A 67-year-old patient currently being treated for anxiety secondary to narcotic withdrawal was started on three anti-anxiety medications that were subsequently tapered to diazepam only. Because the patient also reported insomnia, we added controlled-release zolpidem (Ambien CR) 12.5 mg at bedtime. When the patient returned to the clinic, he reported relief of severe anxiety symptoms after taking the zolpidem in the morning (against our advice). Do any data support the use of zolpidem as an anxiolytic agent?
—Eric Busse and Shailendra K. Saxena, MD, PhD, Omaha

There are no data to support the use of zolpidem as an anxiolytic agent. In fact, some data suggest using zolpidem in this fashion exposes the patient to the risk of zolpidem dependence and withdrawal (J Psychopharmacol. 2003;17:131-135). However, the writers raise a fascinating question about zolpidem’s clinical effects, and there is every reason to believe that for some individuals, zolpidem has anxiolytic properties. To understand why this is so and why it is somewhat surprising requires a brief review of zolpidem’s activity at the GABAA receptor (J Clin Psychiatry. 2002;63:179-180). Zolpidem’s hypnotic activity results from its specific agonism at the a1 subunit of the GABAA receptor. Conventional benzodiazepines, such as diazepam, are relatively nonspecific in GABAA subunit binding. Their anxiolytic properties are mediated by agonism at the a2, a3, and a5 GABAA subunits (Proc Natl Acad Sci USA. 2005;102:915-920). Some have suggested that in humans, zolpidem may not be as specific to the a1 subunit specific as most preclinical data, which is based mainly on work with rodents, would suggest. Reports of zolpidem craving and dependence suggest that high doses may overcome specific a1 subunit binding and result in agonistic effects at other GABAA subunits. In an experiment using inhaled carbon dioxide to provoke anxiety, zolpidem produced anxiety reduction comparable to that of alprazolam (J Psychopharmacol. 2009;23:117-122). Thus, in the case presented here, zolpidem’s presumptive activity at a2, a3, and a5 GABAA subunits may have augmented the anxiolytic effect of diazepam. (Although both diazepam and zolpidem are cytochrome P-450 3A4 substrates, there is no pharmacokinetic interaction between them.)
—David Brody, MD, physician in charge, Psychiatric Outpatient Service, Beth Israel Medical Center, New York City (128-13)