JOUHNALOFTHE

NEUROLOGICALSCIENCES

Juurmd of the Neurological Sciences 142( 1996)151-152

Case report

Fluoxetine and restless legs syndrome

Rohit Bakshi *&Paylm~ntOf”N~urO[vg~,uni[er,ri~ of California, Los Angeles, UCL4 School @Mcdi6ine und UCLA Medical Center, Los Angeles,CA,USA

Received 22 April 1996;accepted 26 May 1996

Keywords: Fluoxetine; Restless legs syndrome; Restlessness; Ekbom’s syndrome

Fluoxetine is a selective serotonin reuptake inhibitorcommonly prescribed worldwide for the treatment of de-pression. It has been associated with several neurologicaladverse reactions, including anxiety, sexual dysfunction,inappropriate secretion of antidiuretic hormone, and vari-ous extrapyramidal side effects (Coulter and Pillans, 1995;Gram, 1994). Among the myriad of complications, a rela-tionship between fluoxetine and pre-existing restless legssyndrome (Ekbom, 1960) has not been previously de-scribed. A patient has come to my attention who developeda dose-dependent exacerbation of pre-existing, mild rest-less legs syndrome requiring discontinuation of fluoxetine.

Case report. A 22-year-old woman presented with com-plaints of an episodic problem with discomfort of bothlegs. She reported an approximately weekly, annoyingsensation of ‘restlessness’ of the legs, which would lead toan irresistible need to rub or move them. The symptomswould typically develop while seated or supine, such aswhile lying in bed to sleep, taking a long automobile ride,or sitting at a movie theater, nearly always in the lateevening or night. Leg movements, such as flexion, stretch-ing, bicycling motions, standing or pacing would providerelief. She denied hypomania, jitteriness, tremulousness, orgeneralized restlessness. The symptoms arose two weeksafter she began taking fluoxetine (20 mg per day) fordepression and became considerably worse after the dosewas increased to 40 mg per day. She recalled as anadolescent having similar problems with restlessness of thelegs which were considerably more mild, occurring nomore frequently than monthly, and not prompting medicalattention. For the past decade, since her late teenage years,

* Corresponding author. Present address: Department of Neurology,State University of New York at Buffalo, 3 Gates Circle, Buffalo, NY14209, USA. Tel: + 1 (716) 887-4437; Fax: + 1 (716) 887-4440.

she had experienced these symptoms rarely, resulting inminimal, tolerable discomfort per episode.

Other than taking oral contraceptives for the past sixyears, she denied taking any medications. There was nohistory of exposure to neuroleptics. She denied other medi-cal problems or substance abuse. General physical andneurological examination were entirely unremarkable.There was no evidence for parkinsonism, neuropathy, orradiculopathy. Serum studies were unremarkable, includ-ing complete blood count, electrolytes, magnesium, bloodurea nitrogen, creatinine, transaminases, vitamin B*Z,fo-late, iron, total iron binding capacity, ferritin, and thyroidstimulating hormone.

Approximately one month later, fluoxetine was in-creased to 60 mg per day for the treatment of depression.She again came to my attention one week later, noting aneven more severe restlessness of the legs which beganoccurring daily, Polysomonography was recommended, butthe patient preferred a medication change. In consultationwith her psychiatrist, fluoxetine was discontinued and shewas kept free of medications. Six weeks later, she reporteda near resolution of restlessness in the legs. During thenext three years of observation, she has remained medica-tion-free. The restlessness occurs only rarely (every fewmonths) and the episodes are mild. She has not beenre-challenged with fluoxetine or other psychotropic medi-cations.

Discussion. This patient developed the clinical featuresof restless legs syndrome (RLS), a neurological entity firstdescribed by Ekbom (1960). This condition developedduring adolescence and then became mild during earlyadulthood. However, after beginning fluoxetine therapy fordepression, her symptoms of RLS recurred and escalatedwith increasing doses. After discontinuation of fluoxetine,the symptoms improved promptly, and the patient’s RLSsymptoms became infrequent. Other known precipitant of

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152 R, Bakshi/Jourmd oj’the Neurological Scienses 142 (1996) 151–152

RLS were excluded, including iron, ferritin or folate defi-ciency, electrolyte disturbances, uremia, and neuropathy(Lang, 1993).

It could be argued that rather than an exacerbation ofRLS, my patient developed acute akathisia, a well-knownadverse effect related to fluoxetine (Lipinski et al., 1989).However, her restlessness was worse while supine, isolatedto the legs, and occurred nocturnally, consistent with RLS(Ekbom, 1960). Although leg restlessness may occur aspart of acute akathisia, she had no additional features ofakathisia, such as generalized restlessness, dysphoria, im-patience, irritability, or jitteriness. Akathisia involves lessconspicuous limb sensations and is present at all times ofthe day, and often is most prominent while the patient isstanding (Lang, 1993). In addition, my patient had pre-ex-isting, mild RLS before being exposed to fluoxetine whichdid not fully resolve three years after its discontinuation.Therefore, it is likely that this case represents fluoxetine-induced exacerbation of mild RLS, rather than acuteakathisia. Other psychoactive medications have been asso-ciated with RLS, including cimetidine (O’Sullivan andGreenberg, 1993), anticonvulsants (Milne, 1992), andlithium (Terao et al., 1991).

The mechanism of the exacerbation of RLS by fluoxe-tine remains speculative. Several other similar extrapyra-midal side effects, such as akathisia, tremor, dyskinesias,and dystonia have been associated with fluoxetine (Coulterand Pillans, 1995; Gram, 1994; Lipinski et al., 1989).These adverse effects may relate to fluoxetine’s selectiveenhancement of serotonin transmission, which results inthe inhibition of dopaminergic neurons (Meltzer et al.,

1979). Consistent with this hypothesis, dopamine depletionis thought to play a central role in the pathophysiology ofRLS; dopamine antagonists worsen RLS and dopamineagonist therapy improves RLS (Kaplan and Mason, 1992).

In summary, I have presented a patient who developeda dose-dependent, reversible, prominent re-activation ofRLS associated with fluoxetine. Clinicians should be awareof this potential interaction when beginning fluoxetine inpatients with RLS.

References

Coulter, D,M,, Pillans, P.L (1995) Fluoxetine and extrapyramidal sideeffects. Am. J. Psychiatry, 152: 122–125.

Ekbom, K.A. (1960) Restless legs syndrome. Neurology, 10: 868–873.Gram, L,F. (1994) Fluoxetine. N Engl. J. Med., 331: 1354-1361,Kaplan, B., Mason, N.A, (1992) Levodopa in restless legs syndrome.

Ann. Pharmacother., 26: 214–216.Lang, A.E. (1993) Akathisia and the restless legs syndrome. In: Parkin-

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Lipinski, J.F., Mallaya, F., Zimmerman, P., Pope, H.G. (1989) Fluoxe-tine-induced akathisia: Clinical and theoretical implications. J. Clin.Psychiatry, 50: 339–34’2,

Meltzer, H.Y., Young, M., Metz, J., et al. (1979) Extrapyramidal sideeffects and increased serum prolactin following ffuoxetine, a newantidepressant. J. Neural Trans., 45: 165–175.

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O’Sullivan, R.L., Greenberg, D.B. (1993) Hz antagonists, restless legssyndrome, and movement disorders. Psychosomatic, 34: 530–532.

Terao, T., Terao, M., Yoshimura, R., Abe, K. (1991) Restless legssyndrome induced by lithium. Biol. Psychiatry, 30: 1167–1170.