Objective: To determine if activating or sedating adverse events (AEs) affect the efficacy of adjunctive brexpiprazole and quetiapine extended-release (XR) in major depressive disorder (MDD).
Methods: In Delphinus (NCT01727726), patients with MDD and inadequate response to antidepressant treatments (ADTs) were randomized (2:2:1 ratio) to adjunctive brexpiprazole (2–3 mg/day), placebo or quetiapine XR (150–300 mg/day). Patients were grouped post hoc according to the presence of activating (akathisia, restlessness, agitation, insomnia, anxiety) and sedating (sedation, somnolence, fatigue) AEs. Correlation coefficients (r) between the presence of activating/sedating AEs and the change from baseline to Week 6 in Montgomery–Åsberg Depression Rating Scale (MADRS; clinician-rated) and Sheehan Disability Scale (SDS; patient-rated) scores were calculated.
Results: Activating AEs were experienced by 11.7% (23/197) of patients randomized to ADT+brexpiprazole and 9.0% (9/100) of patients randomized to ADT+quetiapine XR; sedating AEs were experienced by 7.1% (14) and 25.0% (25) of patients, respectively. Activating AEs did not correlate with MADRS or SDS scores in the ADT+brexpiprazole group (r=0.02, p=0.83; r=0.01, p=0.90, respectively) or ADT+quetiapine XR group (r=-0.20, p=0.058; r=-0.14, p=0.19, respectively). Sedating AEs did not correlate with MADRS score in the ADT+brexpiprazole group (r=0.08, p=0.28), but were associated with increased efficacy in the ADT+quetiapine XR group (r=0.25, p=0.017). Sedating AEs were associated with worse SDS score in the ADT+brexpiprazole group (r=-0.26, p=0.0004); no correlation was observed in the ADT+quetiapine XR group (r=-0.17, p=0.13).
Conclusions: Side effect profiles and any potential associated biases should be taken into account when using adjunctive antipsychotics for the treatment of MDD.