Adjunctive pimavanserin brought clinically meaningful improvement in patients with anxious major depressive disorder inadequately responsive to standard antidepressants alone in a post hoc analysis of the CLARITY trial, Bryan Dirks, MD, reported at the virtual congress of the European College of Neuropsychopharmacology.
This is an intriguing observation, because it’s estimated that roughly 50% of individuals with major depressive disorder (MDD) have comorbid anxiety disorders or a high level of anxiety symptoms. Moreover, anxious depression has been associated with increased risk of suicidality, high unemployment, and impaired functioning.
CLARITY was a phase 2, multicenter, randomized, double-blind, placebo-controlled clinical trial whose positive results for the primary outcome have been published (J Clin Psychiatry. 2019 Sep 24;80[6]:19m12928. doi: 10.4088/JCP.19m12928). Because the encouraging findings regarding pimavanserin’s impact on anxious depression came from a post hoc analysis, the results need replication. That’s ongoing in a phase 3 trial of adjunctive pimavanserin versus placebo in patients with MDD, according to Dr. Dirks, director of clinical research at Acadia Pharmaceuticals, San Diego.
The CLARITY post hoc analysis included 104 patients with baseline MDD inadequately responsive to an SSRI or a serotonin norepinephrine reuptake inhibitor and anxious depression as defined by a Hamilton Depression Rating Scale (HAMD-17) anxiety/somatization factor subscale score of 7 or more. Twenty-nine of the patients were randomized to 34 mg of adjunctive oral pimavanserin once daily, and 75 to placebo. At 5 weeks, the HAMD-17 anxiety/somatization factor score in the pimavanserin group had dropped by a mean of 5 points from a baseline of 8.8, a significantly greater effect than the 2.8-point drop in placebo-treated controls.
By week 5, the treatment response rate as defined by at least a 50% reduction in HAMD-17 total score from baseline was 55% with pimavanserin and 22% with placebo. The remission rate as indicated by a HAMD-17 total score below 7 was 24% in the pimavanserin group, compared with 5% with placebo. These results translated into an effect size of 0.78, considered by statisticians to be on the border between medium and large. Those response and remission rates in patients with anxious depression were higher with pimavanserin and lower with placebo than in the overall CLARITY trial.
as defined by a HAMD-17 total score of 24 or more plus an anxiety/somatization factor score of 7 or greater. Seventeen such patients were randomized to adjunctive pimavanserin, 36 to placebo. At 5 weeks, the mean HAMD total score had dropped by 17.4 points from a baseline of 27.6 in the pimavanserin group, compared with a 9.3-point reduction in controls.
“Of note, significant differences from placebo were observed as early as week 2 with pimavanserin,” Dr. Dirks said.
Pimavanserin is a novel selective serotonin inverse agonist with a high affinity for 5-HT2A receptors and low affinity for 5-HT2C receptors. At present pimavanserin is Food Drug Administration–approved as Nuplazid only for treatment of hallucinations and delusions associated with Parkinson’s disease psychosis, but because of the drug’s unique mechanism of action it is under study for a variety of other mental disorders. Indeed, pimavanserin is now under FDA review for a possible expanded indication for treatment of dementia-related psychosis. The drug is also under study for schizophrenia as well as for MDD.
The CLARITY trial and this post hoc analysis were sponsored by Acadia Pharmaceuticals.
SOURCE: Dirks B. ECNP 2020. Abstract P 094.