Clinical Edge

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No increased risk of suicide with pimavanserin in patients with MDD

Key clinical point: Adjunctive pimavanserin is not associated with an increase in suicidal ideation in patients with major depressive disorder (MDD).

Major finding: During stage I, Hamilton Depression Rating Scale item 3 (suicide) score was significantly reduced with pimavanserin vs. placebo from baseline at week 3 (effect size, 0.431; P = .012). Changes from baseline in the Columbia-Suicide Severity Rating Scale did not indicate any increase in suicidality with pimavanserin vs. placebo (stage I: 17.3% vs. 18.1%; stage II: 13.8% vs. 20.7%). No adverse events consistent with suicidal behavior were reported.

Study details: The findings are based on a secondary post hoc analysis of the CLARITY randomized trial involving 207 patients with MDD.

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


"This paper is a post hoc analysis of a trial where pimavanserin, a 5HT-2a serotonin receptor inverse agonist/antagonist and to a lesser extent at 5HT-2c receptors, was used off-label to investigate its ability to perform as an augmentation strategy for depressives who failed to remit on SSRI or SNRI antidepressants. The main study showed it was effective in treating depression and this secondary analysis showed no worsening of suicidal side effect symptoms. This analysis is important as the FDA has a black box warning for US antidepressants in this area. Mechanistically, in the case of depression management, we are capitalizing on the typical antidepressant properties afforded to us by the sedating antidepressants (trazodone, nefazodone, and mirtazapine) where antagonizing these two receptors affords improvement in restorative slow wave sleep, lowering of activating serotonergic side effects and promoting glutamate, dopamine and norepinephrine down stream in the CNS which may keep side effects low and promote better efficacy after augmentation. Additionally, this augmentation strategy seems to invoke less sedation and metabolic side effects compared to the more commonly used sedating antidepressants. Future comparative studies may be warranted."

Thomas L. Schwartz, MD
Senior Associate Dean of Education, Interim Chair/Professor of Psychiatry
SUNY Upstate Medical University


Shelton RC et al. J Affect Disord. 2020 Aug 26. doi: 10.1016/j.jad.2020.08.051.