Varenicline Withdrawal-Induced Delirium With Psychosis

To the Editor: Varenicline has had promising results for smoking cessation but is associated with psychiatric side effects. As of August 2009, there have been several published reports of suspected varenicline-induced mania or psychosis (1–3), including one case of withdrawal-related hallucinations (4). Pfizer's website lists dissociation, disorientation, and abnormal thinking as possible adverse reactions. In 2008, the Federal Aviation Administration banned the use of varenicline for airline pilots and air traffic controllers because of a Food and Drug Administration (FDA) public health advisory and a report by the Institute for Safe Medication Practices describing psychosis and visual changes as possible side effects. In July 2009, the FDA mandated a boxed warning for the drug. This is the first case report of withdrawal-induced delirium.

"Ms. X," a 32-year-old woman with no pertinent psychiatric or medical history, presented after an acute-onset 1-week episode of altered mental status, agitation, anxiety, and global perceptual disturbance, which began within 2 days after abrupt discontinuation of varenicline. She had previously suffered irritability, mood swings, panic attacks, and insomnia that correlated with varenicline initiation in September 2007 for smoking cessation. She denied coincident drug use. Her family history was positive for bipolar disorder and schizophrenia in second-degree relatives.

Ms. X had taken varenicline only sporadically until late 2008, when she began taking 1 mg twice daily for 2 months. She discontinued the medication abruptly, secondary to ongoing insomnia that impaired her work function. During the following few days, she began to feel "strange," describing confusion, disorientation, and perceptual changes. While listening to music, she heard a "sinister, evil voice." She saw "movements in everything," including fractal patterns on the leaves of trees, and an uncomfortable intensity of color and contrast. She had tactile sensitivity to the point where to touch an object "made it feel like [her] skin and muscles were being ripped apart." Over the week, the sensory misperceptions improved, but her thoughts "felt too big," with associated depersonalization. Over the month, she received relief from benzodiazepines but had "irrational" fears, insomnia, and visual distortions, including objects looking "shiny," the ground appearing to move, or lights appearing "strobe-like." She continued to experience visual changes and memory deficits. Her complete blood count, electrolytes, liver function tests, ceruloplasmin levels, thyroid-stimulating hormone test, and ophthalmic consultation were all normal.

To our knowledge, this is the first report of varenicline-induced or withdrawal-induced delirium. Possible mechanisms include dopaminergic overstimulation secondary to agonism of the α₂β₄ nicotinic receptor in an individual with genetic vulnerability or rebound anticholinergic hallucinosis. Our findings support that a family history of bipolar disorder and/or schizophrenia may heighten the risk of adverse effects with varenicline, and close monitoring is indicated during discontinuation.