Influence of study characteristics, methodological rigour and publication bias on efficacy of pharmacotherapy in obsessive-compulsive disorder: a systematic review and meta-analysis of randomised, placebo-controlled trials.

QUESTION: We examined the effect of study characteristics, risk of bias and publication bias on the efficacy of pharmacotherapy in randomised controlled trials (RCTs) for obsessive-compulsive disorder (OCD). STUDY SELECTION AND ANALYSIS: We conducted a systematic search of double-blinded, placebo-controlled, short-term RCTs with selective serotonergic reuptake inhibitors (SSRIs) or clomipramine. We performed a random-effect meta-analysis using change in the Yale-Brown Obsessive-Compulsive Scale (YBOCS) as the primary outcome. We performed meta-regression for risk of bias, intervention, sponsor status, number of trial arms, use of placebo run-in, dosing, publication year, age, severity, illness duration and gender distribution. Furthermore, we analysed publication bias using a Bayesian selection model. FINDINGS: We screened 3729 articles and included 21 studies, with 4102 participants. Meta-analysis showed an effect size of -0.59 (Hedges' G, 95% CI -0.73 to -0.46), equalling a 4.2-point reduction in the YBOCS compared with placebo. The most recent trial was performed in 2007 and most trials were at risk of bias. We found an indication for publication bias, and subsequent correction for this bias resulted in a depleted effect size. In our meta-regression, we found that high risk of bias was associated with a larger effect size. Clomipramine was more effective than SSRIs, even after correcting for risk of bias. After correction for multiple testing, other selected predictors were non-significant. CONCLUSIONS: Our findings reveal superiority of clomipramine over SSRIs, even after adjusting for risk of bias. Effect sizes may be attenuated when considering publication bias and methodological rigour, emphasising the importance of robust studies to guide clinical utility of OCD pharmacotherapy. PROSPERO REGISTRATION NUMBER: CRD42023394924.

The new European Medicines Agency guideline on antidepressants: a guide for researchers and drug developers.

According to the World Health Organization (WHO), depressive disorders are currently considered as one of the most disabling medical conditions in the world with one of the highest disability-adjusted life years [1] and this situation has apparently been further worsened during the COVID-19 pandemic [2]. Up to two thirds of patients with major depressive disorders (MDD) do not achieve full remission following an adequate first line standard of care and/or experience residual symptoms such as anxiety, impaired cognition, fatigue, sleep disturbance, or anhedonia [3]. Several attempts are often needed to find the most suitable treatment [4]. Thus, there is a need for medicinal products with better efficacy (e.g., faster onset of action, higher rates of response and remission), improved safety and/or more personalised profiles [5].

Ethnic differences in response to atypical antipsychotics in patients with schizophrenia: individual patient data meta-analysis of randomised placebo-controlled registration trials submitted to the Dutch Medicines Evaluation Board.

BACKGROUND: Little is known about the effect of ethnicity on the response to antipsychotic medication in patients with schizophrenia. AIMS: To determine whether ethnicity moderates the response to antipsychotic medication in patients with schizophrenia, and whether this moderation is independent of confounders. METHOD: We analysed 18 short-term, placebo-controlled registration trials of atypical antipsychotic medications in patients with schizophrenia (N = 3880). A two-step, random-effects, individual patient data meta-analysis was applied to establish the moderating effect of ethnicity (White versus Black) on symptom improvement according to the Brief Psychiatric Rating Scale (BPRS) and on response, defined as >30% BPRS reduction. These analyses were corrected for baseline severity, baseline negative symptoms, age and gender. A conventional meta-analysis was performed to determine the effect size of antipsychotic treatment for each ethnic group separately. RESULTS: In the complete data-set, 61% of patients were White, 25.6% of patients were Black and 13.4% of patients were of other ethnicities. Ethnicity did not moderate the efficacy of antipsychotic treatment: pooled ß-coefficient for the interaction between treatment and ethnic group was -0.582 (95% CI -2.567 to 1.412) for mean BPRS change, with an odds ratio of 0.875 (95% CI 0.510-1.499) for response. These results were not modified by confounders. CONCLUSIONS: Atypical antipsychotic medication is equally effective in both Black and White patients with schizophrenia. In registration trials, White and Black patients were overrepresented relative to other ethnic groups, limiting the generalisability of our findings.

