Adjunctive pimavanserin was associated with a significant improvement in anxious depression in patients with major depression who didn’t respond to previous therapy, according to a secondary analysis of the CLARITY study published in the International Clinical Psychopharmacology journal.

Pimavanserin is a potential 5-hydroxytryptamine2A (5-HT2A) receptor antagonist/inverse agonist approved in the United States for treating hallucinations and delusions in patients with Parkinson disease psychosis. The researchers conducted a post-hoc analysis to evaluate the drug’s effects on anxious depression.

The researchers evaluated data from the CLARITY study, a randomized, double-blind, placebo-controlled study in patients with major depression and an inadequate response to previous therapy.

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In the post-hoc analysis, pimavanserin produced a significantly greater effect on the HAMD-17 anxiety/somatization factor score vs. placebo in stage 1 (P = .0003) and across stages 1 and 2 using prespecified weighting (P = 0.0166), but not in stage 2 (P = .980). At week 5 in stage 1, the LS mean (SE) difference between placebo and pimavanserin for the anxiety/somatization factor score was −1.5 (0.41) (95% CI −2.4 to −0.7; P = .0003; Cohen’s d effect size: 0.634).

Anxiety was reported as an adverse event in stage 1 of the CLARITY study in two patients (1.3%).

Limitations include the fact that the study’s post-hoc design was not specified in the original analyses. The researchers also worked with a small sample size, and patients with comorbid anxiety were not prospectively identified.

“Ongoing phase 3 studies, with adjunctive pimavanserin in patients with major depressive disorder, will provide a larger population of patients in which the occurrence of anxious depression and the response to pimavanserin can be examined further,” the researchers concluded.

Disclosure: Several study authors declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Papakostas GI, Fava M, Freeman MP, Shelton RC, Thase ME, Jha MK, et al. Effect of pimavanserin on anxious depression in patients with major depression and an inadequate response to previous therapy: secondary analysis of the clarity study. Int Clin Psychopharmacol. 2020 Nov;35(6):313-321.