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Isolated Oculogyric Crisis on Clozapine Discontinuation

SIR: It is now well known that an abrupt discontinuation of clozapine leads to a discontinuation syndrome characterized by autonomic, behavioral, motor, and psychotic symptoms.¹ We report a case of an isolated oculogyric crisis in a patient who stopped taking clozapine, and discuss the unique nature of this presentation and the putative mechanism of motor symptoms associated with clozapine discontinuation.

Case Report
"Ms. A," an 18-year-old adolescent, was diagnosed with mild mental retardation with behavioral problems, the latter including aggressive and violent behavior, disorganized speech, and disrupted biological functions. She had no history of psychiatric illness. Two months after the onset of these symptoms, she was started on a regimen of haloperidol (up to 10 mg/day), but developed extrapyramidal symptoms which were treated with trihexyphenidyl, 4 mg/day. There was no history of dystonias or dyskinesias on haloperidol. However, as the patient developed akathisia and there was no improvement in symptoms despite being treated with these medications for 5 weeks, both haloperidol and trihexyphenidyl were stopped. Ms. A remained drug-free for the next 3 weeks and was subsequently started on a regimen of clozapine, 25 mg/day, titrated to 300 mg at bedtime over a period of 4 weeks. Her behavioral symptoms showed remarkable improvement with clozapine. Six weeks after commencing clozapine, she inadvertently ran out of her supply of this medication and could not get it refilled on time. Within 48 hours after her last dose, she developed an acute oculogyric crisis. This was characterized by uprolling of the eyeballs lasting for 60–90 minutes at a time and recurring every 2 to 4 hours. The patient immediately consulted her treating psychiatrist, and clozapine was reinstated at its original dose, resulting in dramatic resolution of the oculogyric crisis. During this whole time, no dystonias or dyskinesias in other parts of the body were observed and there was no evidence of nausea, vomiting, diarrhea, perspiration, palpitations, or restlessness. No deterioration in behavioral symptoms was reported. Her neurological examination results, other than the aforementioned focal dystonia, were unremarkable and so were the results of a head computed tomography (CT) scan.

Comment
This case provides some unique insights into our understanding of the mechanism of discontinuation-emergent movement disorders with clozapine. This patient had no prior history of neuroleptic-induced dystonia or dyskinesia, and the speculation that clozapine discontinuation may have led to reemergence of these movement disorders may not be valid in this case. In addition, this patient exhibited oculogyric crisis, whereas other investigators have reported mainly limb-axial and neck dystonia/dykinesia with clozapine discontinuation.¹ Cholinergic rebound has been hypothesized to be responsible for the symptoms associated with clozapine discontinuation.² Moreover, reports of cholinergic excess in patients on cholinesterase inhibitors, leading to acute dystonia, further support the putative role of cholinergic rebound in the emergence of dystonias on clozapine discontinuation.³ However, if this were the sole mechanism, our patient would have exhibited other peripheral signs and symptoms of cholinergic withdrawal. In line with this, cholinergic rebound occurs after chronic cholinergic blockade, and our patient had been treated with clozapine for only 6 weeks, which may not be sufficient to cause supersensitivity of the muscarinic receptors. Animal studies have shown that M4 muscarinic receptors exert an inhibitory effect over striatal D1 dopamine receptor-mediated locomotor stimulation.⁴ Thus, it can be hypothesized that the removal of this muscarinic inhibition of the dopaminergic system in the striatum as a result of clozapine discontinuation may result in functional dopaminergic supersensitivity, manifesting as movement disorders. This suggests that besides cholinergic supersensitivity, other neurotransmitters also may play a part in the emergence of motor symptoms following clozapine discontinuation. Further research in this realm is encouraged.

REFERENCES

1. Ahmed S, Chengappa KN, Naidu VR, et al: Clozapine withdrawal-emergent dystonias and dyskinesias: a case series. J Clin Psychiatry 1998; 59:472–477[Medline]
2. Verghese C, deLeon J, Nair C, et al: Clozapine withdrawal effects and receptor profile of typical and atypical antipsychotics. Biol Psychiatry 1996; 39:135–138[CrossRef][Medline]
3. Kwak YT, Han IW, Baik J, et al: Relation between cholinesterase inhibition and Pisa syndrome. Lancet 2000; 355:222
4. Gomeza J, Zhang L, Kostenis E, et al: Generation and pharmacological analysis of M2 and M4 muscarinic receptor knockout mice. Life Sci 2001; 68:2457–2466[CrossRef][Medline]

This article has been cited by other articles:

				R. Chakraborty and A. Chatterjee Clozapine-Induced Oculogyric Crises Ann. Pharmacother., November 1, 2007; 41(11): 1916 - 1916. [Full Text] [PDF]

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