Review of withdrawal catatonia: what does this reveal about clozapine?

Matthew Lander,Tarun Bastiampillai,Jitender Sareen

doi:10.1038/s41398-018-0192-9

Abstract

Withdrawal symptoms are common upon discontinuation of psychiatric medications. Catatonia, a neuropsychiatric condition proposed to be associated with gamma-aminobutyric acid (GABA) hypoactivity due to its robust response to benzodiazepines, has been described as a withdrawal syndrome in case reports but is not a well-recognized phenomenon. The authors undertook a review of withdrawal catatonia with an aim to understand its presentation as well as the medications and psychoactive substances it is associated with. The review identified 55 cases of withdrawal catatonia, the majority of which occurred upon discontinuation of benzodiazepines (24 cases) and discontinuation of clozapine (20 cases). No other antipsychotic medications were identified as having been associated with the onset of a catatonic episode within 2 weeks following their discontinuation. Increasing GABA activity and resultant GABA receptor adaptations with prolonged use is postulated as a shared pharmacological mechanism between clozapine and benzodiazepines that underlie their association with withdrawal catatonia. The existing evidence for clozapine’s activity on the GABA system is reviewed. The clinical presentations of benzodiazepine withdrawal catatonia and clozapine withdrawal catatonia appear to differ and reasons for this are explored. One reason is that benzodiazepines act directly on GABAA receptors as allosteric agonists, while clozapine has more complex and indirect interactions, primarily through effects on receptors located on GABA interneurons. Another possible reason for the difference in clinical presentation is that clozapine withdrawal catatonia may also involve receptor adaptations in non-GABA receptors such as dopamine and acetylcholine. The findings from our review have implications for the treatment of withdrawal catatonia, and treatment recommendations are provided. Further research understanding the uniqueness of clozapine withdrawal catatonia among antipsychotic medication may give some insight as to clozapine’s differential mechanism of action.

Highlights

Catatonia is a serious neuropsychiatric condition that has been associated with a wide range of psychiatric, medical, neurologic, and drug-induced conditions
The cases described eight different types of medications causing withdrawal catatonia, including withdrawal catatonia related to benzodiazepines (24 cases), clozapine (20 cases), combined alcohol and benzodiazepines (4 cases), alcohol (2 cases), glutethimide (2 cases), zolpidem (1 case), gabapentin (1 case), and gamma-hydroxybutyric acid (1 case)
Further research and conclusions We conducted a comprehensive review on the phenomenon of withdrawal catatonia with a goal of identifying all medications and psychoactive substances associated with it

Summary

Introduction

Catatonia is a serious neuropsychiatric condition that has been associated with a wide range of psychiatric, medical, neurologic, and drug-induced conditions. A severe and life-threatening form that is associated with autonomic instability and fever is known as malignant catatonia. Benzodiazepines are the first-line treatment for catatonia regardless of the underlying cause[1] with high treatment response rates[2–5]. Benzodiazepines exert their effects on GABAA receptors, which are classified as ligand-gated ion channels. When GABA binds to its binding site on the GABAA receptor, it increases the frequency of opening of the receptor chloride channel, allowing more chloride to pass through, resulting in an inhibitory effect. Benzodiazepines are classified as a positive allosteric modulator, as they

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