A retrospective and in silico study on the augmentation of risperidone in the treatment of adolescent treatment-resistant depression: efficacy evaluation, adverse reaction analysis, and molecular mechanistic insights

Background Major depressive disorder (MDD) in adolescents remains a significant public health challenge. Treatment-resistant depression (TRD) affects a substantial proportion of cases and is associated with chronic symptoms, comorbidities, and elevated suicide risk. Standard treatments frequently show limited success, leading to off-label consideration of atypical antipsychotics as augmentation agents. Risperidone has shown promise in adults, but data in adolescents are limited. This retrospective study evaluates clinical outcomes of risperidone augmentation in adolescent TRD, complemented by in silico modeling of potential molecular interactions. Methods Retrospective data from 50 adolescents (aged 12–18) with DSM-5 MDD and TRD (non-response to ≥2 antidepressants) were analyzed. Risperidone (0.25–2 mg/day) was added to ongoing antidepressants for ≥8 weeks. Efficacy was assessed via changes in CDRS-R and HAM-D scores, response (≥50% reduction), and remission rates. Adverse events were documented. In silico molecular docking and 200 ns MD simulations explored risperidone’s interactions with selected targets (DRD2, 5-HT2AR, SERT, and NMDA) using available PDB structures. Results Mean age was 15.4 years; 56% female. Depression scores improved: CDRS-R decreased from 64.3 to 38.9 (mean change −25.4 points), HAM-D from 23.6 to 12.1 (mean change −11.5 points). Response rates were 64% (CDRS-R) and 60% (HAM-D); remission rates were 40% and 36%, respectively. Baseline severity was associated with response (OR 1.22, p = 0.01). Common adverse events (mostly mild-moderate) included weight gain (24%), sedation (16%), and EPS (12%). Docking and MD simulations suggested favorable binding, particularly to DRD2 and 5-HT2AR. Conclusion In this retrospective cohort, risperidone augmentation was associated with symptom improvement in adolescents with TRD and showed an acceptable short-term safety profile. In silico analyses suggest potential interactions with monoaminergic receptors that may contribute to its effects. These findings are hypothesis-generating and require confirmation in prospective randomized controlled trials.