, the qualitative and quantitative parameters of safety reporting were determined. Regression analyses were conducted to assess characteristics of trials influencing safety reporting.The primary and secondary outcomes in the systematic review of the adverse events associated with mirtazapine were defined as the proportion of patients having each of 43 adverse events listed in the modified version of the WHO Adverse Reaction Terminology, and the proportion of patients experiencing at least one adverse event, respectively. Meta-analyses were conducted for these outcomes.Results: Twenty-five RCTs involving 4842 patients were identified as meeting our inclusion criteria. With regard to safety reporting, only two trials and no trials were rated as ‘adequate’ in terms of the reporting of clinical adverse events and laboratory-determined toxicity, respectively. The proportion of text in the results sections of the study reports devoted to safety reporting was a mean of 22%. No associations were observed between the adequacy of safety reporting and any characteristics of the trials; however, sample size over 100 participants in total and over 50 subjects in a study arm, double blindness and sponsorship by the company marketing mirtazapine were significantly associated with a greater number of reported adverse events in mirtazapine recipients.In terms of individual adverse events, mirtazapine was significantly less likely to cause hypertension or tachycardia (risk ratio [RR] 0.51) and tremor (RR 0.43) than tricyclic antidepressants (TCAs). In comparison with selective serotonin uptake inhibitors (SSRIs), mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 3.68), increased salivation (RR 3.66), somnolence (RR 1.62) and fatigue (RR 1.45), but less likely to cause flatulence (RR 0.26), sweating (RR 0.28), sexual dysfunction (RR 0.34), tremor (RR 0.37), nausea or vomiting (RR 0.40), sleep disturbance (RR 0.55) and diarrhoea (RR 0.61). In comparison with the serotonin-noradrenaline (norepinephrine) reuptake inhibitor (SNRI) venlafaxine, mirtazapine was significantly more likely to cause fatigue (RR 2.02), but less likely to cause sleep disturbance (RR 0.03), sweating (RR 0.03) and constipation (RR 0.25). Relative to trazodone, mirtazapine was significantly more likely to cause weight gain or increased appetite (RR 4.00). Approximately 70% of patients treated with mirtazapine experienced at least one adverse event, with no significant difference in comparison with other antidepressants.Conclusions: The study confirmed the paucity of adequate safety reporting in trials comparing mirtazapine with other types of antidepressant in the acute-phase treatment of depression in adults. Based on the available evidence, mirtazapine appears to have a unique adverse-event profile. Using these findings, clinicians can inform their patients, not only of the simple frequency of adverse events with mirtazapine, but also of the relative difference in the frequency of adverse events in comparison with that of other antidepressants, to aid pragmatic clinical decisions.

Efficacy and Tolerability of Milnacipran in the Treatment of Major Depression in Comparison with Other Antidepressants : A Systematic Review and Meta-Analysis

AbstractBackground: Milnacipran, a dual serotonin-noradrenaline reuptake inhibitor, is one of the newer antidepressants that clinicians use for the routine care of patients with major depression. We undertook a systematic review and meta-analysis of randomized controlled trials that compared the efficacy and tolerability of milnacipran with other antidepressants. Objective: To assess the efficacy and tolerability of milnacipran in comparison with TCAs, SSRIs and other drugs in the acute phase of treatment for major depression. Methods: We searched the Cochrane Collaboration Depression, Anxiety and Neurosis Controlled Trials registers, journals, conference proceedings, trial databases of the drug-approving agencies and ongoing clinical trial registers for all published and unpublished randomized controlled trials that compared the efficacy and adverse events of milnacipran versus any other antidepressant. The search was conducted in December 2006 and updated in May 2007. No language restrictions were applied. All relevant authors were contacted to supplement any incomplete reporting in the original papers.Randomized controlled trials comparing milnacipran with any other active antidepressants as monotherapy in the acute phase of treatment for major depression were selected. Participants were aged ≥18 years, of both sexes and with a primary diagnosis of unipolar major depression. Studies were excluded when the participants had specific psychiatric and medical co-morbidities. Two independent reviewers assessed the quality of trials for inclusion, and subsequently extracted data. Disagreements were resolved by consensus. Meta-analyses were conducted for efficacy and tolerability outcomes. Sixteen randomized controlled trials (n = 2277) were included in the meta-analyses. Results: No differences were found in achieving clinical improvement, remission or overall tolerability when comparing milnacipran with other antidepressants. However, compared with the TCAs, fewer patients taking milnacipran were early treatment withdrawals due to adverse events (number needed to harm (NNH) = 15; 95% CI 10, 48). Significantly more patients taking TCAs experienced adverse events compared with milnacipran (NNH = 4; 95% CI 3, 7). Conclusions: The overall effectiveness and tolerability of milnacipran versus other antidepressants does not seem to differ in the acute phase of treatment for major depression. However, there is some evidence in favour of milnacipran over TCAs in terms of premature withdrawal due to adverse events and the rates of patients experiencing adverse events. Milnacipran may benefit some patient populations who experience adverse effects from other antidepressants in the acute phase of treatment for major depression.

Are the Cochrane group registers comprehensive? A case study of Japanese psychiatry trials

BackgroundLanguage bias is a form of publication bias and constitutes a serious threat to meta-analyses. The Cochrane Controlled Trials Register is one attempt to remedy this and now contains more than 300,000 citations. However we are still unsure if it provides comprehensive coverage, particularly for non-English trials.MethodsWe have recently established a comprehensive register of Japanese trials of psychotropic drugs through extensive personal contacts, electronic searches and handsearches. We examined two Cochrane psychiatry group registers against this Japanese database.ResultsThe Japanese register contained 56 reports of randomized controlled trials (RCTs) of antidepressants for depression but the Cochrane Depression, Anxiety and Neurosis group register contained 18, with an overlap of only nine. The Japanese register contained 61 reports of RCTs of neuroleptics for schizophrenia and the Cochrane Schizophrenia group register contained 36, with an overlap of only six. Taking account of some duplicate publications, only a quarter to a third of all relevant Japanese RCTs were retrievable from the Cochrane group registers.ConclusionsSimilar, or worse, yields may be expected with RCTs conducted in other East Asian countries, and in other fields of medicine. What evidence there is suggests that this situation may lead to a systematic over estimate of treatment effect.