Cognitive effects, pharmacokinetics, and safety of zuranolone administered alone or with alprazolam or ethanol in healthy adults in a phase 1 trial.
Level 2 - randomized trial
Randomized, double-blind, placebo-controlled crossover trial
PubMed 39394685 · doi:10.1177/02698811241282777
What was done
In a phase 1, two-part, two-period, randomized, double-blind, placebo-controlled crossover trial, healthy adults received zuranolone (50 mg once daily for 9 days) or placebo. Participants also received coadministered alprazolam (1 mg; Part A, N = 24), ethanol (0.7 g/kg in males, 0.6 g/kg in females; Part B, N = 25), or matching placebo on days 1, 5, and 9. Cognition was evaluated using a computerized battery, alongside pharmacokinetics and safety monitoring.
What was found
Zuranolone alone produced small-to-moderate cognitive decline compared to placebo (Cohen's |d| = 0.126–0.76). Coadministration with alprazolam (Cohen's |d| = 0.6–1.227) or ethanol (Cohen's |d| = 0.054–0.5) generally exacerbated cognitive impairment relative to zuranolone alone. Peak pharmacodynamic impairment occurred at approximately 5 hours and resolved by 12 hours post-dose. No pharmacokinetic interactions were detected, and adverse events were mostly mild to moderate with similar incidence across groups.
Why it matters
These findings establish that zuranolone exhibits additive central nervous system depressant effects when combined with other GABAergic substances like benzodiazepines and alcohol, informing clinical safety warnings and patient counseling.
Limits
The study was conducted in a small sample of healthy volunteers (total N = 49) rather than patients with postpartum depression. The abstract does not detail domain-specific cognitive test results, long-term outcomes, or exact adverse event rates.
Cited by
- supports Alcohol functions pharmacologically as a central nervous system depressant.