Aripiprazole Therapy for Nicotine Dependence

Sir: Tobacco use poses a substantial health risk and increases morbidity and mortality, predominantly due to cardiovascular and respiratory pathophysiologic effects. The prevalence of nicotine dependence in the general population is about 24%.¹ Nicotine dependence is relatively difficult to treat. Unassisted individual efforts at smoking cessation are associated with low success rates. With such efforts, as few as 3% to 5% of individuals remain abstinent at 1 year.²

Bupropion is the only non–nicotine-based treatment that is approved for smoking cessation. We present a case report of aripiprazole therapy leading to smoking cessation.

Case report. Mr. A, a 21-year-old white man with a history of major depressive disorder, presented to the outpatient clinic for follow-up care. Approximately 1 month prior to this visit, he was hospitalized for worsening of depression with suicidal ideations. In addition, there was evidence of paranoid thoughts. At that time he also met DSM-IV criteria for alcohol abuse and nicotine dependence. He reported smoking 1 pack of cigarettes daily for the past 1 year. His Modified Fagerstrom Tolerance Questionnaire³ score at admission was 7, indicative of severe nicotine dependence.

During his weeklong hospital stay, aripiprazole therapy was initiated. He was subsequently discharged on aripiprazole, 10 mg/day; trazodone, 50 mg at bedtime; and acetaminophen, 650 mg 3 times daily. The patient was compliant with his outpatient treatment plan. While on aripiprazole therapy, the patient continued smoking for a few days. While on the above regimen of medications, he noticed a lack of “high” from the cigarettes as well as fewer cravings for nicotine use. Thus, he was able to quit smoking within a week of his discharge. His Modified Fagerstrom Tolerance Questionnaire score decreased to zero. He attributed these results to aripiprazole.

He continued to be nicotine abstinent for the next 2 weeks until he ran out of aripiprazole. While off aripiprazole therapy, he relapsed and went back to smoking. Approximately a week later, he resumed aripiprazole therapy and was simultaneously able to quit smoking again. During his outpatient visit, 5 weeks later, he did not meet criteria for nicotine dependence, which he again attributed to the aripiprazole. The patient was not drinking alcohol during his outpatient follow-up. However, he did not report any effect of aripiprazole on his desire for alcohol.

Current research in the neurobiology of substance abuse suggests that dopaminergic mechanisms are involved in motivation, reward, and reinforcement. It has been postulated that decreased dopamine function in addicted subjects results in decreased sensitivity to non–drug-related stimuli (including natural reinforcers) and disrupts frontal inhibition, both of which contribute to compulsive drug intake and impaired inhibitory control.⁴ Thus, enhancing dopamine function could theoretically help motivate addicted subjects in activities that provide alternative sources of reinforcement, counteract conditioned responses, enhance their ability to control their drive to take drugs, and interfere with their compulsive use.⁴

There have been several animal studies demonstrating dopamine release in response to nicotine administration.^5–7 Also, there have been some human studies examining the effects of dopamine agonism and antagonism on smoking behavior. Haloperidol, a dopamine antagonist, has been shown to increase smoking in patients with schizophrenia⁸ and in nonpsychiatric patients.^9,10 On the other hand, bromocriptine, a dopamine agonist, has been shown to significantly decrease smoking rate in a sample of nonpsychiatric patients.¹⁰ This hypothesis was further tested in a randomized double-blind fashion by observing the smoking behavior of 20 subjects after alternate administration of bromocriptine and haloperidol on separate occasions in the same subjects. A variety of cigarette smoking measures showed that subjects smoked more on haloperidol than on bromocriptine treatment.¹¹ Bupropion, a drug approved for smoking cessation, is also thought to act by inhibiting neuronal norepinephrine and dopamine uptake, leading to enhanced synaptic dopamine concentration.¹²

Aripiprazole is a novel atypical antipsychotic drug with a unique mechanism of action: it inhibits central dopaminergic neuron activity by a partial agonistic effect on the presynaptic D₂ dopamine autoreceptors and also acts as an antagonist at postsynaptic D₂ dopamine receptors.¹³ Through this mechanism, aripiprazole exerts activity as a dopamine agonist in hypodopaminergic states while acting as a dopamine antagonist when dopaminergic activity is increased.^14,15 Aripiprazole also acts as a partial agonist at 5-HT_1A serotonin receptors and as an antagonist at the 5-HT_2A serotonin receptors.¹³

Thinking in line with the current theory that hypodopaminergic states promote addictive behaviors, it is plausible that aripiprazole's dopamine-agonistic properties could be useful in the treatment of nicotine dependence. There is another case report suggesting that aripiprazole might decrease cravings and reduce alcohol use.¹⁶ In our case, the relationship between aripiprazole therapy and smoking cessation is further strengthened by the fact that the patient relapsed when he was off aripiprazole treatment. The reintroduction of aripiprazole decreased the reinforcing effects of nicotine and subsequently helped the patient stay abstinent.

This case suggests a cause-and-effect relationship between aripiprazole treatment and smoking cessation. It is also apparent that aripiprazole blocked the positive reinforcing properties of nicotine and decreased craving. In summary, the partial dopamine agonists such as aripiprazole are a promising class of drugs for treatment of addictive disorders. However, further research using double-blind placebo-controlled studies is needed to clarify this potential association. If this effect is replicated, aripiprazole would be a welcome addition to our treatment armamentarium for addictive disorders. Furthermore, if our observation is borne out in suitable studies, a patient's smoking status might be an additional factor to consider in selecting therapy for patients requiring an antipsychotic.