A Phase 2, Randomized, Double-Blind, Placebo-Controlled Study of Adjunctive Pimavanserin in Patients With Major Depressive Disorder and an Inadequate Response to Therapy (CLARITY)

Abstract

Objective: Pimavanserin is a 5-hydroxytryptamine-2A antagonist and inverse receptor agonist. This phase 2 study examined 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 nonresponders were re-randomized to placebo or pimavanserin for an additional 5 weeks. Key endpoints were change from baseline to the end of each stage in 17-item Hamilton Depression Rating Scale (HDRS-17) total score and Sheehan Disability Scale (SDS) score. Results: Between December 2016 and October 2018, 207 patients were randomized. For the prespecified pooled Sequential Parallel Comparison Design analyses of Stages 1 and 2, the least squares (LS) mean (SE) difference for the HDRS-17 total score was −1.7 (0.85) (P = .039) and for the SDS score was −0.8 (0.29) (P = .004). At week 5 of Stage 1, LS mean (SE) difference for pimavanserin versus placebo was significant for changes on the HDRS-17 (−4.0 [1.09], P = .0003) and SDS (−1.2 [0.40], P = .0036) with effect sizes of 0.626 and 0.498, respectively. Early and sustained separation of pimavanserin from placebo (P < .05) occurred at 1 week. The most common adverse events with pimavanserin were dry mouth, nausea, and headache. Conclusions: Pimavanserin demonstrated robust efficacy in patients with MDD and an inadequate response to an SSRI or SNRI. Tolerability was consistent with previous experience. Trial Registration: ClinicalTrials.gov identifier: NCT03018340 J Clin Psychiatry 2019;80(6):19m12928 To cite: Fava M, Dirks B, Freeman MP, et al. A phase 2, randomized, doubleblind, placebo-controlled study of adjunctive pimavanserin in patients with major depressive disorder and an inadequate response to therapy (CLARITY).

Improvement of sexual functioning during treatment of MDD with adjunctive pimavanserin: A secondary analysis

“…In the primary study, 207 patients were randomized at 27 study sites between December 2016 and October 2018 (Figure 1). At baseline, treatment groups were generally comparable for demographic and clinical characteristics (Fava et al, 2019). A greater proportion of patients in the pimavanserin group had a HAMD‐17 total score ≥24 (40.4% vs. 32.3%) and a CGI‐S score of 5 (markedly ill) or 6 (severely ill; 48.1% vs. 38.7%).…”

“…A detailed description of the study methodology was previously published (Fava et al, 2019). In brief, this was a multicenter, randomized, double‐blind, and placebo‐controlled study in patients with MDD and inadequate responses to treatment with a SSRI or SNRI.…”

“…CLARITY was a randomized, double‐blind, and placebo‐controlled study that demonstrated robust efficacy of adjunctive pimavanserin in patients with MDD and an inadequate response to treatment with an SSRI or SNRI (Fava et al, 2019). Given the fact that pimavanserin acts as a potent inverse agonist at 5‐HT 2A receptors, and to a lesser extent at 5‐HT 2C receptors (Vanover et al, 2006), and that 5‐HT 2 antagonism has been shown to be helpful in the treatment of sexual dysfunction (Johnson‐Agbakwu, Brown, Yuan, Kissling, & Greenblatt, 2018; Stryjer et al, 2009), we conducted additional analyses from CLARITY to address (a) whether adjunctive pimavanserin augments or improves sexual functioning versus placebo; (b) if this effect is accounted for by changes in depression severity; and (c) if there are baseline factors that moderate the improvement in sexual function with pimavanserin.…”

Extending the Specificity of DRL 72-s Behavior for Screening Antidepressant-Like Effects of Glutamatergic Clinically Validated Anxiolytic or Antidepressant Drugs in Rats

“…Given the functional interactions in corticothalamic circuitry between 5-HT2A and mGlu2 receptors on DOI-induced head twitches and DRL 72-s behavior (Benneyworth et al, 2007;Gewirtz and Marek, 2000;Marek et al, 2001;Marek et al, 2000), we also tested the effects of LY354740 alone and together with the SSRI fluoxetine since 5-HT2A receptor antagonists enhance the antidepressant-like effects of fluoxetine or the tricyclic antidepressant desipramine (Marek et al, 2005;Ardayfio et al, 2008). These positive preclinical effects of 5-HT2A receptor antagonists and SSRIs have recently been translated to treatment-refractory patients with MDD (Fava et al, 2019). LY354740 failed to exert robust antidepressant-like effects when administered alone or even when administered in combination with selective serotonin reuptake inhibitor fluoxetine.…”

Effect of pimavanserin on anxious depression in patients with major depression and an inadequate response to previous therapy: secondary analysis of the clarity study

“…Pimavanserin is approved in the United States by the Food and Drug Administration for treating hallucinations and delusions in patients with Parkinson’s disease psychosis. In a phase 2, randomized, placebo-controlled study (CLARITY), adjunctive pimavanserin demonstrated a significant improvement of depressive symptoms in patients with MDD and an inadequate response to previous treatment ( Fava et al ., 2019 ). This was a post hoc analysis of CLARITY was undertaken to evaluate the effects of adjunctive pimavanserin vs. placebo in a subgroup of patients with MDD and a baseline score ≥7 on the six-item HAMD-17 anxiety/somatization factor.…”