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There is evidence for nicotinic hypercholinergic mechanisms in depression. Clinical relationships between tobacco use and depression suggest important effects of nicotine in major depressive disorder (MDD). It has been hypothesized that cigarette smoking may exert antidepressant effects, presumably mediated through stimulation of nicotinic acetylcholine receptor systems. We compared the nicotinic antagonist, mecamylamine hydrochloride (MEC), with placebo as an augmentation strategy for patients with MDD who were refractory to selective serotonin reuptake inhibitor (SSRI) treatment.Twenty-one SSRI-treated subjects with MDD were randomized to MEC (up to 10 mg/d; n = 11) or placebo (PLO group; n = 10) during an 8-week trial. The primary outcome measure was the change in depressive symptoms assessed using the 17-item Hamilton Depression Rating Scale during the 8-week trial.There was a significant reduction in 17-item Hamilton Depression Rating Scale scores in the MEC versus PLO groups, as evidenced by a significant medication × time interaction (F1,19 = 6.47, P < 0.05). Five (45.5%) of 11 subjects in the active study medication group demonstrated a 50% or more decrease in depressive symptoms from baseline as compared with 1 (10%) of 10 subjects assigned to placebo medication, but this difference was not significant (P = 0.15; Fisher exact test). The primary side effects of MEC were constipation and orthostatic hypotension.These preliminary findings suggest that the nicotinic acetylcholine receptor antagonist, MEC, may have utility as an augmentation strategy for patients with SSRI-refractory MDD.