Clinical case

A 33-year-old female, housewife, married and with two children, was brought to the psychiatric emergency section after presenting symptoms of disorganised thinking and associated anxiety symptoms. The patient had no previous personal or family psychiatric history, nor had suffered any significant illnesses. She showed no toxic consumption except tobacco consumption (20 cigarettes/day) for years. The patient was treated with varenicline for 12 days (0.5 mg/day for the first 3 days and 1 mg/day for the 9 following days) before going to hospital. On the fourth day of treatment, being the first day the patient took 1 mg/day, she began to feel headache, nausea and insomnia, so she decided to stop taking the prescribed medicine on her own. On arrival to the emergency department, the patient presented phenomena of thought insertion and delusion in relation to a conspiracy against her by her husband's family through her computer. She had not been able to tell which was the reality, which caused her anxiety and restlessness, etc. Her family thought that her condition could be related to taking a new medication that had been scheduled for days. Also explained that 4 days after the patient stopped varenicline, she changed her behaviour, showing behavioural disturbances, disorganised speech, insomnia, thought insertion, delusions and auditory hallucinations. The patient reported that through the Internet the information about her life had been spread, using messages she had sent a friend, all with marked feelings of guilt. No evidence of depressive symptoms and expansiveness. Given her state the patient was admitted in the psychiatric section of the hospital. On admission, a comprehensive study was performed to rule out other possible aetiologies of psychotic symptoms (toxic, cranial CT, EEG, complete blood test, etc.). During her hospitalisation, risperidone was prescribed to 10 mg/day, with adequate tolerance. Progressively proceeding, the psychotic symptoms remitted and subsequently she was discharged after 19 days of hospitalisation. The patient was referred to outpatient clinic to maintain ambulatory monitoring and at discharge, she was prescribed a risperidone 9 mg/day.

Four weeks after, risperidone was reduced and actually, 8 months after psychotic episode, she takes 3 mg/day.

Discussion

The interest of our case is that it is the first report of a psychotic episode in a subject without personal or family history, 4 days after the withdrawal of varenicline. We suggest the withdrawal of varenicline as a cause, but it is possible that it could have simply accelerated a process that would have occurred otherwise.

Following a review of previous literature in this regard, we note several cases of psychosis in relation to the varenicline, both during treatment and after making the withdrawal, and others in which various psychiatric symptoms occurred (Table 1).

From this comparison we observe: the use of nicotine is twice as high in patients with psychosis than among general population (Reference Levander, Eberhard and Lindström16), so for a reduction of the adverse effects of tobacco, an antitobacco drug-like varenicline would be recommended. Patients with a history of schizophrenia may experience an activated psychotic relapse with taking it (Reference Freedman5). However, there are also descriptions of cases of schizophrenia that after treatment with varenicline experienced no exacerbation of psychotic symptoms (Reference Fatemi17–Reference Anghelescu19). We can interpret this clinical observation by the indirect dopamine-releasing properties of varenicline (Reference Rollema, Coe, Chambers, Hurst, Stahl and Williams20).

We cannot say that there are gender differences regarding the psychiatric side effects of varenicline. As for the age range they occur, between 25 and 63 years, especially in the third and fourth decade of life, perhaps because they are the ages at which most secondary prevention on the harmful effects of tobacco are done.

In the three cases in which symptoms occurred after the medicine withdrawal, they were psychotic. These three cases have in common that they had no previous personal history; however, our case has no family history of schizophrenia. Psychosis may have occurred because of downregulation of the cholinergic system such that the abrupt lack of cholinergic stimulation, as a result of the withdrawal from varenicline, induced an anticholinergic response (Reference Laine, Marttila and Lindeman12). Other possible mechanisms include dopaminergic overstimulation secondary to the alpha-2 beta-4 nicotinic receptor in an individual with genetic vulnerability (Reference May and Rose14).

In those with personal history of mood disorder, an exacerbation of the symptoms occurs and may be accompanied by psychotic symptoms, mainly manic episodes. 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 physiopathology of mania (Reference Janowsky, Overstreet, Bloom and Kupfer21). In the case of Kohen et al. (Reference Kohen and Kremen6), they propose that the release of catecholamines, such as dopamine, was probably related to induction of mania in the patient.

Further research is needed to evaluate in depth the safety of varenicline, particularly among smokers with active or previous psychiatric history. Meanwhile, doctors should carefully monitor the use of this medicine.