Placebo response rates and potential modifiers in double-blind randomized controlled trials of second and newer generation antidepressants for major depressive disorder in children and adolescents: a systematic review and meta-regression analysis

Abstract

Children and adolescents with major depressive disorder (MDD) appear to be more responsive to placebo than adults in randomized placebo-controlled trials (RCTs) of second and newer generation antidepressants (SNG-AD). Previous metaanalyses obtained conflicting results regarding modifiers. We aimed to conduct a meta-analytical evaluation of placebo response rates based on both clinician-rating and self-rating scales. Based on the most recent and comprehensive study on adult data, we tested whether the placebo response rates in children and adolescents with MDD also increase with study duration and number of study sites. We searched systematically for published RCTs of SNG-AD in children and/or adolescents (last update: September 2017) in public domain electronic databases and additionally for documented studies in clinical trial databases. The log-transformed odds of placebo response were meta-analytically analyzed. The primary and secondary outcomes were placebo response rates at the end of treatment based on clinician-rating and self-rating scales, respectively. To examine the impact of study duration and number of study sites on placebo response rates, we performed simple meta-regression analyses. We selected other potential modifiers of placebo response based on significance in at least one previous pediatric meta-analysis and on theoretical considerations to perform explorative analyses. We applied sensitivity analyses with placebo response rates closest to week 8 to compare our data with those reported for adults. We identified 24 placebo-controlled trials (2229 patients in the placebo arms). The clinician-rated placebo response rates ranged from 22 to 62% with a pooled response rate of 45% (95% CI 41-50%). The number of study sites was a significant modifier in the simple meta-regression analysis [odds ratio (OR) 1.01, 95% CI 1.01-1.02, p = 0.0003, k = 24) with more study sites linked to a higher placebo response. Study duration was not significantly associated with the placebo response rate. The explorative simple analyses revealed that publication year may be an additional modifier. However, in the explorative multivariable analysis including the number of study sites and the publication year only the number of study sites reached a p value ≤ 0.05. The self-rated placebo response rates ranged from 1 to 68% with a pooled response rate of 26% (95% CI 10-54%) (k = 6; n = 396). This meta-analysis confirms a high pooled placebo response rate in children and adolescents based on clinician ratings, which exceeds that observed in the most recent meta-analysis of placebo effects in adults (36%; 95% CI 35-37%) published in 2016. However, and similar to findings in adults, the pooled response rates based on self-ratings were substantially lower. In accordance with previous meta-analyses, we corroborated the number of study sites as significant modifier. In Ramona Meister, Mariam Abbas and Jochen Antel contributed equally to the study.

Antidepressants in Children and Adolescents: Meta-Review of Efficacy, Tolerability and Suicidality in Acute Treatment

“…Overall, the evidence from our meta-review is only partially in line with the current license status of antidepressants in children and adolescents. In fact, our findings support: (1) the current license of fluoxetine for MDD; (2) the approval of fluoxetine and sertraline for OCD [e.g., USA ( 1 ); UK ( 2 )]; (3) the lack of approval of antidepressants for ADHD. However, our results are in contrast with: 1) the absence of license for fluvoxamine and paroxetine for ADs [e.g., US ( 1 ), UK ( 2 ), France ( 23 )]; 2) the FDA approval of escitalopram for acute and maintenance treatment of depression ( 24 )]; 3) the license for fluvoxamine and clomipramine for OCD ( 1 ).…”

“…For instance, in the USA, fluoxetine and escitalopram are Food and Drug Administration (FDA)-approved for major depressive disorder (MDD), fluoxetine, sertraline, fluvoxamine, and clomipramine for obsessive-compulsive disorder (OCD), duloxetine for generalized anxiety disorder (GAD) and the combination of olanzapine and fluoxetine for bipolar depression ( 1 ). In the UK, fluoxetine is licensed for MDD, fluvoxamine and sertraline for OCD, and imipramine for nocturnal enuresis ( 2 ). Furthermore, some antidepressants are used by clinicians for non-licensed indications, such as amitriptyline for neuropathic pain and, historically, TCAs, in particular imipramine, have been used for the management of attention-deficit/hyperactivity disorder (ADHD).…”

“…Despite this increase in the rate of prescriptions and notwithstanding their licensed indication for a number of disorders, the use of antidepressants in children and adolescents remains controversial. In particular, the efficacy and tolerability of antidepressants for MDD in young people have been questioned, in the light of a high placebo response rate ranging from 22% to 62% ( 2 ) and the “black box warning” issued by the FDA in 2004, advising of the increased risk of suicidal behaviors among children treated with SSRIs ( 3 ). The FDA warning was based on an analysis published more than one decade ago about industry-sponsored randomized controlled trials (RCTs).…”

Effect of vitamin D deficiency on depressive symptoms in child and adolescent psychiatric patients: results of a randomized controlled trial

“…In adults, the depression severity assessed via BDI also correlates only moderately with clinicial ratings using Hamilton Depression Rating Scale [ 40 ]. RCTs focussing on the effects of pharmacological antidepressants and/or psychotherapy have revealed larger effect sizes for both verum and placebo when clinician-based ratings were considered in comparison to self-ratings [ 41 - 43 ]. Accordingly, we recommend that future RCTs should include a clinician rating, ideally as the primary outcome as usual in pharmacotherapy trials, to answer the question whether vitamin D supplementation has antidepressant effects.…”

Historical Controls in Randomized Clinical Trials: Opportunities and Challenges

“…The median duration in 167 antipsychotic trials conducted over the last 60 years was 6 weeks, with a range of 3–28 weeks 4 . Although trial duration has been shown to influence some indications (i.e., Crohns), 5 in other conditions, the relationship between study duration and placebo response rate is less clear (i.e., in major depressive disorder (MDD)) 6 . In trials that use non‐traditional designs, like adaptive, 7 and placebo‐run‐in trial designs—developed to minimize the impact of increasing placebo response—it is hard to determine how much of the time on placebo can be contributed to historical control models 7 .…”