Psychopharmacology Reviews: Bupropion for Restless Legs Syndrome

David Ginsberg, MD

Dr. Ginsberg is Director of Outpatient Services, Tisch Hospital’s Department of Psychiatry, New York University Medical Center

Restless legs syndrome (RLS) is a common disorder with a prevalence in the general adult population ranging from 2–15% (Zucconi et al. 2004). It is characterized by deep sensations of creeping inside the calves whenever sitting or lying down. While these dysesthesias are rarely painful, they tend to be agonizingly relentless, resulting in an almost irresistible urge to move the legs. Not surprisingly, RLS often interferes with sleep. A number of psychotropic drugs have been associated with RLS including conventional and atypical neuroleptics as well as serotonin selective reuptake inhibitors (SSRIs) (Sanz-Fuentenebro et al. 1996; Kraus et al. 1999; Wetter et al. 2002; Pinniti et al. 2005).

Various medical conditions are associated with RLS including iron deficiency, end-stage renal disease, pregnancy, rheumatoid arthritis, Parkinson’s disease, and certain types of cancer (Zucconi et al. 2004; Lee et al. 2004). While the mechanism underlying RLS is not fully understood, it is believed to involve a dysfunction of dopaminergic systems, with dopamine receptor antagonists being the most likely agents to precipitate this syndrome (Allen 2004). In addition, since iron is a cofactor at the rate-limiting step in the production of dopamine, inadequate iron stores due to iron deficiency can decrease dopamine production and may also result in RLS (Allen 2004). Other than discontinuing the offending medication, other treatments for RLS that may be of benefit involve the use of dopaminergic agonists such as ropinrole, pramipexole, and pergolide; opiates; benzodiazepines; beta-blockers; and anticonvulsants including carbamazepine and gabapentin. Now comes a report of 3 patients in whom the dopamine-norepinephrine reuptake inhibitor bupropion was an effective remedy for RLS (Kim et al. 2005).

In the first case, a 34 year-old woman admitted for chemotherapy of recurrent breast cancer presented complaining of restlessness, disturbed sleep, and a “creepy-crawling” sensation in both legs. The unpleasant sensation worsened at night and was relieved by moving the legs, consistent with RLS. She first experienced symptoms of RLS 18 years prior, but the condition had worsened during the preceding 3 months concurrent with the return of her breast cancer. On an RLS severity scale of 10 items rated 0-4 each, her overall score was 24/40. She was also depressed, with a Hamilton Rating Scale for Depression (HAM-D) score of 21/50. Routine laboratory tests were normal. At the time of consultation, her medication regimen consisted of the chemotherapy drugs doxorubicin 54 mg and docetaxel 80 mg, as well as dolasetron mesylate 100 mg as needed for nausea, oxycodone 40 mg as needed for pain, and pantoprazole 40 mg. Chemotherapy was administered for 3 days/1 cycle. Clonazepam 0.25 mg at bedtime was ineffective in ameliorating the RLS. In order to treat the depression, sustained-release (SR) bupropion 150 mg was initiated daily in the morning. By the end of the first day, the patient noticed a substantial decrease in restlessness and in the unpleasant sensation in the legs: the RLS severity score had declined to 9/40. By the third day of bupropion treatment, the RLS completely resolved. Depression and insomnia persisted. The following day, the patient was discharged from the hospital. Upon return home, she developed vomiting and therefore discontinued the bupropion. By the time of readmission to the hospital 10 days later for the next cycle of chemotherapy, her RLS symptoms had recurred, with an RLS severity score of 21/40. Bupropion SR 150 mg/day was reinstituted, and the RLS symptoms completely resolved within a few days, despite ongoing chemotherapy. Over the next 3 weeks, the patient’s insomnia and depression significantly improved, consistent with a decline in her HAM-D score to 4/50. Over the ensuing 4 months during which the patient underwent another 7 cycles of intermittent chemotherapy, these improvements in RLS and depression persisted.

In the second case, a 46 year-old woman with a history of radical mastectomy and chemotherapy for breast cancer 15 months prior, now in remission, was referred for evaluation of agitation, sleep disturbance, and pain in the extremities that had persisted for 2 months. During the evaluation she admitted to a 2 month history of depression. Her HAM-D score was 24/50. Citalopram 10 mg/day and lorazepam 1 mg/day were initiated. Over the next 3 weeks, citalopram was increased to 30 mg/day. By week 6 of treatment, her depression had significantly improved nearly to the point of remission (HAM-D score of 8/50) however her insomnia persisted. Further evaluation revealed the daily occurrence of unpleasant sensations, which resembled sharp pain and restlessness, in all four extremities, particularly the legs. Worst at night, the unpleasant sensations were relieved by leg movement, consistent with RLS, which had actually begun 6 years prior. The RLS symptoms worsened over the 2 months prior to presentation, but had actually decreased in intensity after treatment with citalopram and lorazepam. At that point, her RLS severity score was 22/40. Citalopram was replaced by bupropion SR 150 mg every morning. By the end of the first day, the patient reported an 80% subjective improvement in her RLS symptoms. By the third day, the RLS symptoms completely remitted. By week 2 of bupropion SR therapy, the patient reported that she no longer felt depressed and that she was sleeping very well. On her own, she decided to discontinue the bupropion SR because she believed that she didn’t need it anymore. Approximately 5 days later, mild paresthesia and restlessness recurred, prompting a visit to the psychiatric clinic. Her mood appeared slightly elated. Her RLS severity score was 10/40. Due to concerns about inducing hypomania, bupropion SR was not readministered. Since laboratory testing indicated iron deficiency (ferritin 34.8 µg/L; iron 58 µg/dL; hemoglobin 12.9 g/dL), ferrous sulfate was prescribed and within a few days all symptoms of RLS completely disappeared.

