Placebo response in pharmacological and dietary supplement trials of autism spectrum disorder (ASD): systematic review and meta-regression analysis.

BACKGROUND: Placebo response in autism spectrum disorder (ASD) might dilute drug-placebo differences and hinder drug development. Therefore, this meta-analysis investigated placebo response in core symptoms. METHODS: We searched ClinicalTrials.gov , CENTRAL, EMBASE, MEDLINE, PsycINFO, WHO-ICTRP (up to July 8, 2018), and PubMed (up to July 4, 2019) for randomized pharmacological and dietary supplement placebo-controlled trials (RCTs) with a minimum of seven days of treatment. Single-group meta-analyses were conducted using a random-effects model. Standardized mean changes (SMC) of core symptoms in placebo arms were the primary outcomes and placebo positive response rates were a secondary outcome. Predictors of placebo response were investigated with meta-regression analyses. The protocol was registered with PROSPERO ID CRD42019125317 . RESULTS: Eighty-six RCTs with 2360 participants on placebo were included in our analysis (87% in children/adolescents). The majority of trials were small, single-center with a duration of 8-12 weeks and published after 2009. Placebo response in social-communication difficulties was SMC = - 0.32, 95% CI [- 0.39, - 0.25], in repetitive behaviors - 0.23[- 0.32, - 0.15] and in scales measuring overall core symptoms - 0.36 [- 0.46, - 0.26]. Overall, 19%, 95% CI [16-22%] of participants were at least much improved with placebo. Caregiver (vs. clinician) ratings, lower risk of bias, flexible-dosing, larger sample sizes and number of sites, less recent publication year, baseline levels of irritability, and the use of a threshold of core symptoms at inclusion were associated with larger placebo response in at least a core symptom domain. LIMITATIONS: About 40% of the trials had an apparent focus on core symptoms. Investigation of the differential impact of predictors on placebo and drug response was impeded by the use of diverse experimental interventions with essentially different mechanisms of action. An individual-participant-data meta-analysis could allow for a more fine-grained analysis and provide more informative answers. CONCLUSIONS: Placebo response in ASD was substantial and predicted by design- and participant-related factors, which could inform the design of future trials in order to improve the detection of efficacy in core symptoms. Potential solutions could be the minimization and careful selection of study sites as well as rigorous participant enrollment and the use of measurements of change not solely dependent on caregivers.

Efficacy and tolerability of pharmacological and non-pharmacological interventions in older patients with major depressive disorder: A systematic review, pairwise and network meta-analysis.

As there is currently no comprehensive evaluation about the efficacy and safety of interventions in elderly patients with major depressive disorder, we did a systematic review and network meta-analysis about all interventions in this population. We searched the specialised register of the Cochrane common mental disorders group, MEDLINE, EMBASE, PsycINFO, CochraneLibrary, ClinicalTrials.gov and the WHO registry until Dec 12, 2017 to identify all randomized controlled trials about the treatment of major depressive disorder in patients over an age of 65. The primary outcome was response defined as reduction of at least 50% on the Hamilton Depression Scale or any other validated depression scale. Secondary outcomes were remission, depressive symptoms, dropouts total, dropouts owing to inefficacy and dropouts due to adverse events, quality of life and social functioning. Additionally, we analysed 116 adverse events. We identified 129 references from 53 RCTs with 9274 participants published from 1990 to 2017. The mean participant age was 73.7 years. In terms of the primary outcome response to treatment the network-meta-analysis showed significant superiority compared to placebo for quetiapine and duloxetine; in addition, agomelatine, imipramine and vortioxetine outperformed placebo in pairwise meta-analyses, and there were also significant superiorities of several antidepressants compared to placebo in secondary efficacy outcomes. Very limited evidence suggests that competitive memory training, geriatric home treatment group and detached mindfulness condition reduce depressive symptoms. Several antidepressants and quetiapine have been shown to be efficacious in elderly patients with major depressive disorder, but due to the comparably few available data, the results are not robust. Differences in the multiple side-effects analysed should also be considered in drug choice. Although there were significant effects for some non-pharmacological treatments, the overall evidence for non-pharmacological treatments in major depressive disorder is insufficient, because it is based on a few trials with usually small sample sizes.

Efficacy, acceptability and tolerability of antipsychotics in patients with schizophrenia and comorbid substance use. A systematic review and meta-analysis.

Patients with schizophrenia and substance related comorbidity or substance induced psychotic disorder are difficult to treat. Although the prevalence of a comorbid substance use is approximately 40% in schizophrenia, such patients are usually excluded from clinical trials. We therefore performed a random-effects meta-analysis of all randomized controlled antipsychotic drug trials in this patient subgroup. We searched multiple databases up to May, 2018. The primary outcome was the reduction of substance user; secondary outcomes were craving, mean reduction of substance use, overall change in schizophrenia symptoms, positive and negative symptoms, response, dropouts, quality of life, social functioning, weight gain, sedation, prolactin, extrapyramidal side effects and use of antiparkinsonian medication. We identified 27 references from 19 RCTs published from 1999 to March 2017 including 1742 participants. The most frequent types of substance abuse were cannabis (8 studies) and cocaine (6 studies) use/dependence. Clozapine was superior to other antipsychotics for reduction of substance use and risperidone to olanzapine for craving. Olanzapine, clozapine and risperidone showed superiority for symptom reduction compared to some other drugs. When reported, results of side-effects followed known patterns. The evidence-base is considerable (19 RCTs), however, firm conclusions cannot be drawn due to small sample sizes of individual studies and insufficient reporting.