Efficacy and safety of perospirone as adjunctive therapy in major depressive disorder patients with inadequate response to antidepressants: a randomized clinical trial.

Background: Adjunctive therapy with a second-generation antipsychotic (SGA) represents a treatment option for major depressive disorder (MDD) patients with inadequate response to antidepressants. Evidence suggests that early initiation of adjunctive SGA treatment may yield greater benefits. This study aimed to investigate the efficacy, safety, and tolerability of adjunctive therapy with perospirone initiated after 4 weeks of antidepressant treatment in MDD patients with inadequate response. Methods: This phase IV, multi-center, randomized, double-blind, placebo-controlled trial assessed the efficacy, safety and tolerability of perospirone as an adjunct to serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs) in patients with MDD who showed inadequate response to SSRIs/SNRIs. Patients with moderate-to-severe depression (defined as a baseline Montgomery-Åsberg Depression Rating Scale [MADRS] score of ≥20) who exhibited a reduction of <50% in the total score of MADRS after receiving at least one antidepressant at an adequate dose for at least four weeks during the current episode were included in the study. The primary intervention timepoint was set at week 4, with treatment initiation permitted up to week 8. Eligible patients were randomized 1:1 to the perospirone group (perospirone + SSRIs/SNRIs) or the placebo group (placebo + SSRIs/SNRIs) and received treatment for 8 weeks. Perospirone was administered once or twice daily at an initial dose of 4-8 mg/day and a maintenance dose of 12-48 mg/day, based on symptom severity and patient tolerance. The study, conducted across 10 Chinese hospitals between December 16, 2021 and June 19, 2024, evaluated the primary efficacy endpoints of response (≥50% reduction in the MADRS score) and remission (MADRS score ≤10) rates at the end of the 8-week treatment. The study was registered at www.chictr.org.cn (ChiCTR2200063354). Findings: A total of 210 participants were randomized into the two groups (108 were assigned to the perospirone group and 102 to the placebo group). Compared to the placebo group, more patients in the perospirone group achieved remission at week 8 (55.2% vs. 38.9%, odds ratio [OR] = 1.944, 95% confidence interval [CI]: 1.060-3.564, p = 0.032), and the proportions of participants with clinical response were comparable between the two groups (67.8% vs. 60.0%, OR = 1.406, 95% CI: 0.759-2.605, p = 0.28). Most common adverse events (AEs) were mild arousal-related symptoms, autonomic dysfunction, and extrapyramidal symptoms. Treatment discontinuation rates due to AEs were low and comparable in both groups, with no significant safety concerns. Interpretation: Early adjunctive treatment with perospirone for 8 weeks may confer potential benefits, particularly in MDD patients who exhibit inadequate response to SSRIs/SNRIs and present with more severe symptoms requiring rapid improvement. While the treatment demonstrated acceptable tolerability and safety profiles, the observed efficacy should be interpreted with caution and regarded as hypothesis-generating due to the lack of multiplicity adjustment. Further confirmatory randomized controlled trials are warranted to validate these findings. Funding: The study was supported by the STI2030-Major Projects (grant 2021ZD0202000), National Natural Science Foundation of China (grant 82201693 and 82471555), Hunan Provincial Natural Science Outstanding Youth Foundation (grant 2025JJ20093), Science and Technology Innovation Program of Hunan Province (grant 2024RC3057), Sanming Project of Medicine in Shenzhen (grant SZSM202311025), and Reboscience (Zhuhai) Pharmaceutical Research Co., Ltd., and sponsored by Livzon Pharmaceutical Group Inc.