Galova et al.

BMC Psychiatry (2019) 19:73

https://doi.org/10.1186/s12888-019-2055-1

CASE REPORT Open Access

A case report of cholinergic rebound

syndrome following abrupt low-dose
clozapine discontinuation in a patient with
type I bipolar affective disorder
Andrea Galova1 , Patricia Berney1, Jules Desmeules2, Ioannis Sergentanis3 and Marie Besson1*

Abstract
Background: Rebound cholinergic syndrome is a rare, but well known unwanted phenomenon occurring after
abrupt clozapine discontinuation. There have been previous reported cases of cholinergic rebound in the literature;
however, these reports described cholinergic rebound following cessation of high doses of clozapine in patients
diagnosed with schizophrenia. Here, we report a case of rebound cholinergic syndrome and catatonia in a male
patient three days after abrupt discontinuation of 50 mg of clozapine prescribed for type I bipolar affective disorder.
Case presentation: A 66-year old male of Spanish origin, treated for type I bipolar affective disorder for 15 years
and for Crohn disease, was brought to the emergency department because of a sudden onset of mutism, dysphagia
and trismus. He was described catatonic and presented hypertension, tachycardia and tachypnea. His body temperature
was normal and the laboratory tests were unremarkable at presentation. A head CT and an EEG were in the normal
range.
While reviewing his history, it appeared the he was on clozapine 50 mg a day, first introduced 2 months ago, during a
previous hospitalization for a manic episode resistant to other mood stabilizers. For an unknown reason, the patient’s
psychiatrist stopped clozapine three days before the admission and replaced it by risperidone 5 mg and quetiapine 200
mg daily. A cholinergic rebound syndrome was then evoked. The patient’s ability to speak recovered dramatically and
fast after the intravenous administration of 2.5 mg of biperiden supporting the diagnosis. Risperidone and quetiapine
were also stopped. The patient fully recovered in 20 days after the reintroduction of 50 mg of clozapine and 2.5 mg of
biperiden daily.
Conclusions: This case report underscores that cholinergic rebound syndrome may occur in patients suffering from
bipolar affective disorders, being on clozapine as a mood stabilizer. The low dose clozapine does not preclude severe
manifestations of the phenomenon. Progressive tapering should therefore be adopted in any case.
Keywords: Withdrawal syndromes-cholinergic rebound syndrome-low dose clozapine -bipolar affective disorder-
Pharmacodynamic properties-overlapping switch strategies-case report

* Correspondence: Marie.Besson@hcuge.ch
1
Psychopharmacology Unit, Clinical pharmacology and toxicology division,
Acute Medicine Department, Geneva University Hospital, Geneva, Switzerland
Full list of author information is available at the end of the article

© The Author(s). 2019 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
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(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Galova et al. BMC Psychiatry (2019) 19:73 Page 2 of 5

