Abstract
Restless legs syndrome (RLS) is a neurological sensory motor disorder with a wide range of severity, from merely annoying to affecting sleep and quality of life severely enough to warrant medical treatment. It is characterized by an urge to move the legs and is usually associated with abnormal sensations of the leg. It is worsened by rest, relieved by movements, and is severe at night [1]. Prevalence of medically significant RLS is 2–3% and it remains largely undiagnosed [1,2]. Psychotropic drugs implicated in RLS include antidepressants, especially selective serotonin reuptake inhibitors and atypical antipsychotic medications [3–5]. A single case report of clozapine associated RLS has been reported [5].
A 29 year old woman with treatment-resistant paranoid schizophrenia and a history of polysubstance abuse presented with relapse of schizophrenia following cessation of clozapine 500 mg at night and amisulpride 200 mg twice daily. Clozapine was not immediately restarted because her admission electrocardiogram showed right bundle branch block, instead she was commenced on amisulpride 200 mg. The clozapine was restarted 2 weeks later following a physician opinion. On 325 mg/day of clozapine she started reporting hot sensations in both her heels after going to bed associated with an urge to get up and walk or eat something to relieve it. However, her sleep was uninterrupted and these problems never occurred during the day even if she went to sleep. Clozapine was gradually increased to the previous effective dosage along with amisulpride. The hot sensations in her feet and ankle soreness persisted. She had to keep moving her legs until she fell asleep and on a few occasions she would wake up from sleep. Physical examination did not reveal any evidence of local inflammation or other local abnormalities. Investigations such as serum iron, vitamin B12, folic acid, thyroid function, blood sugar, renal and liver functions were all normal. A diagnosis of clozapine induced RLS was made and she was started on diazepam 5 mg/day, which relieved her discomfort for some period of time. However, after 1 year of treatment she had no sustained benefit from diazepam and in fact complained of slight worsening of her symptoms. She was then tried on a combination of paracetamol (500 mg)/codeine phosphate (30 mg) nocte, which like diazepam had some initial but no sustained benefit. As a result she stopped using both diazepam and the paracetamol/codeine combination while continuing the clozapine and amisulpride. In the past 3 months she has occasional experiences of warm sensation of the feet but without sleep disturbance and is not on any medication for the RLS.
Dysesthetic sensations of the feet and ankle, restless leg movements, nocturnal worsening while resting together qualify her symptoms for RLS. Onset of her symptoms had temporal correlation with initiation of clozapine, but the relationship could not be confirmed by ceasing clozapine due to the significant risk of deterioration of her mental state.
She did not complain of these symptoms while on amisulpride alone. A literature search did not find any case reports of amisulpride-induced RLS. Hence it is reasonable to assume that this patient experienced clozapine-induced RLS.
Clinicians need to be aware of this potential side effect especially in patients on clozapine presenting with sleep disturbance. This report also raises queries regarding the natural course of clozapine-induced RLS – is it a fluctuating condition or does tolerance develop over time?