The manicogenic properties of clozapine: a rare but serious potential adverse effect

A 23-year-old man with a history of schizophrenia and substance use disorder (crack cocaine and cannabis) presented with hypomania induced by clozapine. He had no previously documented manic or hypomanic episodes and no notable family history of psychiatric disorders. He had experienced his first psychotic episode in his teenage years when smoking cannabis. A combination of extended-release injectable aripiprazole and clozapine was determined to be the optimal treatment for him at the time; however, he stopped these medications after fleeing the inpatient treatment facility. After this event, he spent 3 months experiencing homelessness and consuming drugs on the streets, namely crack cocaine. He then presented voluntarily to our mental health treatment centre, the same centre he had fled. Upon presentation, he expressed a desire to leave his homeless lifestyle behind. Although he did not exhibit clear signs of disorganization, he admitted to having auditory hallucinations. Given the persistence of these hallucinations despite the reinitiation of treatment with aripiprazole, the decision was made to reintroduce clozapine, which had previously resulted in positive changes without major adverse effects.

Clozapine was initiated at a starting dose of 12.5 mg/d for 2 days, followed by 25 mg/d for 7 days. This was then increased to a therapeutic dose of 50 mg/d. The initial response to clozapine included a noticeable mood shift the next day, characterized by hypomania. The patient exhibited high energy and fast thinking (described as “thoughts racing”), and he engaged in excessive exercise, performing thousands of push-ups and calf raises per day. He frequently asked to go outside and walk around the building. In addition, he displayed grandiosity related to his exercise schedule and expressed a sense of having an awakening, leading him to socialize excessively with everyone on the inpatient unit.

Toxicology screening showed negative results. No reports of drug use were provided by the patient or nursing staff. Differential diagnoses considered included schizoaffective disorder and a first manic episode. The temporal relationship led us to evaluate the possibility of a clozapine-induced hypomanic episode.

Despite the development of hypomanic symptoms, the up-titration of clozapine continued as scheduled, with daily evaluations and monitoring in the inpatient setting. Paradoxically, after a few days, he described a subjective slowing down of his thought process and showed decreased manic symptoms after this up-titration.

Clozapine is a powerful antipsychotic agent, with a vast profile of adverse effects like agranulocytosis, myocarditis, or seizures.1 Although new-onset mania has been repeatedly described as an adverse effect for other antipsychotics,2–6 only 1 case report has described this phenomenon upon starting clozapine.7 Compared with this case report, which documented a severe manic state, the hypomanic state observed in our patient was of lesser intensity.

The mechanism by which clozapine may induce mania is by blockade of the 5-HT_2A and 5-HT_2C serotonin receptors and D1–4 dopamine receptors, with the highest affinity for the D4 dopamine receptor. More specifically, it is hypothesized that low doses of atypical antipsychotics, such as quetiapine, may preferentially block serotonin 5-HT_2A receptors over dopamine D2 receptors. This selective blockade can lead to an increase in dopaminergic transmission, as the inhibition of 5-HT_2A receptors reduces the serotonergic inhibition of dopamine release, thereby increasing dopamine levels in the mesolimbic pathway.2,8,9 Moreover, N-desmethylclozapine (NDMC), a major metabolite of clozapine, exhibits a partial agonist activity at D2 and D3 receptors. This partial agonist activity of NDMC may contribute to the unique clinical profile of clozapine and, in turn, to its potential manicogenic properties.10,11 Furthermore, animal models have shown that prior sensitization with stimulants increases vulnerability to mania-like behaviour when challenged with dopaminergic agents. This could potentially explain how the dopaminergic effects of low-dose clozapine precipitated a manic switch in our patient.12,13

Clozapine remains one of the best options for treating refractory symptoms of schizophrenia and mania, maintaining its position as a potent antipsychotic agent with antisuicidal properties. Our patient’s case underscores the importance of being vigilant for rare adverse effects associated with clozapine, even though it is not commonly known to induce mania. Clinicians should be attuned to these adverse effects and be prepared to adjust or change the causative agent if such effects are observed in their patients.