Why does clozapine cause increased rebound psychosis and catatonia,compared to quetiapine?

To the Editor

Quetiapine was synthesised as a clozapine mimetic (Monahan et al., 2020), also sharing similar pharmacodynamic characteristics to that of clozapine, rapidly dissociating from the D₂ receptor (Lander et al., 2018; Nair et al., 2020). Clozapine has the highest propensity among all antipsychotic medications (including quetiapine) in leading to rebound psychosis and catatonia (occurring less than 1 week following cessation of the antipsychotic), in addition to other discontinuation-related symptoms (Lander et al., 2018; Nair et al., 2020).

Monahan et al. (2020) surprisingly only identified 13 case reports of quetiapine withdrawal with somatic symptoms (not including withdrawal or rebound psychosis) in their recent systematic review. This systematic review specifically excluded quetiapine withdrawal or rebound psychosis and catatonia in their methodology. However, in addition to the relative scarcity of quetiapine somatic withdrawal-related cases, there is also a paucity of quetiapine rebound psychosis and catatonia (onset less than 1 week after cessation) case reports, relative to the described reports of clozapine rebound psychosis and catatonia (Lander et al., 2018; Nair et al., 2020). Previously suggested mechanisms for clozapine rebound psychosis and catatonia related to its rapid dissociation from the D₂ receptor (Lander et al., 2018; Nair et al., 2020). However, we have suggested that mechanisms beyond rapid dissociation from the D₂ receptor are more likely to explain clozapine rebound psychosis and catatonia, including cholinergic rebound, serotonin rebound, GABA_B receptor interactions or a complex multi-receptor interaction (Nair et al., 2020). It is of note that baclofen which is a pure GABA_B agonist has also been associated with rebound psychosis, occurring in cases without a history of schizophrenia (Nair et al., 2020). Clozapine has been shown to potentially bind to the GABA_B receptor (Nair et al., 2020). In this context, we have previously speculated that clozapine rebound psychosis and catatonia may be possibly linked to GABA_B receptor dysregulation (Nair et al., 2020).

It is our view that rebound psychosis and catatonia is relatively unique to clozapine among antipsychotic medications. The fact that both clozapine and quetiapine share rapid dissociation from the D₂ receptor, but not the reported clinical incidence of rebound psychosis and catatonia, suggests that rapid D₂ receptor dissociation may not be the best explanatory model for understanding rebound psychosis and catatonia (Lander et al., 2018; Nair et al., 2020). Further research is required to better understand the biological basis of rebound psychosis and catatonia and specifically why clozapine is more likely to lead to rebound psychosis and catatonia. This may in turn provide further insight into clozapine’s unique effectiveness for treatment-resistant schizophrenia and potentially its underlying mechanism of action.