Impact of patient selection and study characteristics on signal detection in placebo-controlled trials with antidepressants

Abstract

An increasing rate of antidepressant trials fail due to large placebo responses. This analysis aimed to identify variables influencing signal detection in clinical trials of major depressive disorder. Patient-level data of randomized patients with a duloxetine dose ≥ 60 mg/day were obtained from Lilly. Total scores of the Hamilton Depression Rating scale (HAM-D) were used as efficacy endpoints. In total, 4661 patients from 14 studies were included in the analysis. The overall effect size (ES), based on the HAM-D total score at endpoint, between duloxetine and placebo was -0.272. Although no statistically significant interactions were found, the following results for factors influencing ES were seen: a very low ES (-0.157) in patients in the lowest baseline HAM-D category and in patients recruited in the last category of the recruitment period (-0.122). A higher ES in patients recruited in centers with a site-size at but not more than 2.5 times the average site-size for the study (-0.345). Study characteristics that resulted in low signal detection in our database were: <80% study completers, a HAM-D placebo response >5 points, a high variability of placebo response (SD > 7 points HAM-D), >6 post baseline visits per study, and use of an active control drug. Simpler trial designs, more homogeneous and mid-sized study sites, a primary analysis based on a higher cutoff blinded to investigators to avoid the influence of score inflation in mild patients and, if possible, studies without an active control group could lead to a better signal detection of antidepressive efficacy.

Placebo effects in psychiatry: mediators and moderators

“…The most consistent finding is that a low symptom severity at baseline is a strong predictor of the placebo response in schizophrenia, 24 psychosis, 26 children with autism, 27 obsessive-compulsive disorder, 30 attention-deficit hyperactivity disorder, 32 binge-eating disorder, 34 and depression, 19,37,39–43,47,48 despite the fact that in three studies the opposite was reported for schizophrenia, 23 psychosis, 25 and attention-deficit hyperactivity disorder. 33 …”

“…Other factors identified only in some analyses to be associated with higher placebo effect were a high number of study visits 46,48 (but only in older children and adults) and a low level of industry support. 35 …”

“…An unbalanced randomisation and therefore (usually) an increased chance of receiving active medication was the most frequent finding for increased placebo responses across all disorders, including schizo phrenia, 20,22 psychosis, 25 and depression. 41,44,48 Unbalanced randomisation does not seem to affect the placebo effect in children. 46 …”

Neuro-Bio-Behavioral Mechanisms of Placebo and Nocebo Responses: Implications for Clinical Trials and Clinical Practice

“…This approach is often chosen to assign more patients to the active drug in a two-arm trial for ethical reasons or to test more drug dosages against placebo by adding more study arms. As noted early on (Diener et al, 1999), unbalanced randomization may increase the overall placebo response in RCTs, as shown in trials on depression (Papakostas and Fava, 2009;Sinyor et al, 2010;Mancini et al, 2014), schizophrenia (Woods et al, 2005;Mallinckrodt et al, 2010), and psychosis (Agid et al, 2013). It is, however, unclear whether this represents a specific effect in neuropsychiatric disorders, because it has not been observed in other conditions, such as IBS Elsenbruch and Enck, 2015).…”

La respuesta placebo en la depresión: Una revisión sistemática

“…El número de sesiones de seguimiento también parece provocar un impacto terapéutico positivo sobre la respuesta placebo, representando hasta el 40% de dicha respuesta (Posternak & Zimmernan 2007;Mancini, Wade, Perugi, Lenox-Smith & Schacht, 2014), por lo que se sugiere que el impacto terapéutico es acumulativo y proporcional. Este hecho indica que la respuesta placebo depende en gran medida de la atención y el cuidado recibido durante el curso de los ensayos clínicos.…”