Background Herein, we report a case of cholinergic rebound syn-

Withdrawal syndromes are emergent drug adverse drome due to abrupt cessation of a low dose of clozapine
events, due to receptor supersensitivity elicited by a sud- (50 mg daily), prescribed for type I bipolar affective dis-
den drug discontinuation [1]. Such adverse events are order. We would like to highlight the importance of early
well described and easy recognizable when tapering clinical recognition of the syndrome as it may be hindered
down and stopping a wide range of psychotropic medi- by heterogeneous clinical presentations, frequently over-
cation. However, withdrawal syndromes may also occur lapping with other drug syndromes or adverse effects.
when switching from one molecule to another and may Early recognition is obviously essential, since the treat-
be then more difficult to diagnose. ment is specific and usually rapidly successful.
Dopamine and serotonin supersensitivity, as well as
cholinergic rebound syndrome, all belong to the well de- Case presentation
scribed antipsychotic withdrawal syndromes. Special at- A 66-year old male of Spanish origin, known for Crohn
tention should be paid when the switching molecules do disease and type I bipolar affective disorder for at least
not share the same pharmacodynamic or pharmacoki- 15 years, was brought to the emergency department for
netic properties. Overlapping “plateau” switch strategies, sudden mutism that developed within 2 h. In the emer-
or transient prescription of benzodiazepines or anti- gency room, the patient was described catatonic, pre-
cholinergic drugs when an abrupt discontinuation is un- senting with no speech at all, staring, stupor, immobility
avoidable, should be adopted [2]. and rigidity of the four extremities and a trismus. He
Cholinergic rebound syndrome is induced in suscep- was not vomiting. Standardized scale for catatonia was
tible patients after an abrupt discontinuation of a drug not used on admission. Retroactively, according to the
that blocks muscarinic acetylcholine receptors. Its cen- psychiatrist in charge of the initial evaluation of the pa-
tral component is characterized by agitation, confusion, tient, the score on Bush-Francis catatonia scale would
psychosis, anxiety, insomnia, sialorrhea and extrapyram- have been 8.
idal manifestations. Diarrhea, sweating, nausea (with or The patient was diaphoretic, with obvious dysautonomic
without vomiting) and signs of dysautonomia are part of signs: blood pressure was 175/126 mmHg, heart rate was
the peripheral component [2]. 105 bpm and respiratory frequency was 22/min. His
Clozapine is a second generation antipsychotic, which temperature was 36.7 °C. Laboratory results showed a
blocks multiple receptors, including the dopamine D2 mild hyponatremia (Na+ 132 mmol/l, N: 136–144), the
receptors, the serotonin 5-HT 2A and 5-HT2C recep- glomerular filtration rate was 95 ml/min and liver tests
tors, histamine H1, adrenergic α1 and M1 to M5 mus- were as follow: ASAT 33 U/l (N: 14–50), ALAT 30 U/l (N:
carinic receptors [1, 3]. Given its unique high affinity for 12–50), alkaline phosphatase 61 U/l (N: 25–102), γGT 62
muscarinic receptors, clozapine is at a high risk of cho- U/l (N: 9–40). Creatine kinase (CK) blood concentration
linergic rebound syndrome on cessation or when switch- was 56 U/l (N: 47–222) and arterial gasometry was in the
ing for another antipsychotic [3–5]. normal ranges. Hematology was unremarkable, namely
Several case reports of cholinergic rebound syndrome leucocytes were 4.9 G/L, with 79% neutrophils. A brain
have been published, after abrupt withdrawals in schizo- CT excluded an ischemic stroke and a cerebral
phrenic patients needing high doses of clozapine (from hemorrhage. A 24 h-EEG was unremarkable. Clozapine
300 to 900 mg daily) [4, 6–11]. blood level at admission was not determined. While
Besides, an alert to the clinicians was published shortly reviewing the patient history, it appeared that he was hos-
after the commercialization of risperidone, warning that pitalized in a psychiatric ward until 2 months ago for a
cholinergic rebound syndrome may occur when clozapine manic episode, which has required many drug treatment
was switched to risperidone, given the difference of bind- trials because of adverse effects or treatment failure. These
ing affinity on muscarinic receptors between the two com- were namely, a three-fold CK elevation related to olanza-
pounds [12]. Moreover two cases of a severe cholinergic pine, mild leucopenia and agranulocytosis related to aripi-
rebound syndrome after a clozapine-olanzapine switch in prazole, extrapyramidal manifestations on haloperidol and
schizophrenic patients were reported [13]. This may be high dose quetiapine lack of efficacy. Facing this resistant
somehow surprising since olanzapine is also considered to episode a try with clozapine was then made. The patient
have a significant affinity for muscarinic receptors. How- was eventually discharged, stabilized on clozapine 50 mg
ever works comparing in vitro affinity on muscarinic re- daily, with 12.5 mg on demand, valproic acid 500 mg twice
ceptors of atypical antipsychotics showed that the daily and his usual treatment for Crohn disease (mesala-
anticholinergic activity of olanzapine was less pronounced zine 1000 mg, azathioprine 50 mg twice daily).
than the clozapine anticholinergic activity by a factor ten For an unknown reason, clozapine was then abruptly
[14]. This difference as well as administered doses may stopped and replaced by risperidone 5 mg daily associ-
have accounted for the observed withdrawal syndromes. ated with quetiapine 200 mg daily three days before the
Galova et al. BMC Psychiatry (2019) 19:73 Page 3 of 5

