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Clinical Trial
. 2024 Dec;38(12):1122-1136.
doi: 10.1177/02698811241282777. Epub 2024 Oct 11.

Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial

Joi Dunbar  1 , David P Walling  2 , Howard A Hassman  3 , Rakesh Jain  4 , Andy Czysz  1 , Indrani Nandy  1 , Victor Ona  1 , Margaret K Moseley  5 , Seth Levin  5 , Paul Maruff  6
Affiliations
Clinical Trial

Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial

Joi Dunbar et al. J Psychopharmacol. 2024 Dec.

Abstract

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.

Keywords: Cognitive measures; GABAA receptor; drug–drug interaction; postpartum depression; zuranolone.

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Conflict of interest statement

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.

Figures

Figure 1.
Figure 1.
Study design. Note: Participants enrolled in Part A received alprazolam and those in Part B received ethanol. Alprazolam 1 mg, ethanol (males: 0.7 g/kg; females: 0.6 g/kg), or matching placebo was administered as a single dose on days 1, 5, and 9 in each period.
Figure 2.
Figure 2.
Time course of the mean (SD) change from baseline for the Cogstate battery—Part A. (a) Detection test (psychomotor function), (b) identification test (simple attention), (c) One Card Learning test (visual episodic memory), (d) International Digit Symbol Substitution Test (processing speed), and (e) Groton Maze Learning test (executive function). SD: standard deviation; tmax: time to reach maximum observed concentration after dosing. aTime of zuranolone or placebo administration (baseline (0 h)). bTime of alprazolam administration (4 h).
Figure 3.
Figure 3.
Time course of the mean (SD) change from baseline for the Cogstate battery—Part B. (a) Detection test (psychomotor function), (b) identification test (simple attention), (c) One Card Learning test (visual episodic memory), (d) International Digit Symbol Substitution Test (processing speed), and (e) Groton Maze Learning test (executive function). SD: standard deviation; tmax: time to reach maximum observed concentration after dosing. aTime of zuranolone or placebo administration (baseline (0 h)). bTime of ethanol administration (4.5 h).
Figure 4.
Figure 4.
Effect size for the treatment difference at the 5-h time point. (a) Part A (zuranolone with and without alprazolam) and (b) Part B (zuranolone with and without ethanol). Note: Effect size, based on Cohen’s d; d < 0 signals impairment for all cognitive tests. |d| < 0.2 considered trivial, 0.2–0.5 small, >0.5–0.8 moderate, and >0.8 large.
Figure 5.
Figure 5.
Mean (SD) zuranolone, alprazolam, and ethanol concentrations versus time. Error bars indicate SD. (a) Zuranolone (Part A), (b) zuranolone (Part B), (c) alprazolam (Part A), and (d) ethanol (Part B). SD: standard deviation.
Figure 6.
Figure 6.
MOAA/S. Day 5 and 9 data. (a) Part A and (b) Part B. Score responsiveness: 5 Responds readily to name spoken in normal tone; 4 Lethargic response to name spoken in normal tone; 3 Responds only after name is called loudly and/or repeatedly; 2 Responds only after mild prodding or shaking; 1 Responds only after painful trapezius squeeze; 0 No response after painful trapezius squeeze. Times are reported relative to baseline (i.e., zuranolone administration), which correspond to 1, 2, 4, 8, and 20 h following alprazolam dosing and 0.5, 1.5, 3.5, 7.5, and 19.5 h following ethanol dosing. MOAA/S: Modified Observer’s Assessment of Alertness/Sedation.
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