Clozapine rebound mania

To the Editor

There is well-documented evidence that abrupt clozapine discontinuation can result in rebound psychosis (Miller, 2009), but only one report describes clozapine rebound mania (Perényi et al., 1985).

Ms X is a 51-year-old female, with a 35-year history of bipolar affective disorder (BPAD)/schizoaffective disorder. She has had 12 hospitalisations: five preceding and six following the admission where clozapine was commenced (Figure 1).

Figure 1.

Pre-clozapine and post-clozapine periods.

Each admission since 2009 has followed sudden cessation of clozapine. Within 48 hours, she becomes acutely manic characterised by sleep disturbance, extreme agitation, hostility, tangentiality and marked pressure of speech. These manic symptoms result in the need for intensive care and her grandiose and persecutory delusions then become more apparent.

Before clozapine, Ms X had not required electroconvulsive therapy (ECT). However, each of the last five admissions have required ECT, despite resuming clozapine, because of the severity of her manic symptoms. Interestingly, since being commenced on clozapine the interval between hospitalisations has decreased. We believe this is related to non-compliance and rebound mania, which we suggest is an under-recognised clinical entity. Her clozapine dose has also increased with each consecutive admission from 150 mg to 500 mg.

Her usual clozapine serum levels are around 600–1000 μg/L (normal range 350–600 μg/L) but at her most recent admission they were only 162 μg/L, corresponding to a cessation period of 48 hours.

This clinical scenario meets Chouinard’s criteria for an antipsychotic-induced supersensitivity state (Chouinard, 1990) based on the rapid onset of symptoms following cessation, increasing the complexity and acuity of presentations and requiring increased doses of clozapine and ECT as adjunctive treatment. This supersensitivity state likely results from physiological changes in dopamine receptors (DA₂) instigated by chronic antipsychotic administration leading to over-expression of those receptors on abrupt withdrawal. Dopamine supersensitivity states are more pronounced with antipsychotics of short half-life such as clozapine (Miller, 2009). Other explanatory models for clozapine’s propensity to cause supersensitivity states include loose binding to DA₂ receptors, compensatory increases in DA₂ following chronic administration, its therapeutic effectiveness with much lower DA₂ occupancy (Miller, 2009) and potentially rebound effects from other receptors: mainly cholinergic but to a lesser extent serotonergic, noradrenergic and GABA-ergic receptors (Shields et al., 2012). Based on these observations and involvement of dopamine dysregulation in mania, we postulate that chronic administration of clozapine can also result in dopamine supersensitivity mania.

We believe that clozapine rebound mania has been under-reported and -recognised. It is possible that agitation in patients following cessation of clozapine may be interpreted as purely psychosis but could also reflect a manic presentation and that non-recognition of this could lead to under-treatment. Clinicians should be aware that clozapine rebound mania potentially represents a psychiatric emergency that should be recognised immediately to prevent a potentially protracted course of illness.

In a previous report, Shields et al. (2012) have outlined the management for acute clozapine rebound psychosis and we would recommend that this also be applied to rebound mania. Additionally, we suggest if there is poor response to first-phase interventions (Shields et al., 2012) then there could be earlier consideration for ECT to specifically address the affective component.

It would be of research interest to investigate the prevalence of clozapine rebound mania and its possible mechanisms. There is an interesting hypothesis that clozapine’s tendency to cause rebound psychosis may also partially relate to its superior clinical effectiveness for schizophrenia (Miller, 2009). Therefore, by using the same explanatory model, it is possible that clozapine’s potential to cause rebound mania may also account for its potentially superior effectiveness in BPAD (Nielsen et al., 2012).