OBJECTIVE To assess possible antidepressant effects of varenicline augmentation in outpatients with treatment-resistant depressive disorders and nicotine dependence. BACKGROUND Varenicline is a nicotinic acetylcholine receptor alpha4beta2 partial agonist and alpha7 full agonist approved for smoking cessation. Studies of similar compounds have suggested evidence of antidepressant effects. METHODS Eighteen patients (aged 18 to 65 years) were recruited from a general psychiatric outpatient clinic. Inclusion criteria were (1) primary Axis I depressive disorder (DSM-IV-TR criteria), (2) a stable antidepressant or mood stabilizer regimen, (3) persistent depressive symptoms despite adequate treatment, and (4) current cigarette smoking with nicotine dependence. Patients received varenicline (started at 0.5 mg daily and titrated to 1 mg twice daily) in addition to stable doses of their regular psychotropic medications. Depression symptoms, side effects, clinical global impressions, anhedonia, daily cigarette consumption, and vital signs were assessed every 2 weeks for 8 weeks. Baseline and endpoint ratings were compared, and the relationship between mood improvement and smoking cessation was examined. The primary outcome variable was mean change score in depressive symptoms as assessed by the 16-item Quick Inventory of Depressive Symptomatology-Self-Report. The study was conducted between September 2007 and March 2008. RESULTS Fourteen patients (78%) completed the study; 4 discontinued due to side effects, including gastrointestinal effects (n = 3) and worsened mood/irritability (n = 1). Patients demonstrated significant improvement in depression at end point (p < .001), with significant improvement as early as week 2. Eight patients (44%) met criteria for categorical response, and 6 (33%) reached remission criteria; the overall effect size was large. All patients were interested in smoking cessation: 8 (44%) achieved abstinence and 9 (50%) had some reduction in smoking. Improvement in depressive symptoms was correlated with smoking cessation. There was no evidence of treatment-emergent suicidality. CONCLUSIONS Open-label varenicline augmentation was associated with significant improvement in mood in a small sample of outpatient smokers with persistent depressive symptoms. Larger, double-blind studies are needed to investigate potential antidepressant effects of varenicline augmentation. BACKGROUND clinicaltrials.gov Identifier: NCT00525837.