Mirtazapine-Induced Restless Legs Syndrome Treated With Pramipexole

An 80-year-old woman started showing symptoms of depression 1 year before she presented at our hospital. She had no history of depressive-episode sleep-related movement disorders, such as RLS, or periodic limb movement. Her chief complaints were anxiety, depressed mood, a severe loss of interest, and psychomotor inhibition. She scored 22 on the Hamilton Depression Rating Scale (HAM-D, 21 items). Brain MRI data, electroencephalograms, and serum hemoglobin, iron, and ferritin levels were within the normal limits for her age.

On admission, mirtazapine was initiated at 7.5 mg daily and then increased to 45 mg daily. Two days after the increase to 45 mg mirtazapine, the patient suddenly began to present restlessness of her legs, predominantly at the beginning of a night's sleep. Akathisia was ruled out because of the presence of discomfort without any subjective restlessness relieved by stretching, the nocturnal nature of the symptoms, and sleep disturbance. She was clinically diagnosed with RLS per the International Restless Legs Syndrome Study Group Rating Scale (http://irlssg.org), having a score of 25. We tried to perform polysomnography; however, she strongly refused it due to her delusion of negation.

Once pramipexole was initiated at 0.125 mg daily, RLS promptly and substantially subsided. Increasing the pramipexole dose to 0.25 mg improved the patient's depressive symptoms such as loss of interest and psychomotor inhibition. She was discharged on scoring 0 on the International Restless Legs Syndrome Study Group Rating Scale and scoring 5 on HAM-D.

Several case reports have linked RLS with mirtazapine, 5-hydroxytryptamine (5-HT)1 receptor-stimulating properties, and 5-HT2/5-HT3 receptor-blocking properties.¹ In addition, mirtazapine is most likely one of the second-generation antidepressants that induce RLS.²

Antidepressant-induced RLS has been most often observed in women and the elderly,³ which is in accordance with the characteristics of our patient. The pathophysiology of antidepressant-induced worsening of RLS remains unclear, but dopaminergic hypofunction combined with serotonergic and noradrenergic hyperfunction has been proposed as a possible cause.¹ Elderly patients may be particularly vulnerable because of involved monoamine dysfunction.

Instead of antidepressants, the addition of pramipexole had a curative effect both on her depressive symptoms and the pharmacologically induced RLS. Pramipexole is a well-known treatment for RLS and a potentially efficacious augmentation strategy for antidepressants.⁴ In this case, pramipexole gave our patient a treatment benefit for both her depressive symptoms and RLS.

We hypothesize that patients with depression with RLS have been underestimated because of their complicated complaints or hidden sleepless symptoms. Although guidelines for pharmacological management of comorbid depression and RLS have been proposed,⁵ further research is essential to establish the most appropriate algorithm for treating such patients.