Clozapine-associated restless legs syndrome.

To the Editors: Restless legs syndrome (RLS) is a neurological disorder characterized by irresistible movements and dysesthetic sensations in the legs. Its prevalence in general population epidemiological studies is 5% to 10%. Drug-induced RLS, although now a recognized entity, remains an underdiagnosed etiology of secondary RLS. Selective serotonin reuptake inhibitors have long been known to exacerbate RLS, and it has anecdotally been described with atypical antipsychotics. However, there are no reports of clozapine-induced RLS in literature. A case of RLS associated with clozapine is described. The underlying pathophysiological mechanism of this presentation is discussed. Mr A, a 26-year-old man, was diagnosed with bipolar disorder (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision) with a 6-year duration. During one of the manic episodes, he developed severe extrapyramidal symptoms characterized by tremors, bradykinesia, and sialorrhea while on haloperidol 20 mg/d and valproate 1400 mg/d. Subsequently, haloperidol was replaced by clozapine 25 mg/d, which was increased to 50 mg/d over the next 2 days, whereas valproate was continued at the same dose. On the third day of treatment with clozapine (at 50 mg/d), he started experiencing unpleasant sensations in his calves and burning sensation over his feet. These occurred only when he lay in bed at night and would be relieved by moving the legs or walking but would recur on lying in bed. He had initial and middle insomnia. Mr A denied having these symptoms during the daytime. Considering that this may be akathisia, lorazepam (2 mg) was added at bedtime. However, he continued to exhibit the same symptoms, but only at night. Two days later, clozapine was stopped; and that night, Mr A did not experience any uncomfortable sensations or movements of his legs. A week later, the patient agreed to a retrial of clozapine manufactured by a different pharmaceutical company. However, he again developed the same symptoms at night. Subsequently, clozapine was replaced by olanzapine titrated up to 20 mg/d without reemergence of the above symptoms. The dose of valproate remained unchanged throughout the course of treatment. Family history revealed that the patient’s father had evidence to suggest idiopathic RLS. The patient’s neurological examination was unremarkable. Laboratory investigations including serum iron, ferritin, glucose, thyroid-stimulating hormone, and renal function tests were within normal limits. Because of the transient nature and drug-related origin of the abnormal movement, the patient did not consent to polysomnography. This patient met the diagnostic criteria for RLS. Unfortunately, polysomnography data were not available to diagnose or exclude comorbid periodic leg movements in sleep. Akathisia was ruled out on the basis of the presence of dysesthesias in the legs rather than internal restlessness, worsening of symptoms at night, accompanying sleep disturbance, and positive family history. A PubMed search done on June 8, 2006, did not reveal any case of RLS associated with clozapine. Other atypical antipsychotics implicated in RLS include olanzapine, risperidone, and quetiapine. Idiopathic RLS is unlikely because of the lack of history of RLS, the close temporal relationship between clozapine use and RLS, and the reemergence of symptoms with clozapine rechallenge. Efficacy of valproate in treating RLS has been shown, and it is therefore less likely to be an etiological factor in this patient’s presentation. In contrast to our report, clozapine use did not result in reemergence of symptoms in a patient who had developed RLS because of olanzapine. This raises some interesting questions regarding our current understanding of the pathophysiology of RLS. One of the pathophysiological mechanisms of RLS is dopaminergic dysfunction as evidenced by dopamine agonists being the first line of treatment of RLS and dopamine antagonists such as antipsychotics inducing it. If dopaminergic hypofunction is the promulgated mechanism underlying RLS, then clozapine and quetiapine, with lower D2 receptor occupancy compared with other atypical antipsychotics such as risperidone and olanzapine, are less likely to induce RLS as suggested by some investigators. However, this report and the previous report of quetiapineinduced RLS do not support the hypodopaminergic hypothesis for RLS, especially when our patient did not develop RLS with haloperidol and olanzapine, which are more potent D2 antagonists. Thus, more research is needed to elucidate the underlying mechanism of druginduced RLS. In addition, greater awareness among clinicians of the potential association of atypical antipsychotics with RLS and its differentiation from akathisia is encouraged.