Clinical Edge

Summaries of Must-Read Clinical Literature, Guidelines, and FDA Actions

Impact of pimavanserin on anxious depression in patients with MDD

Key clinical point: Adjunctive pimavanserin is associated with a significant improvement in anxious depression in patients with major depressive disorder (MDD) and an inadequate response to previous therapy.

Major finding: Pimavanserin produced a significantly superior effect on the Hamilton depression rating scale (HAMD-17) anxiety/somatization (AS) factor score vs. placebo in stage 1 (P = .0003) and across stages 1 and 2 using prespecified weighting (P = .0166), but not in stage 2 (P = .980). At week 5 in stage 1, the least squares mean (standard error) difference between placebo and pimavanserin for the AS factor score was −1.5 (0.41; P = .0003; Cohen’s d effect size: 0.634).

Study details: In this post hoc analysis of the CLARITY randomized trial, patients with MDD were randomly assigned to receive placebo (n = 152) and pimavanserin (n = 51) in stage 1, and 29 patients each were rerandomized to pimavanserin or placebo in stage 2.

Disclosures: The study was supported by ACADIA Pharmaceuticals. The authors reported ties with various pharmaceutical companies.


“Anxiety commonly accompanies major depression and may adversely affect treatment efficacy. The 2019 CLARITY randomized trial reported that major depression refractory to ongoing SSRI/SNRI improved with pimavanserin augmentation. This post-hoc analysis reported that pimavanserin augmentation of previously ineffective SSRI or SNRI treatment improved anxiety and major depression in the subgroup of patients with anxious depression, and among patients with severe anxious depression.

Pimavanserin is an antagonist/inverse agonist of the 5-hydroxytryptamine2A (5-HT2A) and to a lesser extent, 5HT2c receptors. It has no dopaminergic activity. Pimavanserin is currently approved for treatment of Parkinson’s psychosis, and being studied for other indications.Rodent studies have reported that stimulation of 5HT2a and 5HT2c receptors increase anxiety, while their blockade appears anxiolytic. Thus, given this preclinical evidence for the role of 5HT2a/c in fear circuitry, and based on the antidepressant and anxiolytic efficacy of agomelatine, a melatonin agonist & 5HT2c antagonist, this preliminary evidence deserves further research, and may be new future treatment option for anxious depression.”

A Gita Ramamurthy, MD

Director, Psychiatry Consultation-Liaison Service


Papakostas GI et al. Int Clin Psychopharmacol. 2020;35(6):313-321. doi: 10.1097/YIC.0000000000000328.