Nocebo Effect in Randomized Clinical Trials of Antidepressants in Children and Adolescents: Systematic Review and Meta-Analysis

Abstract

Objective: To compare the incidence of adverse events between active and placebo arms of randomized clinical trials in depressive children and adolescents (C&A) with antidepressant treatments, in order to look for similarities in both groups that allow to establish a possible nocebo effect.Methods: Systematic search strategy (January 1974–March 2013) in electronic databases, conference abstracts, and reference list of systematic reviews and included studies to identify parallel randomized placebo-controlled trials of antidepressants in C&A (<19 years) with major depressive disorder, and one or more interventions of any orally administered antidepressant. The pooled adverse events were calculated based on a fixed-effect model and statistical analysis involved the risk ratio (RR) of adverse events, with 95% confidence intervals (95% CI).Results: Sixteen studies were included in the review, of which seven studies with a sample of 1911 patients had data to include in the meta-analysis. There was similar risk for the incidence of adverse events between non-active and active group (global RR 1.04, 95% CI: 0.97–1.11).Conclusion: Depressive C&A allocated to placebo or active group had similar risk to develop adverse events. These similarities in both groups are attributed to the nocebo effect. It is of note that defining “nocebo” effects is challenging in clinical populations because adverse effects may be attributed to the intervention or may be manifestation of the disease itself. The inclusion of a no-treatment arm may be warranted. Nocebo effects are likely when adverse events of placebo mimic the adverse events of active treatment, as was the case here.

Efficacy and Safety of Selective Serotonin Reuptake Inhibitors, Serotonin-Norepinephrine Reuptake Inhibitors, and Placebo for Common Psychiatric Disorders Among Children and Adolescents

“…The small amount of research on SNRIs for pediatric DD has had mixed results 3 . One meta-analysis on pediatric depression found that while SSRIs differed significantly from placebo, SNRIs and tricyclic antidepressants did not 6 .…”

“…For adult patients with DD, a genuine placebo effect has been demonstrated, as the combination of placebo and supportive care has been shown to be more effective than supportive care alone 13 . Conversely, patients in the placebo group also demonstrate treatment emergent adverse events 6 . However, how response to placebo differs across disorders or other study design features in pediatrics remains understudied.…”

Introducing the ‘Drucebo’ effect in statin therapy: a systematic review of studies comparing reported rates of statin‐associated muscle symptoms, under blinded and open‐label conditions

“…True placebo response would be symptom improvements in the non‐active treatment arm that go above and beyond spontaneous remission in the no‐treatment group. Likewise, true nocebo responses are adverse effects that go above and beyond symptoms in the no‐treatment group’ . While a similar degree of adverse effects in a treatment and placebo group can give reassurance that adverse effects are not drug‐related, it cannot estimate the extent to which expectation of an adverse effect is responsible for the patient experiencing the effect.…”

Specific expectancies are associated with symptomatic outcomes and side effect burden in a trial of chamomile extract for generalized anxiety disorder

“…Experimentally altering patients’ beliefs about whether they are taking an active medication has sometimes been found to enhance the effects of placebos (Vase et al, 2002). Similarly, side effect profiles in the placebo arms of clinical trials often resemble those of the active drug comparator (Mora et al, 2011; Rojas-Mirquez et al, 2014) (i.e., a nocebo effect), and manipulating patients’ side effect expectations affects their reports of side effects (Mondaini et al, 2007; Wise et al, 2009). …”