According to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, only about a third of the patients with recurrent depression achieved remission by the end of the acute phase of antidepressant treatment. Many patients respond only partially to treatment, thus there is a clear need for strategies which can improve the effectiveness of conventional antidepressants.
In a phase 2 double-blind, placebo-controlled trial, Dr. Maurizio Fava and colleagues from the MGH Department of Psychiatry examined the efficacy of adjunctive treatment with pimavanserin in adults with major depressive disorder (MDD) in the CLARITY trial. Pimavanserin (marketed as Nuplazid by Acadia Pharmaceuticals) is an atypical antipsychotic which is FDA approved for the treatment of psychosis associated with Parkinson’s disease. Unlike other atypical antipsychotics, it is not a dopamine receptor antagonist and thus has a slightly different side effect profile.
In this study, 207 adults with MDD who had an inadequate response to antidepressant treatment with an SSRI or SNRI (mean age, 46.2 years; 72.9% women) were randomly assigned to receive augmentation with either pimavanserin (34 mg per day) or placebo.
This study used a sequential parallel comparison design. During the first stage, 52 participants received augmentation with pimavanserin and 155 received augmentation with placebo. Participants who did not respond to placebo during the first 5-week stage of treatment were randomly reassigned to receive either pimavanserin or placebo for the second 5-week treatment stage. The Hamilton Depression Rating Scale (HAMD-17) was used to measure the severity of depressive symptoms.
Fava and colleagues observed a significant reduction in total HAMD-17 scores in patients receiving pimavanserin compared to placebo in both stages of the study. Participants in the pimavanserin group during the first stage experienced highly significant improvements on the HAMD-17 at week 5 (difference = – 4.; P < .001). Primanserin separated from placebo by the end of the first week (difference = – 1.7; P = .04).
The most common adverse events with pimavanserin were dry mouth, nausea, and headache. Overall, adjunctive treatment with pimavanserin was well-tolerated and was associated with low discontinuation rates due to adverse events compared to placebo (1.2% vs. 3.2%).
This study indicates that pimavanserin may have antidepressant activity and could be a novel adjunctive treatment for patients who do not adequately respond to traditional antidepressant therapy. Other atypical antipsychotic agents, such as aripiprazole (Abilify) can be used to augment antidepressants; while pimavanserin is also an atypical antipsychotic agent, it has a unique pharmacological activity as a selective inverse agonist of the serotonin 5-HT2A receptor, but at the same time avoids interaction with dopamine receptors, which may yield a more attractive side effect profile.
ACADIAcadia Pharmaceuticals plans to continue with phase 3 studies beginning this year.
Fava M, Dirks B, Freeman MP, Papakostas GI, Shelton RC, Thase ME, Trivedi MH, Liu K, Stankovic S. 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). J Clin Psychiatry. 2019 Sep 24;80(6). Free Article
