Varenicline is an alpha 4 beta 2 nicotinic receptor partial agonist with dopaminergic effects, approved for smoking cessation. In May 2008, the FDA updated the previous Public Health Advisory and required that all patients should be observed and report to their physicians immediately for any mood or behavior changes, or worsening of preexisting psychiatric illness, during or upon discontinuation of varenicline therapy.

A 48 year old married woman with a history of major depression. She was in antidepressant treatment with 100 mg/day sertraline for 2 years and was euthymic for last 18 months. She never had symptoms of mania or hypomania. She had no family history of psychiatric illness. She was given a prescription by her doctor for varenicline, by dosing titrated to 1-mg BID by day 8. On day 14, she stopped smoking, with no withdrawal symptoms. She had no mood or behaviour changes during 12-week treatment period. At the end of 12 weeks, she was admitted to hospital with the diagnosis of mania with psychotic features.

There are case reports of mania in the context of initiating varenicline treatment, but this is the first case, to our knowledge, of a patient developing mania upon discontinuation of varenicline therapy. In this case we can suspect varenicline withdrawal may have contributed to the emergence of mania; however, this has not been reported in the literature. Also it's possible that antidepressant-like properties of varenicline, may have potentiated the effect of sertraline and a manic shift occurred.