Termination of clozapine treatment due to medical reasons: when is it warranted and how can it be avoided?

To identify the outcome of potentially serious adverse effects of clozapine, particularly those frequently cited as reasons for clozapine discontinuation, and to characterize management strategies for adverse effects that do not warrant discontinuation. A structured search was performed of PubMed and EMBASE from database inception until September 10, 2012, without any language restrictions, using clozapine as the search term. Reference lists of retrieved articles were cross-checked for additional relevant studies. Included in this review were studies that reported on the frequency of the specified clozapine-related adverse effects and that either reported on the grounds for or against clozapine discontinuation or reported on management techniques to maintain patients on clozapine or enable successful clozapine rechallenge. The following side effects were considered important for this review as potential grounds for clozapine discontinuation: neutropenia or agranulocytosis, leukocytosis, thrombocytopenia, thrombocytosis, eosinophilia, leukocytosis, QTc prolongation, electrocardiogram changes, atrial flutter, tachycardia, myocarditis, cardiomyopathy, fever, syncope, diabetes mellitus, diabetic ketoacidosis, diabetic hyperosmolar coma, neuroleptic malignant syndrome, ileus, liver enzyme elevation, or seizure. Study results that supported continuation or discontinuation of clozapine or that provided information on management techniques were abstracted. Of a total of 13,385 search results, data from 81 studies were included in this review. Results suggest that prompt discontinuation of clozapine without rechallenge is indicated for agranulocytosis, myocarditis, cardiomyopathy, and a QTc interval > 500 milliseconds that is confirmed and derived using the appropriate correction method. Clozapine discontinuation with potential rechallenge (provided there is appropriate surveillance and management or prophylactic therapy) is indicated for ileus or subileus, neuroleptic malignant syndrome, venous thromboembolism, and diabetic ketoacidosis or hyperosmolar coma. Neutropenia, leukocytosis, seizures, orthostatic hypotension, severe constipation, and weight gain and metabolic abnormalities, including metabolic syndrome and its components, as well as moderately prolonged myocardial repolarization, need to be managed but do not generally warrant clozapine discontinuation. Eosinophilia, leukocytosis, drug-induced fever, and tachycardia (provided that myocarditis and neuroleptic malignant syndrome are ruled out) can be managed and should rarely lead to clozapine discontinuation. A number of side effects commonly cited as medical reasons for clozapine discontinuation do not necessarily warrant such action. Management techniques are available that allow continuation or rechallenge in relation to a number of clozapine-related side effects.