Effects of zuranolone on next-day simulated driving in healthy adults.

Rationale: Zuranolone is an oral positive allosteric modulator of GABA _A receptors. Due to its central nervous system (CNS) activity, zuranolone may impact activities requiring complex cognition, including driving.
Objective: Evaluate the effect of zuranolone on simulated driving performance.
Methods: In this randomized, double-blind, active- and placebo-controlled, four-period crossover study, treatments included once-nightly zuranolone 50 mg on days 1-7, zuranolone 50 mg on days 1-6 and zuranolone 100 mg on day 7, zopiclone 7.5 mg on days 1 and 7, and placebo on days 1-7. Driving was assessed using a validated simulator. Primary endpoint was standard deviation of lateral position (SDLP), evaluated 9 h post-dose on days 2 and 8. Secondary endpoints included additional driving assessments, cognitive tests, pharmacokinetics, and safety.
Results: Healthy adults (N = 67) enrolled and received ≥ 1 dose. Zuranolone 50 mg increased SDLP versus placebo on days 2 (least squares mean difference [LSMD]: 7.4 cm; p < 0.0001) and 8 (LSMD: 4.6 cm; p = 0.0106). Zuranolone 100 mg evoked a larger increase in SDLP versus placebo on day 8 (LSMD 18.9 cm; p < 0.0001). Reduced performance in other driving assessments and cognition were observed with zuranolone 50 mg on day 2; many resolved by day 8. Despite the SDLP observations, most participants judged themselves capable of driving. Frequent adverse events (≥ 20%) were CNS-related; most were mild/moderate.
Conclusion: Zuranolone impaired simulated driving and reduced cognitive function versus placebo 9 h after administration. Although many impairments resolved after 7 days of dosing, driving remained impaired. These results may inform prescriber decision-making.
Competing Interests: Declarations. Ethical approval: This study was performed in accordance with the Declaration of Helsinki and is consistent with Good Clinical Practice guidelines according to the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use Harmonized Tripartite Guideline, as well as all applicable regulatory requirements. Consent to participate: All participants provided written informed consent. Competing interests: Joi Dunbar, Carrie Vaudreuil, Indrani Nandy, and Victor Ona are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options. Gaetano Morelli has no conflicts of interest to disclose. Rakesh Jain reports research funding from AbbVie, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda and participation on advisory boards for Adamas Pharmaceuticals; Alkermes; Corium; Eisai; Janssen; Lilly; Lundbeck; Merck; Neos Therapeutics; Neurocrine Biosciences; Otsuka; Pamlab; Pfizer; Sage Therapeutics, Inc.; Shire; Sunovion; Supernus; Takeda; Teva Pharmaceuticals; and Usona. Rakesh Jain also reports honoraria for speakers’ bureaus from AbbVie, Alkermes, Almatica, Axsome, Corium, Eisai, Intra-Cellular Therapies, Ironshore, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shire, Sumitomo Pharma, Sunovion, Takeda, Tris Pharma, and Viatris and consulting fees from AbbVie; Acadia; Adamas Pharmaceuticals; Alfasigma; Alkermes; Almatica; Axsome; Biogen Inc.; Boehringer Ingelheim; Cingulate; Corium; Eisai; Evidera; Impel Pharmaceuticals; Janssen; Lilly; Lundbeck; Merck; Neos Therapeutics; Neurocrine Biosciences; Osmotica Pharmaceuticals; Otsuka; Pamlab; Pfizer; Sage Therapeutics, Inc.; Shire; Sumitomo Pharma; Sunovion; Supernus; Takeda; Teva Pharmaceuticals; Transcend Therapeutics; and Viatris. Margaret K. Moseley and Seth Levin are employees of Biogen Inc. and may hold stock. Gary Kay is an employee of Cognitive Research Corporation and may hold stock.
(© 2024. The Author(s).)