Varenicline-induced psychotic depressive episode in a patient with bipolar disorder

Introduction

The majority of smokers attempt cessation numerous times in their lives. Therefore, additional smoking-cessation options with newer and novel medications may contribute to increased success rates. Varenicline is a novel treatment for smoking cessation. This agent is a partial agonist that binds at the nicotinic α4β2 receptor, and it seems to be the most effective smoking-cessation product currently available [Cahill et al. 2009]. As a partial agonist, varenicline produces low to moderate levels of dopamine release, which reduces craving and withdrawal symptoms. In addition, varenicline stimulates the central nervous mesolimbic dopamine system. This system is believed to be involved in the reinforcement and reward neuronal mechanism associated with smoking. As it acts on the central nervous system and its effects include the stimulation of dopamine release, it is possible that it may have an impact on mood and suicide risk [Hughes, 2008; Hays and Ebert, 2003].

Increased neuropsychiatric symptoms such as depressed mood, agitation, and suicidal ideation and behavior have been reported with the use of varenicline. As a result, the FDA added a black box warning in 2009 to alert physicians and patients about these risks [FDA, 2008]. Persons with a psychiatric history might be particularly vulnerable to these side effects, but empirical evidence is limited [Kuehn, 2009]. It is also unclear whether varenicline is equally effective among persons with and without a psychiatric history.

Although not all reported cases about the side effects of varenicline had a psychiatric history, some reports in the current literature have shown exacerbation of symptoms or recurrence of pre-existing psychiatric disorder in those patients who had a psychiatric history [DiPaula and Thomas, 2009].

In this paper, we report the development of a psychotic depressive episode after using varenicline for smoking cessation in a patient with the diagnosis of bipolar disorder.

Case presentation

A 47-year-old male was admitted to our psychiatry outpatient clinic with the symptoms of insomnia, agitation, and suicidal ideations during the last 4 days before his admission. His initial examination revealed paranoid ideas about his wife’s deception. He was arguing with his wife and was trying to keep her in their house. He was repeatedly calling his siblings due to his ideas and feelings that bad things might happen to them. He had been suffering from severe insomnia during the previous 4 days. He also described suicidal ideas racing in his mind. He did not attempt any suicide during this period. The patient described that his complaints had acutely begun after an increase in the daily dose of oral varenicline tablets which was prescribed to him 10 days before by a smoking cessation clinic. He was prescribed 1 mg/day varenicline in the first week of his treatment, and then the dose was increased to 2 mg/day. Thus, he had been using 2 mg/day oral varenicline tablet for the last 3 days when he first presented to our psychiatry outpatient clinic. During the initial days, the patient’s tobacco consumption dropped from 25 to 10 cigarettes/day. However, he had started to experience mild agitation. Other psychiatric symptoms such as insomnia, paranoid ideas and suicidal ideas had emerged on day 7.

His past psychiatric history revealed the diagnosis of bipolar disorder for the last 25 years. His first episode was depressive which necessitated hospitalization. Then he was treated for 12 manic or hypomanic episodes and 7 depressive episodes until his admission. His last episode was 3 years ago, depressive in nature and he had responded well to 400 mg/day oral amisulpirid. He was under 200 mg/day oral amisulpirid treatment when he was admitted to our clinic. He had a cousin who committed suicide in his twenties most probably due to a depressive episode. His medical history was nonsignificant.

In his mental state examination he was oriented to time, person, and place. His associations were slow, however, psychomotor agitation was easily recognized. His thought content included paranoid, depressive, and suicidal ideas. He was apparently dysphoric during his interview.

In light of all of the available data presented above, the patient was diagnosed with bipolar disorder (current episode is depression with psychotic features) according to the DSM-IV diagnostic criteria. Then, varenicline was immediately stopped because it was considered as a triggering and maintaining factor in the current episode of the patient. He was prescribed 600 mg/day dose of quetiapine extended release oral tablets. All psychiatric symptoms and signs of the patient significantly improved within 3 weeks after quetiapine treatment. He is still under 300 mg/day dose of the same treatment.

Discussion

The onset of psychotic depression in this patient after initiation of varenicline treatment for smoking cessation certainly suggests that varenicline has the capacity to induce depression and psychosis at least in patients with a history of mood disorders. This has been reported in another patient with a documented history of bipolar disorder [Kohen and Kremen, 2007; Pumariega et al. 2008]. Possible mechanisms include dopaminergic stimulation secondary to agonism of the α4β2 nicotinic receptor.

Since the approval of varenicline in May 2006, postmarketing surveillance of it suggests an association between varenicline and increased risk of erratic behavior, agitation, suicidal attempt, depression, psychosis, and severe injuries [Williams et al. 2007]. Some of the behavioral changes and mood changes seen in patients who use varenicline may be associated with nicotine withdrawal. However, some occurred in people who continued smoking while they were on varenicline medication [Xi, 2010].

Although clinician and patient reports of adverse events associated with varenicline suggest the possibility of serious side effects, controlled studies are required to quantify the degree of risk, distinguish the side effects of varenicline from the effects of smoking cessation [Gunnell et al. 2009].

The risk for psychiatric side effects from varenicline could be greatly diminished by screening for family history and past history of serious mood disturbance in individuals who are candidates for its use in smoking cessation [Pumariega et al. 2008].

Smoking rates are particularly pronounced among persons with a history of anxiety, depression, bipolar disorder, and psychotic disorder [Ziedonis et al. 2008]. Providing effective cessation treatment to these individuals is important, but there are limited data on the effectiveness of cessation treatments among persons with these conditions [Hall and Prochaska, 2009].

There may be some explanations for the exacerbation of psychotic depression in our patient. First, it is well known that increased dopaminergic activity in the brain plays a crucial role in the etiology of psychotic episodes seen in bipolar disorder [Cousins et al. 2009]. Varenicline, with its partial agonistic effect on nicotinergic receptors, stimulates the release of multiple neurotransmitters including dopamine [Benowitz, 2007]. It also increases the release of dopamine from nucleus accumbens. Dopamine dysregulation is probably responsible for the development of neuropsychiatric adverse reactions due to varenicline. Second, our patient was also taking lower doses of amisulpride for the last 3 years. Amisulpride, at low doses, has the potential to block presynaptic dopamine autoreceptors which consequently lead to the frontotemporal dopamine release [Scatton et al. 1997]. When considered together, our patient was under low-dose amisulpride treatment when he started varenicline treatment. Thus, one may think that both agents would have contributed to an increase in dopaminergic activity in the brain of our patient which biologically underlined the development of a depressive episode with psychotic features in our patient.

This case report provides valuable support of reviously published cases that demonstrate the risk of exacerbation of psychotic symptoms and depression with varenicline use in patients with severe mental illness. With proper assessment and management of varenicline-induced neuropsychiatric effects, healthcare professionals can provide an important role in helping to prevent and manage worsening psychiatric symptoms.