Search

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).)

Background: Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States., Aims: To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol., Methods: This was a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial. Participants received zuranolone 50 mg or placebo once daily for 9 days, and additionally received alprazolam (1 mg, Part A), ethanol (males: 0.7 g/kg; females: 0.6 g/kg, Part B), or corresponding placebo on days 1, 5, and 9. Within each part, participants received all treatment combinations. Cognition was assessed using a computerized test battery; pharmacokinetics and safety were also evaluated., Results: All participants (Part A, N  = 24; Part B, N  = 25) received ⩾1 dose of zuranolone/placebo. Compared to placebo, zuranolone produced small-to-moderate cognitive decline (Cohen's | d | = 0.126-0.76); effects were larger with alprazolam (Cohen's | d | = 0.523-0.93) and ethanol (Cohen's | d | = 0.345-0.88). Zuranolone coadministration with alprazolam (Cohen's | d | = 0.6-1.227) or ethanol (Cohen's | d | = 0.054-0.5) generally worsened cognitive decline when compared with zuranolone alone. Maximal pharmacodynamic effects occurred at approximately 5 h and were resolved by 12 h postbaseline. No pharmacokinetic interactions were observed. Incidence of adverse events was similar between groups; most events were mild or moderate in severity., Conclusion: A general small-to-moderate magnitude decline in cognition occurred with zuranolone alone. Coadministration with alprazolam/ethanol increased the magnitude, but not the duration, of effects compared with single-agent administration. Zuranolone prescribers and patients should be aware of the potential for increased central nervous system-depressant effects if coadministered with GABAergic active compounds such as alprazolam and ethanol., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: David P Walling has received grants or contracts from Acadia, Alkermes, Allergan, Avanir, Biogen, Boehringer Ingelheim, Cerevel, Indivior, IntraCellular, Janssen, J&J PRD, Karuna, Lundbeck, Lupin, Lyndra, Merck, Neurocrine, Novartis, Noven, Otsuka, Pfizer, Roche, Sage, Sunovion, Takeda; and consulting fees from Biogen, Boehringer Ingelheim, Janssen, Lyndra, Merck, and Otsuka.Howard A Hassman is a current employee of CenExel Hassman Research Institute, an independent research site that conducts investigator-initiated and industry-sponsored pharmaceutical trials. He has no conflicts of interest or bias in the conclusions of the current investigation or promotion of the current study results.Paul Maruff is an employee of Cogstate Ltd. and may hold stock and/or stock options.Rakesh Jain reports research funding from AbbVie, Lilly, Lundbeck, Otsuka, Pfizer, Shire, and Takeda; participation on advisory boards for Adamas, Alkermes, Corium, Eisai, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Otsuka, Pamlab, Pfizer, Sage, Shire, Sunovion, Supernus, Takeda, Teva, and Usona; honoraria for speakers’ bureaus from AbbVie, Alkermes, Almatica, Axsome, Corium, Eisai, Intra-Cellular Therapies, Ironshore Pharmaceuticals, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Otsuka, Pamlab, Pfizer, Shire, Sumitomo, Sunovion, Takeda, Tris Pharmaceuticals, and Viatris; and consulting fees from AbbVie, Acadia, Adamas, Alfasigma, Alkermes, Almatica, Axsome, Biogen, Boehringer Ingleheim, Cingulate Therapeutics, Corium, Eisai, Evidera, Impel, Janssen, Lilly, Lundbeck, Merck, Neos Therapeutics, Neurocrine Biosciences, Osmotica, Otsuka, Pamlab, Pfizer, Sage, Shire, Sumitomo, Sunovion, Supernus, Takeda, Teva, Transcend Therapeutics, and Viatris.Andy Czysz was an employee of Sage Therapeutics, Inc., at the time that the study was completed, and may hold stock and/or stock options.Indrani Nandy, Victor Ona, and Joi Dunbar are employees of Sage Therapeutics, Inc., and may hold stock and/or stock options.Margaret K Moseley and Seth Levin are employees of Biogen Inc. and may hold stock.