Levosulpiride-induced rabbit syndrome

To the Editor

Rabbit syndrome (RS) is a rare movement disorder characterized by involuntary, rhythmic, fast, and fine movements of the oral and masticatory muscles along the vertical axis of the mouth. The involuntary movements associated with RS appear after a long period (in most cases months or years) of antipsychotic treatment (Catena et al., 2007). The prevalence of RS ranges from 2.3–4.4% in patients treated with typical antipsychotics (Schwartz and Hocherman, 2004). Catena Dell’Osso and colleagues found 11 cases of RS associated with atypical antipsychotics. Most of them were linked to risperidone and a few were associated with clozapine, olanzapine, quetiapine, and aripiprazole (Catena Dell’Osso et al., 2007). It has been postulated that the underlying mechanism of RS is the supersensitivity of dopamine receptors, possibly due to an underlying predisposition with attention on the basal ganglia, in particular the substantia nigra pars reticulata, which is also implicated in oral dyskinesia (Praharaj et al., 2008). We report a case of RS associated with the use of levosulpiride.

The index-case patient, a 22-year-old single female, with unremarkable family, past and personal history, presented with complaints of delayed motor and language milestones and difficult temperament since early childhood. There was a history of gradual onset of abusive behaviour, anger outbursts, increased activity, increased energy, and impaired biological functions, with an episodic course for 6 years. The patient had short stature and kyphoscoliosis on physical examination. The mental status examination revealed increased expressive gestures, overproductive and loud speech, irritable affect, and delusion of grandeur.

The patient was diagnosed with bipolar affective disorder, currently manic with psychotic symptoms and was treated on an outpatient basis with carbamazepine (600 mg/day^-1) and risperidone (3 mg/day^-1). She developed akathisia, tremors, and rigidity over a period of 2 weeks. Subsequently, the antipsychotic was changed to levosulpiride (100 mg/day^-1). After 2 months, on follow-up, the patient reported the development of oral involuntary movements. The movements were fine, rhythmic, and rapid, along the vertical axis and without lingual involvement. A diagnosis of RS was made and levosulpiride was reduced to 50 mg/day and benzhexol was added. The patient’s RS diminished significantly within next 4 weeks and further improvement was noted at the next follow-up.

RS is believed to be a rare condition affecting only a small fraction of the psychiatric population using antipsychotics. Atypical antipsychotics differ from typical antipsychotics in their effectiveness in psychosis and their side effect profile. Though RS generally appears late, in our case it appeared after 2 months of levosulpiride usage. Our case agrees with the fact that RS develops more commonly in females, though ours was an early-onset case (Wu and Su, 2008).

To our knowledge, there are no reports of levosulpiride-induced RS. Shin et al. (2009) studied the clinical characteristics of patients with levosulpiride-induced movement disorder and found parkinsonism to be the most common side effect, followed by tardive dyskinesia, and isolated tremor. No case of RS was reported. Levosulpiride is a specific inhibitor of the dopamine D₂ receptors, particularly as it binds specifically and stereoselectively to presynaptic D₂ receptors which have sodium-dependent functions. Therefore, the supersensitivity of dopamine receptors could be the underlying mechanism of RS (Praharaj et al., 2008), though this mechanism may be too simplistic, and the actual pathophysiology may vary between individuals. Different antipsychotic drugs were used before levosulpiride, and the fact that the extrapyramidal symptoms (EPS) emerged shows the importance of individual factors (vulnerability) in RS in our case. Vulnerability for drug-induced EPS, the earlier onset of RS (i.e. 2 months), and the rapid improvement which occurred with the reduction in levosulpiride dosage (and the addition of benzhexol) implicates the role of a low-dose mechanistic blockade of dopamine receptors in the genesis of RS. A similar mechanism has been reported in the genesis of resting orolingual tremors with levosulpiride (Kim et al., 2009), but future neurophysiological research of the basal ganglia holds the key to better understanding and improved treatment of this syndrome.