CNS Spectr. 2008;13(6):511-514

Faculty Affiliations and Disclosures

Dr. Pumariega is chair of the Department of Psychiatry at The Reading Hospital and Medical Center in West Reading, Pennsylvania, and professor of psychiatry and behavioral sciences in the Department of Psychiatry and Behavioral Sciences at Temple University School of Medicine in Philadelphia, Pennsylvania. Dr. Nelson is attending psychiatrist in the Department of Psychiatry at The Reading Hospital and Medical Center, partner at DGR and Associates in Wyomissing, Pennsylvania, and clinical assistant professor in the Department of Psychiatry at the Philadelphia College of Osteopathic Medicine. Dr. Rotenberg is a consultant in the Department of Psychiatry at The Reading Hospital and Medical Center and professor of psychiatry and behavioral sciences in the Department of Psychiatry and Behavioral Sciences at Temple University School of Medicine.

Faculty Disclosures: The authors do not have an affiliation with or financial interest in any organization that might pose a conflict of interest.

Submitted for publication: February 6, 2008; Accepted for publication: April 17, 2008.

Please direct all correspondence to: Andres J. Pumariega, MD, The Reading Hospital and Medical Center, 6th Avenue and Spruce St., P.O. Box 16052, Reading, PA 1961.

Abstract

Varenicline is a promising agent with demonstrated efficacy in the promotion of smoking cessation. However, from the time of initial trials, it has been associated with significant psychiatric adverse effects. We describe a case where mixed mood and psychotic disturbance developed in an individual with a history of depression and a family history of bipolar disorder. Based on this case, we hypothesize a possible mechanism of action for these adverse effects and preventive measures that could be undertaken in its effective use.

Introduction

Tobacco use has significant health impact worldwide, accounting for ~5 million premature deaths in 2000.¹ Most effects of nicotine are reversible and the life expectancy of a smoker approaches that of a non-smoker 10 years following discontinuation of smoking.  The majority of smokers will attempt cessation numerous times. Therefore, additional smoking-cessation options with newer, novel medications may contribute to increased success rates. This is especially true for people with the most severe mental illnesses, schizophrenia and bipolar disorder, who have a high prevalence of tobacco abuse. Varenicline binds to the α₄β₂ neuronal nicotinic acetylcholine receptors and produces agonist activity at a significantly lower level than nicotine, preventing nicotine from binding to these receptors and resulting in a lower propensity to tachyphylaxis than nicotine replacement. As a partial agonist, varenicline produces low to moderate levels of dopamine release, which reduces craving and withdrawal symptoms. Additionally, varenicline blocks the ability of nicotine to activate the α₄β₂ receptors, which stimulates the central nervous mesolimbic dopamine system.  This system is believed to be involved in the reinforcement and reward neuronal mechanism associated with smoking. Varenicline also binds with moderate affinity to the serotonin (5-HT)₃ receptors.^2-5 Clinical trials assessing the efficacy and safety of varenicline 1 mg BID compared with bupropion sustained release 150 mg/day and placebo have shown promising results.^2-4 The use of varenicline resulted in a statistically significant increase in continuous abstinence rates after 12 weeks of treatment when studied in >2,000 patients.^2,3 Another study⁴ using varenicline as maintenance therapy for 24 weeks resulted in statistically significant abstinence rates in the varenicline group versus placebo after 24 weeks and remained statistically significant after 52 weeks.

Agitation, aggression, and mood swings were reported as infrequent psychiatric adverse reactions in the preclinical studies of varenicline for Food and Drug Administration approval, and euphoric mood, agitation, and psychosis were reported as rare psychiatric adverse reactions.⁵ However, the FDA issued two recent Med Watch advisories regarding reports of behavioral changes in patients taking varenicline. These have included erratic behavior, new onset of depressed mood, agitation, suicidal ideation, suicidal attempts, and completed suicides within days to weeks of initiating varenicline. Not all the individual affected had pre-existing histories of psychiatric illness.⁶ There have been two recent published case reports of varenicline exacerbating symptoms of schizophrenia⁷ and inducing a manic episode in a patient with bipolar disorder.⁸ In this report, we report on a case of a patient with no pre-existing bipolar disorder and the onset of manic symptoms after initiating varenicline for smoking cessation.

Case Report

This was the first psychiatric hospitalization for this 50-year-old white female. The patient had some increased stressors over the prior few weeks, including some interpersonal stress with her husband as well as dealing with past and current family conflicts in and outside of therapy. During the week prior to admission, she was reported to show some signs of racing thoughts, increased speed in her speech and jumping from topic to topic, and becoming increasingly labile in her mood, with spontaneous crying spells.

On the night prior to admission, she showed markedly increased irritability and some paranoia, especially toward her husband. Further collateral information from her husband revealed that she suddenly announced that she wanted to divorce, although she later told him that she only said this to get his attention. Later on the day of admission, she started to make increasingly bizarre statements, including asking to talk to her husband’s deceased mother, accusing people around her, accusing people around her of plotting against her to do her harm, and calling them all by her mother’s name (with whom she had a conflictual relationship). She was brought for an emergent evaluation by a local psychiatrist. During that evaluation the patient was calling him by her mother’s name. The patient also displayed response to internal stimuli, staring at a wall while being alone in a room and saying “If you get out of here”.  The patient eventually agreed to come into the hospital voluntarily at the urging of her husband and the psychiatrist.