A 48 year-old woman visited a psychiatric clinic with sleep disturbance resulting from restlessness and paresthesia in both legs that was relieved by movement. Commencing 3-4 years prior, her RLS symptoms now occurred 4-5 days per week. Her RLS severity score was 23/40. Interestingly, she had a positive family history of RLS, in her mother and brother. She otherwise had no known medical problems. Laboratory testing revealed an iron deficiency without anemia (ferritin 6.4 µg/L; iron 39 µg/dL; TIBC 479 µg/dL; hemoglobin 12.5 g/dL), which was not treated. The patient was also depressed, with symptoms of diminished interest, fatigue, guilt feelings, and insomnia. Her HAM-D score was 14/50. Bupropion SR 150 mg every morning was initiated. By the third day of treatment, her RLS symptoms had completely remitted (RLS severity score = 0/40) however her insomnia persisted. By week 4 of bupropion SR treatment, her depression also remitted, as evidenced by a HAM-D score of 5/50. The sleep disturbance improved along with the depression. Remission of RLS was maintained, without the addition of any other medication, at last follow-up 2 months later.

In all 3 cases, a low dose of bupropion SR rapidly and completely ameliorated RLS. While all 3 patients also suffered from concomitant depression, which is known to be comorbid with RLS (Rothdach et al. 2000), the improvement in RLS symptoms seen with bupropion SR is unlikely due to treatment of the depression based on the quick onset of response and the fact that serotonin reuptake inhibitor antidepressants have actually been demonstrated to worsen RLS (Bakshi et al. 1996; Hargrave et al. 1998; Sanz-Fuentenebro et al. 1996; Salin-Pascual et al. 1997). Interestingly, there is one prior report of the effectiveness of bupropion SR for periodic limb movement disorder, another dopaminergic dysfunction mediated condition, in patients with depression (Nofzinger et al. 2000). Placebo-controlled trials are indicated to better evaluate the efficacy of bupropion for the treatment of RLS, including in those without concomitant depression or other medical disorders.

REFERENCES

Zucconi M, Ferini-Strambi L. Epidemiology and clinical findings of restless legs syndrome. Sleep Med 2004; 5:293-299.

Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A. Restless legs syndrome and paroxetine. Acta Psychiatrica Scandinavica 1996; 94:482-484.

Kraus T, Schuld A, Pollmacher T. Periodic leg movements in sleep and restless legs syndrome probably caused by olanzapine (letter). J Clin Psychopharmacol 1999; 19:478-479.

Wetter TC, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidone treatment. Pharmacopsychiatry 2002; 35:109.

Pinninti NR, Mago R, Townsend J, et al. Periodic restless legs syndrome associated with quetiapine use (letter). J Clin Psychopharmacol 2005; 25:617-618.

Lee K, Cho M, Miaskowski C, et al. Impaired sleep and rhythms in persons with cancer. Sleep Med Rev 2004; 8:199-212.

Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004; 5:385-291.

Kim S-W, Shin I-S, Kim J-M, et al. Bupropion may improve restless legs syndrome: a report of three cases. Clin Neuropharmacol 2005; 28:298-301.

Rothdach AJ, Trenkwalder C, Haberstock J, et al. Prevalence and risk factors of RLS in an elderly population: the MEMO Study (memory and morbidity in Augsburg elderly). Neurology 2000; 54:1064-1068.

Bakshi R. Fluoxetine and restless legs syndrome. J Neurol Sci 1996; 142:151-152.

Hargrave R, Beckley DJ. Restless legs syndrome exacerbated by sertraline. Psychosomatics 1998; 39:177-178.

Sanz-Fuentenebro FJ, Huidobro A, Tejadas-Rivas A. Restless legs syndrome and paroxetine. Acta Psychiatr Scand 1996; 94:482-484.

Salin-Pascual RJ, Galicia-Polo L, Drucker-Colin R. Sleep changes after 4 consecutive days of venlafaxine administration in normal volunteers. J Clin Psychiatry 1997; 58:348-350.

Nofzinger EA, Fasiczka A, Berman S, et al. Bupropion SR reduces periodic limb movements associated with arousals from sleep in depressed patients with periodic limb movement disorder. J Clin Psychiatry 2000; 61:858-862.