Clozapine-Induced Restless Legs Syndrome Treated With Aripiprazole

“Ms. M,” a 34-year-old woman with a 12-year history of treatment-resistant paranoid schizophrenia, having auditory hallucinations and multiple delusions, had poor response to adequate trials of haloperidol, risperidone, and injection fluphenazine. Because of treatment nonresponse, she was started on clozapine, which was increased to 200 mg. Within a week of starting clozapine, she complained of discomfort in the form of pain in both legs mainly, but also with a lesser intensity in both arms, which would begin within 1 hour of taking clozapine at night. The symptoms were relieved by movement of legs by stretching her muscles by massaging them throughout the night. This would last for 3–4 hours, and she developed initial insomnia. Her neurological examination was within normal limits, with no evidence of peripheral neuropathy. The pain continued to persist even when clozapine was decreased to 100 mg. As the symptoms began after antipsychotic use, akathisia was initially suspected, and promethazine 25 mg was started, with no significant improvement. Hemogram revealed hemoglobin 13 g/dl, normocytic normochromic blood picture with normal total and differential counts. Renal, liver, and thyroid function tests, blood glucose, electroencephalogram, and brain imaging (computed tomography) were within normal limits. Akathisia was ruled out because of the presence mainly of discomfort without any subjective restlessness relieved by stretching, nocturnal nature of symptoms, and accompanying sleep disturbance. She was clinically diagnosed to have restless leg syndrome as per the International Restless Legs Syndrome Study Group Rating Scale (IRLS), having an IRLS score of 27, which indicates severe RLS.⁷ Polysomnography and serum ferritin could not be done for this patient. She was started on diazepam 5 mg. Clozapine was increased to 200 mg because of the severity of psychotic symptoms. She was discharged on clozapine 200 mg and diazepam 5 mg. No improvement in RLS was noted with diazepam 5 mg. She continued to have RLS while being on clozapine for nearly 6 months. Discontinuation of clozapine could not be considered; as the patient was nonresponsive to other treatment; but further increase in clozapine was deferred because of persisting RLS. She was again admitted because of severity of symptoms. At admission, Brief Psychiatric Rating Scale score was 45. She was given aripiprazole 10 mg as an augmenting agent to clozapine. Within 2 days of adding aripiprazole 10 mg, her RLS subsided, with an IRLS score of 4. There was no recurrence of RLS even when clozapine was increased to 300 mg while aripiprazole 10 mg continued. She continues to maintain remission of RLS for 8 months on aripiprazole 10 mg, with an IRLS score of 0. Her current BPRS score is 18 on clozapine 300 mg, with continuing improvement in functioning.

RLS may be a primary condition, or may be secondary to iron deficiency, pregnancy, renal failure, medication side effects, or spinal cord injury. The improvement of RLS symptoms with dopaminergic therapy and reversal of the beneficial effects of dopamine agonists by antagonists supports the role of dopamine in RLS.⁸

There have been reports of antipsychotic-induced RLS with olanzapine,^3,4 quetiapine,⁵ and clozapine. Symptoms of RLS secondary to antipsychotic use has to be initially differentiated from akathisia, in which the desire to move is not necessarily associated with discomfort in the legs; subjective restlessness is very high; and symptoms are not worse at night. In most of the earlier reports of antipsychotic-induced RLS, either antipsychotic dosage was reduced or antipsychotic was stopped and changed. In others, approved drugs for RLS, like ropinirole or propoxyphene was used. In this case, the use of the Naranjo et al. Adverse Drug Reaction Probability Scale⁹ (score: 5) indicated that the adverse effect was probably related to clozapine. Per our knowledge, this is the first case of antipsychotic-induced RLS, in this case clozapine, that was treated by aripiprazole.

This patient had none of the common causes of RLS and the temporal correlation with clozapine intake was considered as an indicator of clozapine being the offending agent.

Aripiprazole has a unique mechanism of weak partial agonism at D₂-like dopamine receptors, with 95% receptor occupancy at clinical doses in PET studies.¹⁰ This unique partial agonism of dopaminergic system also could explain its role in alleviating RLS that is similar to other approved drugs for RLS such as dopamine agonists like ropinirole and pramipexole. Aripiprazole also had the added benefit of having a synergistic effect with clozapine,¹¹ which enabled in improvement in the psychotic symptoms and enabled further increase in clozapine dosage, as well. Therefore, in antipsychotic-induced RLS, aripiprazole could be considered, as it would also have an added antipsychotic effect and, in a case like this, wherein the antipsychotic could not be stopped, as the patient was a nonresponder, and the psychotic symptoms were very severe.