Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial.
PMID 39394685 · Journal of psychopharmacology (Oxford, England) · 2024 · DOI 10.1177/02698811241282777
Authors: Joi Dunbar; David P Walling; Howard A Hassman; Rakesh Jain; Andy Czysz; Indrani Nandy; Victor Ona; Margaret K Moseley; Seth Levin; Paul Maruff
Abstract
Zuranolone is an oral, once-daily, 14-day treatment course approved for adults with postpartum depression in the United States. To assess cognitive effects, pharmacokinetics, and safety of zuranolone, alone or with alprazolam/ethanol. 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. 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. 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.
Humans; Alprazolam; Female; Adult; Male; Double-Blind Method; Cross-Over Studies; Ethanol; Cognition; Young Adult; Drug Interactions; Middle Aged; Adolescent
Cite
Joi Dunbar; David P Walling; Howard A Hassman; Rakesh Jain; Andy Czysz; Indrani Nandy; Victor Ona; Margaret K Moseley; Seth Levin; Paul Maruff. Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial. Journal of psychopharmacology (Oxford, England) (2024). PMID 39394685. DOI 10.1177/02698811241282777.