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Varenicline Augmentation in Depressed Smokers: An 8-Week, Open-Label Study

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 α4β2 partial agonist and α7 full agonist approved for smoking cessation. Studies of similar compounds have suggested evidence of antidepressant effects.

Method: 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.

Trial Registration: clinicaltrials.gov Identifier: NCT00525837

J Clin Psychiatry 2009;70(7):1026–1031. Online Ahead of Print March 24, 2009. doi:10.4088/JCP.08m4441

Received May 29, 2008; accepted Dec. 12, 2008. From the Mood Disorders Research Program, Butler Hospital, and the Department of Psychiatry and Human Behavior, The Warren Alpert Medical School at Brown University, Providence, R.I.

This study was supported entirely by internal, clinically generated funds at Butler Hospital.

Dr. Carpenter has received research support from the U.S. Department of the Interior, the U.S. Department of Defense, UCB Pharma, Sepracor, Pfizer, Cephalon, Cyberonics, and Medtronic; has been a consultant for Abbott, Bristol-Myers-Squibb, Cyberonics, Medtronic, Novartis, Pfizer, Wyeth, and Sepracor; and has received speaker honoraria from AstraZeneca, Pfizer, and Cyberonics. Dr. Price has received research support from the U.S. Department of the Interior, U.S. Department of Defense, UCB Pharma, Sepracor, Pfizer, Cephalon, Cyberonics, and Medtronic, and has received speaker honoraria from AstraZeneca and Jazz Pharmaceuticals. Dr. Tyrka has received research support from the U.S. Department of the Interior, U.S. Department of Defense, UCB Pharma, Sepracor, Pfizer, Cephalon, Cyberonics, and Medtronic. Drs. Philip and Whiteley have no interests to disclose.

Corresponding author and reprints: Lawrence H. Price, M.D., Butler Hospital, 345 Blackstone Blvd., Providence, RI 02906 (e-mail: Lawrence_Price_MD@Brown.edu).