Adjunctive Perospirone Safe, Well-Tolerated for MDD in Phase 4 Trial

Phase 4 data demonstrated the tolerability and safety of perospirone as an adjunctive treatment for patients with major depressive disorder (MDD) across 8 weeks. The study also displayed the efficacy of perospirone for this indication, though investigators noted that this observation should be interpreted with caution.

“…despite the lack of clear evidence supporting significant improvement in the primary outcome, the observed trend toward improved treatment outcomes and the significant rapid-onset effect suggest that early adjunctive perospirone (initiated after 4 weeks of treatment with SSRIs/SNRIs) may be a viable option for patients with MDD who exhibit inadequate response to antidepressants,” wrote study investigator Jin Liu, from the National Clinical Research Center for Mental Disorder and National Center for Mental Disorders at The Second Xiangya Hospital of Central South University in China, and colleagues.

In this phase 4 randomized, double-blind, placebo-controlled trial, investigators sought to assess the efficacy, safety, and tolerability of perospirone as an adjunctive therapy in patients with moderate-to-severe MDD, defined by a baseline Montgomery-Åsberg Depression Rating Scale score of ≥ 20. The primary outcomes included response (≥ 50% reduction in the MADRS score) and remission (MADRS score ≤ 10) at week 8.

Investigators conducted the study across 10 Chinese hospitals between December 16, 2021, and June 19, 2024. The study included 210 participants who began perospirone 4 weeks after antidepressant treatment. Participants either had an inadequate response to serotonin norepinephrine reuptake inhibitors (SNRIs) or selective serotonin reuptake inhibitors (SSRIs), indicated by < 50% reduction in the total MADRS score after receiving ≥ 1 antidepressant at an adequate dose for 4 weeks.

The study randomized participants 1:1 to receive perospirone (perospirone + SSRIs/SNRIs; n = 108) or placebo (placebo + SSRIs/SNRIs; n = 102) for 8 weeks. Treatment was administered 1 or 2 times a day, initially at a dose of 4–8 mg/day and then at a maintenance dose of 12–48 mg/day. The dose depended on symptom severity and patient tolerance.

More patients in the perospirone arm achieved remission at week 8 than patients in the placebo arm (55.2% vs. 38.9%, odds ratio [OR] 1.944; 95% confidence interval [CI]: 1.060 – 3.564; P =.032). However, the perospirone and placebo arms had a comparable clinical response (67.8% vs. 60.0%; OR, 1.406; 95% CI, 0.759 – 2.605, P =.28)

“The high placebo response rate (>40.0%) may have contributed to the attenuated drug-placebo difference, as evidenced by previous studies on MDD,” investigators wrote. “This may be attributed to the inclusion of delayed responders, who exhibited inadequate early improvement yet demonstrated progressive improvement over time in the absence of active intervention…the high incidence of AEs in the placebo group (40.2%) might have prompted patients to perceive themselves as receiving active treatment, regardless of the actual treatment allocation; this expectancy effect could have potentiated the placebo response. Therefore, the lack of significant benefit may not necessarily indicate therapeutic inefficacy but could instead reflect an overestimation of the placebo effect.”

However, since investigators observed a nonsignificant difference between perospirone and placebo in response, they said the efficacy findings should be interpreted with caution and viewed as “hypothesis-generating” because the analyses did not account for multiple comparisons.

“This multi-center, randomized, double-blind, placebo-controlled trial provides the first preliminary evidence for early perospirone adjunctive therapy in MDD patients with inadequate response to antidepressants,” investigators wrote. “The findings suggest that 8 weeks of adjunctive therapy with perospirone may confer potential benefits in improving treatment outcomes, with favorable safety and tolerability profiles.”

References

Liu J, Gao S, Liu B, et al. Efficacy and safety of perospirone as adjunctive therapy in major depressive disorder patients with inadequate response to antidepressants: a randomized clinical trial. The Lancet. Volume 90,103626. https://www.thelancet.com/journals/eclinm/article/PIIS2589-5370%2825%2900560-7/fulltext