A 55-year-old woman is started on zolpidem 10 mg for insomnia. After 3 months she complains of complex sleep-related behaviours (sleep-driving, preparing food with no recall) and next-day cognitive impairment. What is the pharmacological mechanism of these adverse effects?
- A Selective α1 subunit modulation causing hypnosis without amnesia or complex behaviours
- B Non-selective benzodiazepine receptor agonism at GABA-A receptors containing α1, α2, and α3 subunits ✓
- C Orexin receptor antagonism causing excessive REM sleep rebound
- D Histamine H1 blockade causing residual sedation only
Explanation
Zolpidem is a non-benzodiazepine GABA-A receptor positive allosteric modulator (Z-drug). Although classically described as preferentially binding α1-containing GABA-A receptors (sedation/hypnosis), at higher doses or with individual pharmacokinetic variation (reduced first-pass metabolism in women — hence the FDA halved the recommended dose to 5 mg in women in 2013) it binds α2 and α3 subunits, producing amnesia and complex sleep behaviours (parasomnias: sleep-driving, sleep-eating, sleep sex) that are not recalled on waking. Orexin receptor antagonists (suvorexant) promote physiological sleep by blocking wakefulness-promoting signals and carry a different side effect profile.
Reference: Kaplan & Sadock's Synopsis of Psychiatry, 11th ed.
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