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

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.

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

“…Withdrawal cases collected here were recorded according to the related PTs defined in the MedDRA dictionary [35], where withdrawal is described as "the abrupt cessation of a drug use in a habituated person; and a substance specific syndrome following cessation or reduction in intake of a psychoactive substance previously used regularly". Clozapine withdrawal/discontinuation ADRs were the most frequently reported and, as such, current findings confirmed and expanded on previous anecdotal data [6,53,54]. In association with a sudden discontinuation of clozapine, which may be required in cases of blood dyscrasia or suspected myocarditis, instances of withdrawal have already been reported [6,44,54,55].…”

“…Clozapine withdrawal/discontinuation ADRs were the most frequently reported and, as such, current findings confirmed and expanded on previous anecdotal data [6,53,54]. In association with a sudden discontinuation of clozapine, which may be required in cases of blood dyscrasia or suspected myocarditis, instances of withdrawal have already been reported [6,44,54,55]. It is of clear interest that a case of clozapine withdrawal neonatal syndrome was specifically mentioned here as well.…”

Effects of Treatment Discontinuation in Clinical Psychopharmacology

“…In addition, psychotherapy may or may not be helpful [16, 42]. Finally, the safe management of discontinuation of increasingly prevalent combinations of psychotropic drugs presents a challenge [10]. One study found that changing from one antipsychotic to another, at least, could be done as safely with immediate drug-switching as with widely employed “cross-tapering” of doses downward of a discontinued, and upward of a replacement antipsychotic [43].…”

“…Abrupt discontinuation of psychotropic drugs is very common in pregnancy, with greatly increased risk of adverse clinical effects on the mother and unknown impact on the fetus [36, 37]. Additional potential complications include shifts in the metabolic elimination of other prescribed medicines with which SRIs can interact pharmacokinetically [10, 34]. …”

“…In addition to physical and sensory phenomena, reactions sometimes include symptoms also found in the illnesses being treated (especially depression and anxiety), as well as other novel syndromes. Examples of the latter include: withdrawal-emergent dyskinesias [9] or catatonia [10], emergence or worsening of tardive dyskinesia [11, 12], and a proposed tardive psychosis syndrome [13] – all on removal of antipsychotic drugs; new panic symptoms and worsening or new depression or mania after removing an antidepressant [3, 8, 14-16]; and new or increased suicidal behavior after discontinuing lithium [17] and possibly antidepressants [15, 16]. Second and usually somewhat later, symptoms of illnesses being treated can recur more often, sometimes more severely, and much more rapidly than predicted by the natural history of untreated illness, including by comparison to a patient’s own history.…”