Gender differences in the response to antipsychotic medication in patients with schizophrenia: An individual patient data meta-analysis of placebo-controlled studies.

OBJECTIVE: To determine whether gender and menopausal status moderate the response to antipsychotic medication in patients with schizophrenia. METHODS: We analyzed data of 22 short-term placebo-controlled registration trials of antipsychotic medications, which included 5,231 patients with schizophrenia. We applied two-step individual patient data meta-regression analyses to establish the influence of gender and menopausal status on treatment response in mean difference in symptom severity and difference in response (>30% symptom reduction). Analyses were performed both with and without correction for baseline (negative) symptom severity. RESULTS: Antipsychotic treatment is associated with larger mean symptom reduction in women than in men with schizophrenia. The number needed to treat (NNT) for a response in women was 6.9, in men 9.4. Although, we found an age by gender effect, the gender by treatment effect was independent of premenopausal status and baseline (negative) symptom severity. CONCLUSION: In the treatment of schizophrenia we found evidence of a higher response to antipsychotic medication in women relative to men. We found no evidence that this effect was driven by menopausal status, or baseline (negative) symptom severity. Despite the impact of gender and age on effect size in acute antipsychotic treatment, efficacy was clinically relevant in all subgroups.

The impact of second generation antipsychotics on insight in schizophrenia: Results from 14 randomized, placebo controlled trials.

Despite the negative impact of lack of insight on the prognosis, general functioning and treatment adherence, the effect of antipsychotic medication on insight has been investigated only in small samples and uncontrolled studies. In this study we examine whether previously reported effects of antipsychotics on insight from uncontrolled studies can be confirmed in a database including 14 randomized, double-blind, placebo-controlled trials. The database contained placebo-controlled RCTs of five second-generation antipsychotics (SGAs: olanzapine, paliperidone, quetiapine, risperidone and sertindole) and included a total of 4243 patients with schizophrenia. Insight was assessed with item G12 of the Positive and Negative Syndrome Scale (PANSS) at baseline and at six weeks. Overall, SGA treatment resulted in a significantly larger improvement in insight than placebo (0.43 points versus 0.15 points; Hedge׳s g 0.23; p<0.001). However this difference in improvement in insight was largely explained by improvement in other symptoms. In the initial analysis, one of the compounds was significantly less effective in improving insight than the other SGAs, but this difference no longer persisted when improvement in other symptoms was taken into account. The effect of SGAs on improvement in insight was not moderated by geographic region, illness duration or drop-out. The present study showed that SGA treatment of patients with schizophrenia is associated with improved insight, but that this improvement is associated with SGA induced improvements in other symptoms, though the causal relationship may not be established.

Impact of DSM-5 changes on the diagnosis and acute treatment of schizophrenia.

OBJECTIVE: To examine the consequences and validity of changes in Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 diagnostic criteria for schizophrenia, eg, omission of subtypes, using a large dataset of double-blind, randomized, placebo-controlled schizophrenia trials. METHODS: Data from 22 short-term efficacy registration trials of second generation antipsychotics for the treatment of acute psychotic episodes in patients with schizophrenia (N = 5233), submitted to the Dutch regulatory authority were analyzed. We examined whether patients in these pre-DSM-5 trials met the diagnostic criteria for schizophrenia according to DSM-5. Using linear regression, we examined differences in effect size between DSM-IV subtypes and between DSM-5 symptom dimensions. RESULTS: Over 99.5% of the patients met DSM-5 diagnostic criteria for schizophrenia and no differences in effect size were found between schizophrenia subtypes (P = .65). Symptom dimensions that respond best to treatment with second generation antipsychotics were hallucinations, delusions, disorganized speech, and mania (Hedge's g -0.23 to -0.31). CONCLUSIONS: Results of clinical trials in patients with pre-DSM-5 schizophrenia also apply to patients diagnosed with DSM-5 schizophrenia. Omission of the classic subtypes is justified as they are not predictive of response to treatment. The DSM-5 C-RDPSS scale adds valuable information to the categorical diagnosis of schizophrenia, which is relevant for antipsychotic response.

Geographic variation in efficacy of atypical antipsychotics for the acute treatment of schizophrenia - an individual patient data meta-analysis.

