At the conclusion of the 6-week treatment period, preliminary analyses suggested a greater trend toward improvement on subjective measures of insomnia compared with objective sleep measures.
A trial presented at the 2023 SLEEP Annual Meeting, held June 3-7, in Indianapolis, Indiana, demonstrated feasibility and potential benefits of pimavanserin (Nuplazid; Acadia Pharmaceuticals) in the treatment of post-traumatic stress disorder (PTSD)-associated insomnia. A larger, randomized trial is needed to further confirm these benefits.
Led by Laura Marsh, MD, Menninger Department of Psychiatry, Baylor College of Medicine, the pilot, open-label trial (NCT04188392) featured 6 adult veterans with chronic insomnia disorder and PTSD assessed over a period of 6 weeks. Participants completed 7 days of actigraphy monitoring and 2 consecutive in-lab polysomnograms pre-treatment. Primary outcomes were recruitment and retention rates, defined as the total number of individuals recruited into treatment and treatment completion rates, with a goal of 75% completion.
The cohort had a mean age of 35.3 (SD, 6.3) years, comprised of 2 (33.3%) females, 2 (33.3%) Black or African American, and 2 (33.3%) Hispanic individuals, recruited over 5.8 months. Two-thirds (66.7%) had comorbid depression and 1 individual had mild obstructive sleep apnea (OSA), as indicated by Apnea Hypopnea Index score of 5.6. At the conclusion of the 6-month period, all individuals completed treatment.
Among the patient cohort, Insomnia Severity Index (ISI) scores were in the severe range for 4 of 6 individuals (66.7%). Of note, there were no serious adverse events (AEs) or medication discontinuations because of AEs. Preliminary analyses revealed a greater trend toward improvement on subjective measures of insomnia compared with objective sleep measures.
Acadia is currently planning a placebo-controlled trial (NCT05441280) assessing the effect of pimavanserin as a potential treatment for PSTD-associated insomnia. The preliminary study, which has not begun recruitment, is expected to include 60 veterans with insomnia and PTSD who will receive either pimavanserin 34 mg or placebo at bedtime for 8 weeks, with sleep quality compared pre- and post-treatment. Veterans will also complete sleep studies and wear actigraphy watches to better interpret how pimavanserin impacts sleep.2
The trial’s primary outcome will be change in ISI over an 8-week period, while other secondary outcomes include Pittsburgh Sleep Quality Index and PTSD checklist for DSM-5. Enrolled individuals are expected to have insomnia frequency of 3 times per week, ISI scores of 15 (moderate insomnia), determined to have significant PTSD symptoms as per the PTSD Checklist (PCL-5). The trial will exclude those with a current or history of primary psychotic disorder, active suicidal or homicidal ideation, or current moderate or severe alcohol or cannabis use disorder.
Pimavanserin, a selective serotonin inverse agonist and antagonist prefertially targeting 5-HT2A receptors, was approved for the treatment of hallucinations and delusions associated with Parkinson disease psychosis by the FDA in April 2016.
In August 2022, the FDA issued a complete response letter to Acadia for its supplemental new drug application for pimavanserin in patients with AD psychosis. At the time, the agency noted that it could not approve the application as is, and recommended that Acadia conduct an additional trial in AD psychosis. The FDA did note that while the supportive phase 2 AD psychosis—Study-019 (NCT02035553)—data were significant, they are limited in their interpretability.3