Clozapine withdrawal emergent dystonia, oculogyric crisis and rebound psychosis in a single patient

Abstract

Abrupt clozapine withdrawal is heralded by both physiological and psychological symptoms requiring urgent management, out of which dystonic reactions have been reported by only two groups to date [Ahmed et al. 1998;Mendhekar and Duggal, 2006]. We present here the only case reported in the literature to manifest psychotic decompensation, oculogyric crisis and limb-axial dystonia in a single patient due to abrupt clozapine withdrawal and discuss the putative mechanisms underlying this unique presentation. Early recognition of this syndrome is important as symptomatic treatment alone runs the risk of recurrence of the withdrawal symptoms, as seen in our patient, unless clozapine is reinstituted promptly. Case reportMiss 'A' was started eventually on clozapine after sequential trials of trifluoperazine, flupentixol, haloperidol, chlorpromazine and amisulpiride failed to alleviate her schizophrenic symptoms. During her 18 years of diagnosed illness, all these medications were tried for adequate doses and duration, and polytherapy was also tried judiciously. But medication adherence was always erratic and eventual personality deterioration ensued over the years. She now needed assistance even for basic self-care needs and her clinical picture was dominated mainly by negative symptoms. Clozapine was titrated up to 400 mg in divided doses over 4 weeks and some response in self-care and communication was noted.After 6 months on clozapine, her carer stopped refilling her prescriptions and the patient's selfcare and socialization deteriorated further. She was restarted on clozapine and the target doses of 400 mg were achieved over 4 weeks. After 5 days on this dose, the treating team was alarmed by a sudden drop in her consciousness and axillary temperature rise of 101°F with total constipation. An abdominal lump was palpable and, on clinical suspicion of acute intestinal obstruction, all medications including clozapine were stopped considering its strong anticholinergic properties. All routine investigations including creatine phosphokinase (CPK), toxicology, virology and bacteriological scans came out to be within normal range and an abdominal computerized tomography (CT) scan diagnosed a large dermoid cyst.It was observed that 5 days following discontinuation of medications, the patient became acutely violent, assaultive, talked irrelevantly and showed inappropriate emotional reactions, and had to be calmed down by parenteral benzodiazepines. The very next day, she developed acute oculogyric crisis characterized by uprolling of the eyeballs sustained for 60-90 minutes at a time for 3 times over that day, and profound axial and lower limb dystonia. The dystonia was very severe with the patient shouting continuously in pain and was not able to move at all. Intramuscular promethazine 50 mg was administered and the dystonia disappeared in minutes. Her dystonia recurred the very next day and intramuscular promethazine 50 mg was repeated with prompt response. Detailed neurological examination revealed nothing except the focal ...

Antipsychotic Withdrawal Symptoms: A Systematic Review and Meta-Analysis

“…Abrupt withdrawal of haloperidol was associated with a significant increase in dyskinesia beginning in the second week post-withdrawal in a study with fifteen participants with schizophrenia ( 36 ). A case series ( 37 ) and case report ( 38 ) indicated occurrence of dyskinesia and dystonia after abrupt withdrawal of clozapine. In another study with 34 children, 6 to 12 years of age and diagnosed with schizophrenia, 41% of the children showed involuntary movements and ataxia after withdrawal of different antipsychotics (i.e., fluphenazine, haloperidol, thioridazine, trifluoperazine, and thiothixene) ( 39 ).…”

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

“…The clozapine multi-receptor agonism/antagonism is likely responsible for the occurrence of discontinuation/withdrawal symptoms. Indeed, the clozapine pharmacodynamic profile may well include: (a) a dopaminergic super-sensitivity, with the risk of a dopaminergic psychosis and symptoms such as dystonias, dyskinesias, and catatonia [38,[56][57][58][59]; (b) a cholinergic rebound, inducing in vulnerable patients a rapid worsening of psychosis, agitation, confusion, insomnia, and symptoms including nausea, vomiting, diarrhea, headache, diaphoresis, and abnormal movements, such as dystonias and dyskinesias [6,54,56,57,[60][61][62][63][64]. Consistent with this, symptoms appear to regress rapidly with the help of anti-cholinergic drugs; (c) a serotonergic syndrome, which may occur even without the concomitant use of a serotonergic agent [10,39,61].…”

Olanzapine-Induced Withdrawal Oculogyric Crisis in an Adolescent With a Neurodevelopmental Disorder

“…Other reports of withdrawal OGC have most commonly been reported following rapid clozapine discontinuation or taper, and less commonly following olanzapine discontinuation or taper. [3][4][5] Karaş et al 5 described withdrawal emergent dyskinesia and supersensitivity in a 59-year-old man after self-discontinuing olanzapine (10 mg/day) following 2 years of treatment on this dosage. Following olanzapine discontinuation, he acutely experienced fears of being followed and hurt, insomnia, and involuntary chewing, and lip smacking, which previously were not present.…”

“…Upon rapid withdrawal of olanzapine or clozapine, the super-sensitized receptors react excessively to acetylcholine, with resultant muscle motor end plate hyperactivity (e.g., dystonia). 3 In line with this hypothesis, re-initiation of the antipsychotic or administration of a potent anticholinergic (e.g., diphenhydramine or benztropine) should resolve the acute and painful muscle symptoms.…”

“…2 Additionally, published case reports describe withdrawal emergent dystonia and OGC in adult patients following abrupt discontinuation of clozapine. 3,4 A single case report details OGC occurring in an adult patient following discontinuation of olanzapine. 5 Our case report describes an adolescent female with a complex psychiatric history and Fragile X syndrome, who developed an OGC within 12 hours of decreasing her olanzapine dose (50% dose reduction).…”