Generalizability of efficacy results from medication trials across geographic regions is disputed. Geographic differences in factors such as patient characteristics, treatment practices and disease definitions might lead to differences in effect sizes across regions. This study examined geographic variation in efficacy results of schizophrenia trials with atypical antipsychotics using individual-patient data meta-analysis. Twenty-two studies including in total 5233 patients from three regions (North America, Europe, and the rest of the world) were included in the random effects meta-analysis. The effect size in North American patients was smaller in terms of mean change from baseline and in terms of responders (Hedge׳s G=0.37, 95% CI 0.28-0.46; OR 1.71, 95% CI 1.35-2.17) as compared to patients in Europe (Hedge׳s G=0.56, 95% CI 0.34-0.79; OR 2.25, 95% CI 1.62-3.12) and the rest of the world (Hedge׳s G=0.53, 95% CI 0.12-0.75; OR 2.61, 95% CI 1.66-4.17). The differences were not statistically significant. The observed differences remained when the confounding effect of unequal distribution of compounds was controlled for by analyzing separately the compounds that were studied across all three regions. Based on these results it cannot be excluded that there are differences in efficacy results of atypical antipsychotics trials across geographic regions. The observed trend towards differential efficacy across geographic regions warrants further examination of the determinants of these differences.

Insomnia medication: do published studies reflect the complete picture of efficacy and safety?

Selective publication can have a deleterious effect on evidence based medicine, health policy decision making and treatment guidelines. Using the European Public Assessment Reports (EPARs) as reference, this study examined selective publication and selective reporting of efficacy and safety of insomnia medication. EPARs of with three insomnia medications were used to identify all clinical trials that were performed between 1998 and 2007 for the purpose of registration in the EU. The matching publication for each trial was searched through a systematic literature search. Accuracy of information in the publications was examined by comparison to the information in the EPARs. Only 55% of the trials with insomnia medications identified in EPARs were published. Positive trials were approximately two times more likely to be published. The lag time from study completion to publication was shorter for the positive compared to the negative trials. Sample size did not correlate with publication of negative trials. The meta-analysis of the effect size of insomnia medication was 1.6 times larger in the published data compared to the complete data. While the primary end points of the trials were reported reliably in the publications, remarkable inconsistencies were detected in the reporting of the secondary end points, methods, results and, especially safety. In conclusion, selective publication and reporting lead to an overestimation of efficacy and underestimation of safety of insomnia products. Authors of treatment guidelines should be aware of this bias. EPARs/FDA reviews provide a more unbiased view of the benefit-risk balance of insomnia and other medications and hence these documents should be consulted by e.g. authors of meta-analyses and of treatment guidelines.

Influence of intensive versus conventional glucose control on microvascular and macrovascular complications in type 1 and 2 diabetes mellitus.

In type 1 and 2 diabetes mellitus patients, hyperglycaemia is independently related to the development of microvascular and macrovascular complications. Glycaemic targets and the benefits of intensive versus conventional glucose control are under debate. The purpose of this review is to provide an overview of the randomized controlled trials and meta-analyses comparing the effects of intensive versus conventional glucose control on microvascular and macrovascular complications in type 1 and 2 diabetes. MEDLINE and Cochrane database searches were performed with a limit on randomized controlled trials or meta-analysis and keywords related to glucose control and diabetes. In addition, related articles and reference lists of relevant articles and guidelines were reviewed. Nine randomized controlled trials, three in type 1 and six in type 2 diabetes, and four meta-analyses in type 2 diabetes were reviewed. These studies included more than 30,000 patients. On the basis of these trials and meta-analyses, it can be concluded that intensive glucose control has a beneficial effect on microvascular complications (retinopathy, nephropathy, neuropathy) in both type 1 and type 2 diabetes patients. The risk reduction of developing a microvascular complication varied between 25% and 76%. Particularly in patients with type 2 diabetes, there was a 10-15% decrease in nonfatal myocardial infarction with intensive glucose control, but no effect on stroke, cardiovascular death or all-cause mortality was observed. There was a beneficial effect of intensive glucose control on cardiovascular disease in patients with type 1 diabetes in only one trial. In all studies, intensive glucose control was associated with at least twice the risk for serious hypoglycaemia than the conventional-control group. In conclusion, compared with conventional glucose control, intensive glucose control is associated with fewer microvascular complications in both type 1 and type 2 diabetes, a decrease in coronary events, especially in type 2 diabetes, and more serious hypoglycaemia.