The clinical presentation on admission oriented the differential diagnosis toward a neurological condition such as a stroke, an intracerebral hemorrhage or epilepsy. They were excluded by a brain CT and a 24 h-EEG. The remaining possibility was a drug related condition, namely neuroleptic malignant syndrome, risperidone overdose or cholinergic rebound syndrome. Neuroleptic malignant syndrome was eventually not retained in the absence of body temperature and CK elevation. The rapid recovery after administration of the anticholinergic biperiden and clozapine reintroduction one day after admission pointed out to a cholinergic rebound syndrome.
To the best of our knowledge, this is the first report describing a cholinergic rebound syndrome following an abrupt interruption of a low dose clozapine (50 mg only) prescribed for bipolar affective disorder. Due to clozapine high affinity for muscarinic receptors, cholinergic rebound syndrome is a well-known emergent adverse event but traditionally considered in schizophrenic patients on high dose [4, 6,7,8,9, 11]. According to a previous study evaluating clozapine 200 mg daily for at least a month abrupt withdrawal, half of the 28 schizophrenic patients developed mild withdrawal symptoms. They included agitation, headache and nausea [8]. In addition, 20% (five patients) presented with moderate to severe withdrawal symptoms (nausea with vomiting, diarrhea, psychosis) needing specialized care. Manifestations took place within 24 h to 3 days after clozapine withdrawal.
Our case report underscores that cholinergic rebound syndrome may occur the same way in patients suffering from bipolar affective disorders, having clozapine as a mood stabilizer. Moreover, the low dose of clozapine does not preclude severe manifestations of cholinergic rebound syndrome. Therefore, progressive tapering must be adopted in any case.
Clozapine plasma concentration was not determined on admission, hence a drug-drug interaction, accounting for higher values than expected according to the dose, could not be definitely excluded. However, the only cytochrome p450 (CYP) blockers found in the patient treatment on admission was valproic acid that is a strong CYP 2C9 inhibitor. Clozapine main metabolite pathway is CYP 1A2 whereas CYP 2C9 is only a minor route [15]. A clinically significant interaction was therefore not strongly expected.
Signs of catatonia at initial clinical presentation, was confounding as it does not belong to the classical description of cholinergic rebound syndrome [2]. However, several cases of a cholinergic rebound syndrome or clozapine withdrawal syndrome manifested with catatonia as the main feature have been described in the literature [11, 16,17,18,19,20,21,22]. Catatonia is a complex phenomenon that has been associated with a wide range of medical conditions. Drug-related catatonia is classically linked to dopamine receptor blockade, whereas drug-withdrawal catatonia are frequently described after benzodiazepines and clozapine withdrawal [23]. Given the complex interaction between the dopamine and the cholinergic systems in motor function regulation [24] and the use of anticholinergic medication to counterbalance the effect of dopamine blockade, a sudden cholinergic overdrive may be advocated as an explanation to clozapine withdrawal catatonia.
Another point worth mentioning is a possible participation of a risperidone overdose to the extrapyramidal features as well as the autonomic instability presented by the patient (dysphagia, trismus and rigidity of the four extremities). The introduction of 5 mg of risperidone was abrupt instead of slowly titrated in this patient, who has developed extrapyramidal manifestations on haloperidol in the past. Moreover, according to different sources and clinical experience, 0,5 to 2 mg of the risperidone would have been a more appropriate equivalent dose to 50 mg clozapine, based on their antipsychotic activity [25]. Since clinical manifestations of exaggerated dopamine blockade and cholinergic rebound are overlapping and since the efficacy of anticholinergic drug administration to counteract the effect of dopamine blockade is in some cases well described [26, 27], the exact contribution of both phenomenon is undeterminable and remains subject to interpretation.
In conclusion, we presented the first case of severe cholinergic rebound syndrome due to a low dose clozapine abrupt withdrawal administered as a mood stabilizer. This case highlights the need of being aware of the pharmacodynamic properties of psychotropic drugs, especially since their indications broaden.
The psychotropic drug associated syndromes or adverse events are overlapping. Clinicians should consider drugs pharmacodynamic properties when switching or stopping psychotropic medications. It would allow a rapid recognition of sometimes puzzling clinical manifestations and rapid introduction of the appropriate treatment.
Clozapine cholinergic rebound syndrome may be prevented by systematically adopting the overlapping “plateau” switch strategies, when switching from clozapine to another antipsychotic due to its unique muscarinic affinity. When abrupt discontinuation is needed, in case of severe agranulocytosis for example, the introduction of an anticholinergic agent is recommended. Trihexyphenidyl (1 mg per 40 mg clozapine), benztropine (4 mg) [28] and atropine (1 mg) [21] have been described. Biperiden was chosen in our case because it is the only oral anticholinergic registered in Switzerland. If clozapine-withdrawal symptoms, namely catatonia, mania or rebound psychosis are resistant to progressive tapering or anticholinergic substitution, electroconvulsive therapy may be proposed according to some authors [29].