Past psychiatric history was pertinent for the patient undergoing psychotherapy for depression for a few years in the past, with a past trial of sertraline (dosage not recalled), with mixed benefit but no clear worsening. She had no history of suicide attempts. Her brother has a diagnosis of bipolar disorder with psychosis and multiple hospitalizations. The patient also believed there may be untreated bipolar in other members of the family. Medical history was pertinent for having a biopsy of a benign breast lump with some calcification 2 months prior to admission. She went through menopause ~5 years prior to admission, and had not suffered any perimenopausal symptoms for at least 2 years. She had no allergies. The only medication she had recently taken was varenicline for smoking cessation, starting ~3 months prior to admission and continuing until the day of admission. Upon review of systems, the patient denied any physical symptoms of illness except for feeling chronically tired. Upon physical exam, her vital signs were stable and her physical examination was normal and unremarkable, including a normal neurologic examination. Upon admission, she was distractible and tangential, and it was difficult to obtain a clear history. She admitted to greatly decreased sleep and some racing thoughts. The patient was displaying psychomotor activation, and significant irritability.  Her speech was somewhat rapid and pressured. Her psychomotor activity was normal. Her mood was “upset,” and her affect was tearful and distraught. Her thought process was tangential, with flight of ideas and a high degree of distractibility. She denied any suicidal or homicidal ideation, intent, or plan. She denied auditory or visual hallucinations, but displayed a fair amount of paranoia as well as some response to internal stimuli. Insight and judgment were poor.

Laboratory data (complete blood cell, 8-panel chemistry, liver function tests, and urinalysis) were all within normal limits. Her thyroid-stimulating hormone was 4.737, and her levorotatory thyroxine was 0.9. Hormonal studies were not performed due to her postmenopausal status. Her urine drug screen was positive for benzodiazepines, accounted by lorazepam administered to her upon admission for agitation, with no prior history of benzodiazepine use.  The working diagnoses were Axis I: bipolar disorder mixed with psychotic features; Axis II: deferred; Axis III: no acute medical problems; Axis IV: some stress from family conflicts; and Axis V: Global Assessment of Functioning score of 35.

The patient was admitted to an adult psychiatric unit and immediately administered intramuscular aripiprazole 9.75 mg as well as lorazepam 1 mg for her agitation and psychotic symptoms. Varenicline was discontinued. She was agitated and continued to have rapid speech and to make paranoid statements. She was fairly disorganized and had poor sleep on her first night of admission. Aripiprazole was increased to 15 mg/day on the following day and administered orally, and further increased to 20 mg 2 days later, divided in two doses. She was still making some paranoid statements 3 days after admission. However, that evening the patient had a fairly abrupt turnaround, stating that she felt much calmer and not endorsing any paranoia toward her husband. On the fourth day of hospitalization, she continued to state that she felt “a lot better,” showed a fair amount of insight with regard to her condition given her brother’s history, and was asking appropriate questions about preventing this in the future. After a session with her husband and the unit social worker, it was felt that it was appropriate for her to continue follow-up as an outpatient.

At discharge, the patient was well groomed. Her speech was normal in rate, tone, and latency, and her thought processes were logical and linear. Her mood was “a lot better.” Her affect was neutral. She denied any delusions or hallucinations. She denied any suicidal or homicidal ideation, intent, or plan. Her insight and judgment appeared fair. She has continued in outpatient follow-up, with no recurrence of mood disturbance or psychosis, with maintenance medications at this time being aripiprazole 20 mg/day. Most recently, the patient has indicated that, in retrospect, she began to experience mood symptoms 4–6 weeks prior to admission (intermittent increased energy and decreased energy with irritability).  She even recalled an incident during that time period where, after coming out of a bank and into her car, she noted to herself “I never stopped talking in there.”

Discussion

The onset of mania in this patient with no prior history of manic symptomatology after initiating varenicline treatment for smoking cessation is certainly suggestive of varenicline having the capacity of induce mania and psychosis in a vulnerable individual. Though this has been reported in another patient with a documented history of bipolar disorder,⁷ this is the first case we are aware of where an individual with only a past history of depression developed mania after exposure to varenicline. Given her family history of bipolar disorder, it is possible that the patient may have had an underlying bipolar depression, which rendered her additionally vulnerable to this adverse effect. Recent psychosocial stressors such as the discovery of a breast lump and family conflicts could have contributed to her psychotic manic break.

Since varenicline displaces nicotine from acetylcholine receptors, produces low to moderate levels of dopamine release, and stimulates the central nervous mesolimbic dopamine system, it may well upset the balance in cholinergic-adrenergic tone, which has been implicated in the physiology of mania. Its dopaminergic agonist action also has the potential to trigger psychotic symptoms.

Bupropion is a dopamine agonist that has been associated with suicidal ideation, worsening depression, psychosis, and mania.⁹ Goldberg and colleagues¹⁰ have proposed that the use of adrenergic agonist antidepressants, particularly bupropion, by individuals with bipolar depression render them at greater risk for mania and mood instability, even in the face of a mood stabilizer. Given the similarity of pharmacologic mechanism of action, the possibility exists that varenicline could similarly increase the risk for mood instability in vulnerable individuals, with added psychosocial stressors possibly tipping them into mania, depression, and/ or psychosis.

Conclusion

Thus far, the warnings from the FDA about the use of varenicline have been non-specific in terms of risk factors for adverse mood, psychotic, and agitation effects, recommending caution with any history of mental illness.⁶ Cases involving such adverse effects could be analyzed for the presence of either a family history of bipolar disorder or a history of depressive or bipolar disorder in their past. If these factors turn out to be significant, cautionary warnings could possibly be more specific to risk factors. Greater specificity may serve to better prevent such adverse reactions as well as to retain the use of this valuable agent for smoking cessation where indicated. Additionally, more precise studies about the role that nicotine addiction serves in the pathophysiology of mood and psychotic disorders may also be invaluable in improving the treatment and prevention of these disorders.

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