emergency admission. Besides valproid acid was de- for higher values than expected according to the dose,
creased to 300 mg daily. could not be definitely excluded. However, the only cyto-
Therefore, the hypothesis of a cholinergic rebound chrome p450 (CYP) blockers found in the patient treat-
syndrome was evoked, with a potential contribution of ment on admission was valproic acid that is a strong
risperidone overdose in the catatonic manifestation. Ris- CYP 2C9 inhibitor. Clozapine main metabolite pathway
peridone and quetiapine were stopped and biperidene is CYP 1A2 whereas CYP 2C9 is only a minor route
2.5 mg intravenously was administrated leading to a dra- [15]. A clinically significant interaction was therefore not
matic recovering of the patient’s ability to speak within strongly expected.
minutes after application. Other manifestations (nausea, Signs of catatonia at initial clinical presentation, was
sweating, tachycardia, hypertension) took few days to re- confounding as it does not belong to the classical de-
cover on clozapine 50 mg and daily oral administration scription of cholinergic rebound syndrome [2]. However,
of 2.5 mg of biperiden. The patient was eventually dis- several cases of a cholinergic rebound syndrome or clo-
charged twenty days after admission with only mild bra- zapine withdrawal syndrome manifested with catatonia
dykinesia and gait instability. His mental state was stable as the main feature have been described in the literature
during the whole hospital stay. [11, 16–22]. Catatonia is a complex phenomenon that
has been associated with a wide range of medical condi-
Discussion and conclusion tions. Drug-related catatonia is classically linked to
The clinical presentation on admission oriented the dif- dopamine receptor blockade, whereas drug-withdrawal
ferential diagnosis toward a neurological condition such catatonia are frequently described after benzodiazepines
as a stroke, an intracerebral hemorrhage or epilepsy. and clozapine withdrawal [23]. Given the complex inter-
They were excluded by a brain CT and a 24 h-EEG. The action between the dopamine and the cholinergic sys-
remaining possibility was a drug related condition, tems in motor function regulation [24] and the use of
namely neuroleptic malignant syndrome, risperidone anticholinergic medication to counterbalance the effect
overdose or cholinergic rebound syndrome. Neuroleptic of dopamine blockade, a sudden cholinergic overdrive
malignant syndrome was eventually not retained in the may be advocated as an explanation to clozapine with-
absence of body temperature and CK elevation. The drawal catatonia.
rapid recovery after administration of the anticholinergic Another point worth mentioning is a possible partici-
biperiden and clozapine reintroduction one day after ad- pation of a risperidone overdose to the extrapyramidal
mission pointed out to a cholinergic rebound syndrome. features as well as the autonomic instability presented
To the best of our knowledge, this is the first report by the patient (dysphagia, trismus and rigidity of the
describing a cholinergic rebound syndrome following an four extremities). The introduction of 5 mg of risperi-
abrupt interruption of a low dose clozapine (50 mg only) done was abrupt instead of slowly titrated in this patient,
prescribed for bipolar affective disorder. Due to cloza- who has developed extrapyramidal manifestations on
pine high affinity for muscarinic receptors, cholinergic haloperidol in the past. Moreover, according to different
rebound syndrome is a well-known emergent adverse sources and clinical experience, 0,5 to 2 mg of the risper-
event but traditionally considered in schizophrenic pa- idone would have been a more appropriate equivalent
tients on high dose [4, 6–9, 11]. According to a previous dose to 50 mg clozapine, based on their antipsychotic ac-
study evaluating clozapine 200 mg daily for at least a tivity [25]. Since clinical manifestations of exaggerated
month abrupt withdrawal, half of the 28 schizophrenic dopamine blockade and cholinergic rebound are over-
patients developed mild withdrawal symptoms. They in- lapping and since the efficacy of anticholinergic drug ad-
cluded agitation, headache and nausea [8]. In addition, ministration to counteract the effect of dopamine
20% (five patients) presented with moderate to severe blockade is in some cases well described [26, 27], the
withdrawal symptoms (nausea with vomiting, diarrhea, exact contribution of both phenomenon is undetermin-
psychosis) needing specialized care. Manifestations took able and remains subject to interpretation.
place within 24 h to 3 days after clozapine withdrawal. In conclusion, we presented the first case of severe
Our case report underscores that cholinergic rebound cholinergic rebound syndrome due to a low dose cloza-
syndrome may occur the same way in patients suffering pine abrupt withdrawal administered as a mood
from bipolar affective disorders, having clozapine as a stabilizer. This case highlights the need of being aware
mood stabilizer. Moreover, the low dose of clozapine of the pharmacodynamic properties of psychotropic
does not preclude severe manifestations of cholinergic drugs, especially since their indications broaden.
rebound syndrome. Therefore, progressive tapering must The psychotropic drug associated syndromes or ad-
be adopted in any case. verse events are overlapping. Clinicians should consider
Clozapine plasma concentration was not determined drugs pharmacodynamic properties when switching or
on admission, hence a drug-drug interaction, accounting stopping psychotropic medications. It would allow a
Galova et al. BMC Psychiatry (2019) 19:73 Page 4 of 5

rapid recognition of sometimes puzzling clinical mani- Received: 3 October 2018 Accepted: 11 February 2019
festations and rapid introduction of the appropriate
treatment.
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