Efficacy of Antipsychotic Augmentation Therapy in Treatment-Resistant Obsessive-Compulsive Disorder: A Systematic...

Obsessive-compulsive disorder (OCD) is a chronic neuropsychiatric condition. While selective serotonin reuptake inhibitors (SSRIs) are a standard treatment, many patients experience an inadequate response to monotherapy. For individuals with treatment-resistant OCD (TR-OCD), antipsychotic augmentation is a commonly utilized pharmacological strategy. This review aimed to systematically review the literature and conduct a frequentist network meta-analysis (NMA) to evaluate the comparative efficacy, safety, and tolerability of first-, second-, and third-generation antipsychotic augmentation in adults with TR-OCD. A systematic search was conducted from database inception to March 2026. Double-blind randomized controlled trials (RCTs) and observational studies evaluating antipsychotic augmentation of ongoing SRI therapy in adults with TR-OCD were included. The primary outcome was the mean change in the Yale-Brown Obsessive-Compulsive Scale (Y-BOCS) total score. The secondary outcomes included categorical treatment response (Y-BOCS reduction ≥ 35%) and tolerability. Pairwise meta-analyses utilized an inverse-variance random-effects model with Hartung-Knapp-Sidik-Jonkman (HKSJ) adjustment. The NMA established an empirical treatment hierarchy using surface under the cumulative ranking curve (SUCRA) probabilities. The certainty of the evidence was evaluated using the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach. Forty-three studies (22 RCTs and 21 observational studies) encompassing 890 patients were included. Pairwise meta-analysis of the RCTs demonstrated that, as a class, antipsychotic augmentation was significantly superior to placebo in reducing continuous Y-BOCS scores (standardized mean difference (SMD) = -0.49; 95% CI: -0.99 to -0.00; p < 0.05) and increasing the odds of categorical response (odds ratio (OR) = 2.38; 95% CI: 0.97 to 5.86). The NMA revealed a distinct hierarchy of efficacy: haloperidol exhibited the largest effect compared to placebo (SMD = -1.34; SUCRA = 0.799), followed by olanzapine (SMD = -0.80; SUCRA = 0.596), risperidone (SMD = -0.74; SUCRA = 0.625), and aripiprazole (SMD = -0.57; SUCRA = 0.532). The evidence for quetiapine (SMD = -0.45; SUCRA = 0.450) and paliperidone (SMD = -0.22; SUCRA = 0.356) was less robust and indistinguishable from that of the placebo. Although haloperidol was highly efficacious, its use was limited by poor tolerability. Risperidone and aripiprazole demonstrated the most optimal balance of robust anti-obsessional efficacy and acceptable tolerability. Preliminary data highlighted the potential of third-generation agents, such as brexpiprazole. Antipsychotic augmentation is a highly effective, evidence-based strategy for managing TR-OCD. Based on comparative efficacy and tolerability profiles, risperidone and aripiprazole are the preferred augmenting agents. The routine use of quetiapine should be reconsidered because of its marginal superiority over placebo. Future large-scale active-comparator RCTs are essential to define the long-term metabolic burden and evaluate novel agents to advance precision psychiatry in refractory OCD.