Managing clozapine discontinuation – acute and chronic maintenance strategies

Focus on Clozapine Withdrawal- and Misuse-Related Cases as Reported to the European Medicines Agency (EMA) Pharmacovigilance Database

“…It was here confirmed, on a large-scale basis, that, following the abrupt reduction of clozapine dosage a discontinuation/withdrawal syndrome may occur. This may involve possible severe and long-lasting symptoms [10,59,67,84]. Moreover, although this may be an unusual event, it is here suggested that cases of misuse/abuse/dependence could occur in patients with a concomitant SUD and this is despite clozapine being of clinical value for the treatment of dual diagnosis.…”

“…Consistent with this, symptoms appear to regress rapidly with the help of anti-cholinergic drugs; (c) a serotonergic syndrome, which may occur even without the concomitant use of a serotonergic agent [10,39,61]. In fact, acting as a 5-HT2A antagonist, long-term clozapine use may be associated with receptor downregulation, and thus, its abrupt discontinuation might lead to receptors' upregulation [65,66]; (d) a sudden decrease in gamma-aminobutyric acid (GABA) activity, with the development of catatonic symptoms which may include, mutism, waxy flexibility, staring, posturing, mannerisms, negativism, and also restless, irrelevant speech, and psychomotor agitation [6,67]. The clozapine agonist action on GABA receptors can explain both the drug-drug interaction between clozapine and benzodiazepines, and the flumazenil therapeutic effect in clozapine intoxication cases [6]; and (e) a modification of norepinephrine levels, with clozapine abrupt discontinuation in chronic patients possibly resulting in an increase in suicidal behavior [1,68].…”

“…Discontinuation should be seen here as distinct from the withdrawal scenario associated with alcohol and other addictive substances, a scenario which commonly presents together with craving, drug seeking behavior, and the inability to stop drug use [71,72]. Thus, if a discontinuation of clozapine is needed, the molecule should be gradually tapered off over several weeks rather than abruptly discontinued, except in cases of emergency (e.g., agranulocytosis), and only with close clinical monitoring [10,67,73]. There are no established guidelines regarding which antipsychotic to choose after withdrawal of clozapine [73], although anticholinergics and olanzapine may be the treatment of choice for preventing withdrawal [53].…”

The Treatment of Clozapine-Withdrawal Delirium with Electroconvulsive Therapy

“…However, rarer syndromes have also been associated with clozapine withdrawal, such as delirium [ 3 ], catatonia [ 4 ], serotonin syndrome [ 5 ], NMS [ 6 ], and movement disorders such as dystonias and dyskinesias [ 7 ]. The diverse presentation of clozapine-withdrawal states is likely secondary to its broad pharmacological profile, with antagonistic effects in serotonergic, cholinergic, dopaminergic, and histaminergic receptors leading to rebound hyperactivity in these systems, along with rebound dysregulation of gamma-aminobutyric-acid- (GABA-) ergic pathways as a result of clozapine's activity on GABA receptors [ 4 , 8 , 9 ]. Treatment of clozapine-withdrawal syndromes should be targeted at particular neurotransmitter systems depending on the symptoms and signs observed; for example, benztropine and cyproheptadine have been suggested as treatments for cholinergic and serotonergic rebound symptoms, respectively [ 5 , 9 ].…”

Clozapine withdrawal catatonia, psychosis and associated neuroleptic malignant syndrome

“…Clozapine withdrawal psychosis is well recognised and has been documented with onset within 14 days. The mechanism likely relates to loose binding to DA2 receptors, compensatory increases in DA2 following chronic administration, its therapeutic effectiveness with much lower DA2 occupancy (Miller, 2009) and potentially rebound effects from other receptors: mainly cholinergic but to a lesser extent serotonergic, noradrenergic and GABA-ergic receptors (Shields et al, 2012). The main therapeutic strategy to resolve clozapine withdrawal psychosis is reinstatement of clozapine, which was delayed in this case due to concerns about induction of NMS.…”