Reducing the Risk of Withdrawal Symptoms and Relapse Following Clozapine Discontinuation

Is It Feasible to Develop Evidence-Based Guidelines?

Graham Blackman; Ebenezer Oloyede; Mark Horowitz; Robert Harland; David Taylor; James MacCabe; Philip McGuire


Schizophr Bull. 2022;48(1):176-189. 

In This Article

Abstract and Introduction


Clozapine is the only antipsychotic that is effective in treatment-resistant schizophrenia. However, in certain clinical situations, such as the emergence of serious adverse effects, it is necessary to discontinue clozapine. Stopping clozapine treatment poses a particular challenge due to the risk of psychotic relapse, as well as the development of withdrawal symptoms. Despite these challenges for the clinician, there is currently no formal guidance on how to safely to discontinue clozapine. We assessed the feasibility of developing evidence-based recommendations for (1) minimizing the risk of withdrawal symptoms, (2) managing withdrawal phenomena, and (3) commencing alternatives treatment when clozapine is discontinued. We then evaluated the recommendations against the Appraisal of Guidelines for Research and Evaluation (AGREE) II criteria. We produced 19 recommendations. The majority of these recommendation were evidence-based, although the strength of some recommendations was limited by a reliance of studies of medium to low quality. We discuss next steps in the refinement and validation of an evidence-based guideline for stopping clozapine and identify key outstanding questions.


Clozapine is a dibenzodiazepine antipsychotic that was first developed in 1959.[1] It is the only effective treatment for patients with schizophrenia who are treatment-resistant,[2] and the most effective treatment for schizophrenia more generally.[3–5] There are certain circumstances, however, where it is necessary to stop clozapine with estimates of discontinuation ranging between 16% and 66%.[6–15] There are several reasons to stop clozapine, however they can be broadly divided into indications leading to either emergency, or elective discontinuation (Table 1). Emergency discontinuation of clozapine is typically indicated when patients experience potentially life-threatening adverse effects, such as agranulocytosis, myocarditis, or neuroleptic malignant syndrome.[16] In some situations, clozapine can be reinitiated once the clinical concern has resolved, or has been mitigated. Examples where clozapine can be discontinued electively include intolerable (but not immediately life-threatening) adverse effects, lack of treatment response, patient preference, and poor adherence. There are also some instances where clozapine can be discontinued after full recovery has been achieved.[17,18] In contrast to stopping clozapine in an emergency, elective discontinuation usually allows a period of consultation, information gathering, and preparation as well as the option of stopping clozapine more gradually.

Discontinuing clozapine in patients with schizophrenia is associated with an increased risk of relapse of psychotic symptoms.[21,22] This is particularly problematic in patients with treatment-resistant schizophrenia, as other antipsychotic drugs are unlikely to be effective. Furthermore, clozapine can be associated with a range of withdrawal symptoms. These include catatonia, sleep disturbance, confusion, autonomic dysfunction, neuromuscular and gastrointestinal symptoms, as well as psychotic symptoms that can be worse than the underlying condition.[22–24] A recent international pharmacovigilance study found that withdrawal symptoms account for a substantial proportion of all clozapine-related adverse drug reactions.[25]

Clinicians may be reluctant to initiate treatment with clozapine due to the concern that once treatment has started, discontinuation is hazardous and difficult to manage. Unlike starting clozapine, there are very few recommendations around how to safely discontinue clozapine.[26] The recognition that abrupt discontinuation can result in withdrawal symptoms brought about a recommendation for gradual tapering in 1995[27] and subsequent guidance documents have recommended that discontinuation takes place over one to two weeks.[16,28] However, there is evidence to suggest that this taper period may be too short. Furthermore, there is an absence of guidance on the wider aspects of clozapine discontinuation, such as managing withdrawal symptoms and selecting alternative antipsychotic treatment. Simple, evidence-based recommendations around the safe discontinuation of clozapine would help to address this issue. We therefore sought to assess the feasibility of developing guidelines that cover these topics based on the available evidence.