Managing clozapine discontinuation – acute and chronic maintenance strategies

Clozapine is recommended for treatment resistant schizophrenia and its use has increased significantly in Australia over the last 10 years (Malalagama et al., 2011). However, clozapine non-adherence can limit its use and abrupt discontinuation has been documented to induce acute psychosis and rarely catatonia in certain patients, which is distinct from the underlying illness (Bastiampillai et al., 2009; Moncrieff, 2006). Traditionally, the term ‘supersensitivity psychosis’ refers to the phenomenon whereby chronic administration of dopamineblocking drugs increases sensitivity of dopamine receptors in the mesolimbic system and results in a withdrawal psychosis when dopamine receptor blockade ceases (Moncrieff, 2006). Clozapine, however, also has complex actions on other neurotransmitters including cholinergic, serotonergic, histaminergic, and alpha-adrenergic systems (Miller, 2009). Clozapine has particularly potent antimuscarinic effects and hence cholinergic rebound may contribute to the symptom profile when patient discontinue clozapine abruptly (Miller, 2009). We report the case of a 50-yearold man with a 25-year history of treatment-resistant schizophrenia. At the age of 39 he was commenced on clozapine 350 mg daily, which led to a marked improvement in mental state. However, he rapidly relapsed into severe psychotic episodes within 48 hours of non-adherence to clozapine. He had 10 such admissions during the 3-year period from 2006 to 2009 (mean 10.6 days, range 4–22 days). There were no admissions noted when he was compliant with clozapine. His relapses were characterised by florid delusions of a religious and grandiose nature, command auditory hallucination, and aggression. In September 2009 depot risperidone 37.5 mg was co-administered with the expectation that this strategy would protect against supersensitivity psychosis, due to dopaminergic hyperactivity. This combination was continued for 2 years. However, he experienced severe psychotic relapses within 48 hours of noncompliance to clozapine, resulting in three inpatient admissions (mean 15.3 days, range 12–21 days). His symptoms resolved with restitution of clozapine. While the period of non-compliance remained consistent across all admissions since 2006, we note that the length of hospital stay was markedly reduced when clozapine was recommenced at regular maintenance doses (six admissions, mean 7.6 days) rather than up-titrated from 12.5 mg (seven admissions, mean 15.1 days). In our patient, clozapine and depot risperidone co-administration proved ineffective in reducing the severity of symptoms and prolonging the time to relapse. This is consistent with the literature that clozapine withdrawal psychosis is not entirely due to the dopaminergic supersensitivity mechanism (Miller, 2009). Based on the observations on this case and literature review we suggest the following strategies to manage clozapine discontinuation both in the acute and maintenance phases. In the acute phase after clozapine discontinuation, clinicians should be aware of the potential for withdrawal psychosis and look specifically for signs of cholinergic rebound (agitation, headache, nausea and vomiting, insomnia, and diaphoresis). Clozapine levels should ideally be measured at the time of admission. Our case demonstrated that reinstating regular-dose clozapine promptly has the greatest impact on time to recovery. Hence if the patient has ceased clozapine within the last 48 hours, the regular dose should be resumed immediately. However, if a period greater than 48 hours has lapsed, clozapine should be resumed as 12.5–25 mg/day as per prescribing guidelines in order to prevent the risk of respiratory arrest and orthostatic hypotension (Novartis, 2010). If clozapine is titrated slowly, oral preparations with anticholinergic potency like chlorpromazine may better serve to control agitation and psychosis. Administrations of benztropine (4 mg) and atropine (1 mg) have been used in situations of cholinergic rebound (Dilsaver, 1983) and hence may also play a role in clozapine withdrawal. Patients and carers should be offered Letters