To The Editor: We report a case of a manic episode in a patient with a history of bipolar disorder who was started on varenicline for smoking cessation. The case raises the possibility of inducing a manic episode with varenicline and using caution when prescribing it to patients with bipolar disorder.
A 63-year-old man with a history of bipolar disorder had been stable while receiving valproic acid for 5 years. The patient was admitted to an inpatient psychiatric unit and met criteria for a manic episode. He began exhibiting manic symptoms one week after starting varenicline (1 mg, twice daily) for smoking cessation. There was reported compliance with valproic acid, and his level on admission was 59.7. The patient had a negative urine drug screen; all other laboratory studies were normal. There were no other changes in his medication regimen, and he did not smoke cigarettes while on varenicline or after his admission to the hospital.
Varenicline was discontinued upon admission. The patient continued receiving valproic acid, up to a dose of 2 g per day. He was also started on olanzapine, up to 10 mg daily at bedtime. Within one week of admission, the patient was euthymic, without psychotic or manic symptoms.
Varenicline was approved by the Food and Drug Administration (FDA) in 2006 for smoking cessation. Varenicline binds with high affinity and selectivity at alpha4beta2 neuronal nicotinic acetylcholine receptors. Its efficacy is the result of its activity at a subtype of the nicotinic acetylcholine receptor, where its binding produces agonist activity while simultaneously preventing nicotine binding to the alpha4beta2 receptors. During abstinence, varenicline stimulates low-level dopamine release by binding to alpha4beta2 receptors located on dopamine neurons (1).
Agitation, aggression, and mood swings were reported as infrequent psychiatric adverse reactions in the preclinical studies for FDA approval of verenicline. In addition, euphoric mood, agitation, and psychosis were reported as rare psychiatric adverse reactions.
Several studies have shown that centrally active cholinergic agonists possess antimanic properties. Imbalance in cholinergic and adrenergic tone has been postulated in the pathophysiology of bipolar disorder, with relative cholinergic hypoactivity being implicated in the pathophysiology of mania (2). The release of catecholamines, such as dopamine, was likely related to the induction of mania in our patient.
Due to the high rate of smoking in bipolar disorder patients, smoking cessation agents may be used in a great number of patients with the disorder. However, our findings suggest a possible link between the onset of manic symptoms and treatment with varenicline in a patient with bipolar disorder. In this case, there was a temporal relationship between the beginning of therapy and the onset of symptoms. There were no other medication changes in our patient’s regimen. A MEDLINE literature search revealed no case reports or studies regarding manic symptoms with varenicline. Our case highlights the need to use caution when prescribing the drug to patients with bipolar disorder.
1.Coe JW, Brooks PR, Vetelino MG, Wirtz MC, Arnold EP, Huang J, Sands SB, Davis TI, Lebel LA, Fox CB, Shrikhande A, Heym JH, Schaeffer E, Rollema H, Lu Y, Mansbach RS, Chambers LK, Rovetti CC, Schulz DW, Tingley FD 3rd, O"Neill BT: Varenicline: An alpha4beta2 nicotinic receptor partial agonist for smoking cessation. J Med Chem 2005; 48:3474–3477
2.Janowsky DS, Overstreet DH: Acetylcholine and mood disorders, in Psychopharmacology: The Fourth Generation of Progress Bloom. Edited by Bloom FE, Kupfer DJ. New York, Raven Press 1995, p 946
The authors report no competing interests.
This letter (doi: 10.1176/appi.ajp.2007.07010173) was accepted for publication in March 2007.