Zolpidem increases GABA in depressed volunteers maintained on SSRIs

• Volunteers were on stable SSRIs for the treatment of major depressive disorder.
• Participants received an acute oral dose of the hypnotic zolpidem.
• Zolpidem elevated GABA in the anterior cingulate and thalamus.
• Zolpidem in the presence of SSRIs may have therapeutic effects in depression.

Individuals with major depressive disorder (MDD) often use hypnotics like zolpidem (Ambien®) to improve sleep in addition to their selective serotonin reuptake inhibitor (SSRI) regimen. SSRIs act in part to restore disrupted GABAergic activity, but benzodiazepines and related drugs have been shown to lower GABA in a way that may be counter to these therapeutic effects. The present within-subject, single-blind, placebo-controlled study measured changes in GABA in the anterior cingulate (ACC) and thalamus of volunteers maintained on SSRIs for the treatment of MDD (n=14) following zolpidem (10 mg) administration. In addition to neurochemical measurements obtained using proton magnetic resonance spectroscopy (1H MRS) at 4 T, a series of questionnaires were administered to assess subjective effects associated with acute zolpidem exposure. Zolpidem elevated GABA levels in both voxels of interest (P<0.05) in the depressed participants, which could imply normalization, given the lower baseline levels associated with depression. The subjective drug experience in the depressed cohort was similar to that reported previously by healthy volunteers, and no relationships existed between GABA increases and the observed behavioral effects. Aside from treating insomnia, using zolpidem in the presence of SSRIs may have some unidentified therapeutic effects for depressed individuals.