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Clozapine Rechallenge Following Neuroleptic Malignant Syndrome

A Systematic Review

Lally, John MB MSc MRCPsych*†‡§; McCaffrey, Cathal MB, BCh; O'Murchu, Conall MB, BCh; Krivoy, Amir MD*; Guerandel, Allys MD; MacCabe, James H. PhD, MSc, MBBS, BSc, FRCPsych; Gaughran, Fiona MD, MB, BCh, BAO, FRCPI, FRCP, FRCPsych

Journal of Clinical Psychopharmacology: July/August 2019 - Volume 39 - Issue 4 - p 372–379
doi: 10.1097/JCP.0000000000001048
Review Article

Purpose/Background Neuroleptic malignant syndrome (NMS) has been described with most antipsychotics, most commonly first generation. Clozapine has also been associated with NMS.

Methods/Procedures We conducted a systematic review to identify all studies investigating or describing (a) clozapine rechallenge following suspected NMS associated with clozapine, (b) clozapine use after suspected NMS associated with another antipsychotic, and (c) rechallenge with nonclozapine antipsychotics after suspected clozapine-associated NMS.

Findings/Results We identified 51 reports detailing 67 cases. Thirty-eight described clozapine administration after NMS on a nonclozapine antipsychotic; 12 described a clozapine rechallenge after an NMS on clozapine monotherapy; and 17 described the use of nonclozapine antipsychotics after an NMS on clozapine. The outcome of clozapine rechallenge was favorable (no recurrence of NMS) in 92% (n = 11) of cases after an NMS on clozapine and in 79% (n = 30) of those prescribed clozapine following NMS on a nonclozapine antipsychotic. Most (82%; n = 14) cases after NMS on clozapine had no recurrence of NMS on receiving a nonclozapine antipsychotic.

No mortality was reported with any of these interventions.

Implications/Conclusions Our findings suggest that rechallenge following clozapine NMS is possible, and with careful risk-benefit analysis consideration, a clozapine rechallenge can be made. A publication bias in favor of cases in which rechallenge was successful is probable and is an important limitation.

From the *Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, United Kingdom;

Department of Psychiatry, Royal College of Surgeons in Ireland, Beaumont Hospital;

Department of Psychiatry, School of Medicine and Medical Sciences, University College;

§St Vincent's Hospital Fairview; and

School of Medicine and Medical Sciences, University College Dublin, Dublin, Ireland; and

National Psychosis Service, South London and Maudsley NHS Foundation Trust, London, United Kingdom.

Received November 15, 2018; accepted after revision March 18, 2019.

Reprints: John Lally, MB MSc MRCPsych, PO63, Department of Psychosis Studies, Institute of Psychiatry, Psychology and Neuroscience, King's College London, De Crespigny Park, London, United Kingdom SE5 8AF (e-mail:

J.H.M. and F.G. are both senior authors.

F.G. is, in part, funded by the National Institute for Health Research Collaboration for Leadership in Applied Health Research & Care Funding scheme. F.G. and J.H.M. receive support from the National Institute for Health Research (NIHR) Biomedical Research Centre at South London, and Maudsley NHS Foundation Trust. The views expressed in this publication are those of the authors and not necessarily those of the National Health Service, the NIHR, or the Department of Health and Social Care.

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Online date: June 13, 2019

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