Person:

Freeman, Marlene

ABSTRACT Objective: This was an analysis of pimavanserin, a 5-hydroxytryptamine 2A antagonist/inverse receptor agonist, on dysregulated sleep in patients with major depressive disorder (MDD) by DSM-5 criteria and an inadequate antidepressant response.

Methods: For this analysis of CLARITY, a Phase 2 study of adjunctive pimavanserin, sleep/wakefulness disturbances were measured with the sum of Hamilton Depression Rating Scale (HAMD) insomnia items (Items 4, 5, and 6) and the Karolinska Sleepiness Scale (KSS). Outcomes included change from baseline for HAMD insomnia score >3, correlation between the HAMD insomnia score and KSS, and change from baseline for the Sheehan Disability Scale (SDS) and Unproductive Days subscore in patients with a baseline KSS >6.

Results: The study was conducted between December 2016 and October 2018. At baseline, HAMD insomnia factor score >3 occurred in 76% with placebo and 85% with pimavanserin. The overall LS mean (standard error) weighted difference was -0.5 (0.32) with a 95% confidence interval (CI) -1.2 to, 0.1 (p=0.088) at Week 5. Improvement was observed with pimavanserin vs. placebo at Weeks 2, 3, and 4, with effect sizes of 0.370 to 0.524 (p<0.05). For KSS, the LS mean difference at Week 5 was -1.1 (0.30), 95% CI -1.7 to, -0.5 (p=0.0003; effect size: 0.627) for pimavanserin vs. placebo. Among those with a KSS >6 at baseline (n=120 placebo and n=42 pimavanserin), the LS mean difference in the SDS mean score at Week 5 was -1.1 (0.46), 95% CI -2.0 to, -0.2 (p=0.019; effect size: 0.442) for pimavanserin vs. placebo.

Conclusions: Adjunctive pimavanserin significantly improved sleep/wakefulness sleep disturbance during treatment of MDD, which was associated with greater improvement in function. This study was registered at clinicaltrials.gov: NCT03018340.

Key Words: insomnia, major depressive disorder, pimavanserin, sleep

Objective: Pimavanserin is a 5-hydroxytryptamine2A antagonist/inverse receptor agonist. In this Phase 2 study, we studied the efficacy and safety of pimavanserin as adjunctive therapy in patients with major depressive disorder (MDD). Methods: This was a multicenter, randomized, double-blind, placebo-controlled study in patients with DSM-5–defined MDD and an inadequate response to a selective serotonin reuptake inhibitor (SSRI) or serotonin-norepinephrine reuptake inhibitor (SNRI). Using a 2-stage sequential parallel-comparison design, patients were initially randomized in a 3:1 ratio to placebo or pimavanserin added to ongoing SSRI or SNRI therapy; at 5 weeks, placebo non-responders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage for the HAMD-17 total score and Sheehan Disability Score (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled SPCD analyses of Stages 1 and 2, the LS mean (standard error) difference for the HAMD-17 total was (-1.7 (0.85), p=0.039) and the SDS was (-0.8 (0.29), p=0.004). At Week 5 of Stage 1, LS mean (standard error) difference for pimavanserin vs. placebo was significant for changes on the HAMD-17 (-4.0 [1.09], p=0.0003) and SDS (-1.2 [0.40], p=0.0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (p<0.05) occurred at 1 week. Most common AEs with pimavanserin were dry mouth, nausea, and headache. Conclusion: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI/SNRI. Tolerability was consistent with previous experience.