Refractory Restless Legs Syndrome Likely Caused by Olanzapine

Abstract

We report a case of severe restless legs syndrome (RLS) that occurred as a side effect of olanzapine therapy. It was refractory to treatment with 2 mg of clonazepam and 3 mg ropinirole. There was partial relief with propoxyphene, however, it was stopped because of side effects. The symptoms disappeared once olanzapine was switched to another antipsychotic medication. Only two prior published reports associate olanzapine usage with development of RLS. In one report, low-dose benzodiazepines and ropinirole were associated with resolution of RLS symptoms stating dopamine depletion as the likely etiology. In our patient, however, RLS due to olanzapine was refractory to the trial of both high-dose benzodiazepine and ropinirole. This suggests that RLS occurring as a side effect of olanzapine therapy may have additional causative mechanisms beyond simple dopamine depletion as postulated before. High-dose narcotics, if tolerated, may be an alternative in such refractory cases.

Citation:

Khalid I; Rana L; Khalid TJ; Roehrs T. Refractory Restless Legs Syndrome Likely Caused by Olanzapine. J Clin Sleep Med 2009;5(1):68-69.

A 54-year-old female with 13-year history of major depression was seen in the psychiatry clinic because of manic symptoms. She had been on multiple antidepressant medications in the past with frequent relapses and poor response to therapy. She was maintained on paroxetine, and was being tapered over to duloxetine for her worsening depression when the manic episode unmasked. A diagnosis of bipolar disorder with acute manic episode and psychotic features was made, and the patient was admitted to an inpatient psychiatric facility. All of her medications were discontinued; olanzapine was initiated, and her psychotic symptoms improved. She was discharged after one week, on a therapeutic regimen of 20 mg of daily olanzapine.

Soon after starting olanzapine, while still an inpatient, the patient started experiencing unpleasant, deep paresthesias along with creeping crawling sensation in the legs in the evening. The symptoms increased in severity over time, particularly after discharge. They became so severe that she could not lie down in bed at night; she reported that she was able to relieve them only by walking. The symptoms would last through most of the night; the symptoms then decreased in the early morning. Her mood was otherwise good, and she did not report any other symptoms (including parkinsonian symptoms). A diagnosis of restless legs syndrome (RLS) was made. Her score on the International Restless Legs Scale was 36. Although the diagnosis of akathisia was entertained, clinical suspicion was low and patient did not respond to an empiric trial of benztropine, diphenhydramine, and atenolol. She underwent a thorough work-up, including measurement of iron and iron stores, BUN, creatinine, thyroid profile, glucose, rheumatoid factor, and clinical evaluation of other causes for restless legs syndrome. All findings were normal, including a normal serum ferritin level of 74 ng/mL (normal laboratory value ≥ 11 ng/mL). There was no history of caffeine intake.

Although the symptoms of RLS clearly began a day after starting olanzapine, given the patient’s good psychiatric recovery, it was decided to continue olanzapine and add therapy for RLS. The patient was placed on escalating doses of clonazepam up to 2 mg at night with no improvement. Clonazepam was then switched to ropinirole, which was slowly increased to 3 mg. The patient still had no relief and continued to have severe RLS symptoms. Along with ropinirole, propoxyphene was added to her regimen. She finally had partial relief with 130 mg of propoxyphene at bedtime and was able to sleep a few hours without symptoms. However, the RLS symptoms eventually woke her from sleep; she would then try to relieve her leg discomfort by walking, but she was drowsy and confused and bumped into things. Further increase in the narcotic dose was, therefore, not deemed safe.

It was finally decided to switch her olanzapine to aripiprazole. All medicines for RLS were discontinued. Olanzapine was then gradually tapered, and her symptoms subsided completely three days after the last dose of olanzapine. She has been maintained on aripiprazole and divalproex sodium without any complaints since then.

DISCUSSION

The stimulation of dopamine D₂ receptors has been proposed to cause the beneficial effects of RLS therapy.¹ Both olanzapine and aripiprazole are atypical antipsychotics, with aripiprazole acting as a partial agonist and olanzapine as a potent antagonist at the dopamine D₂ receptor.² Antipsychotic-induced RLS has been attributed to the blocking of such dopamine receptors.^3,4

Olanzapine has been associated with RLS in two published reports.^3,5 In these reports, patients developed symptoms of RLS, which resolved once olanzapine was discontinued. In one reported case series, low-dose benzodiazepines and ropinirole were associated with resolution of RLS symptoms and it was postulated that dopamine agonists may be used in relieving antipsychotic-induced RLS.³ In our patient, however, RLS due to olanzapine was refractory to the trial of both high-dose benzodiazepine and ropinirole. We know that weight profiles in patients treated with olanzapine are significantly associated with single nucleotide polymorphisms (SNP) in certain genes, e.g., SNP rs7412 of APOE gene.⁶ It was shown that in this SNP, the frequency of the minor allele was < 20% in patients weighing 40-60 kg and about 40% in patients weighing > 100 kg.⁶ Likewise, it is possible that there may be additional functional polymorphisms of other genes that alter not only the metabolism, but also the clinical response and side effect profile of olanzapine in certain patients (e.g., functional polymorphism of ABCB1 gene resulting in high brain olanzapine levels).⁷ Though the underlying etiology still has to be fully explored, our case nevertheless highlights the fact that RLS occurring as a side effect of olanzapine therapy likely has additional causative mechanisms beyond simple dopamine depletion as previously postulated.³

RLS arises from supraspinal sources, which favor facilitation of the flexor reflex and emergence of the RLS phenotype. Dopamine agonists like L-Dopa decrease early flexor reflex while increasing late flexor reflex.⁸ Opioids have been shown to relieve both the motor and sensory symptoms of RLS along with both early and late flexor reflex.⁸ They also have a potentiated effect when used in conjunction with D₂ receptor agonists like ropirinole.⁹ Our patient, likely for these reasons, had a partial response when high-dose propoxyphene was added to ropinirole. However, further escalation in narcotic dosage was not done due to the side effects.

The symptoms in our patient resolved when olanzapine was switched to aripiprazole. The difference in action on D₂ receptors (see above) or other dopamine receptors between the two drugs may explain why RLS was not seen with aripiprazole.

While future research focuses on further exploration of antipsychotic-induced RLS, the plausible solution in the interim is to switch olanzapine to another antipsychotic agent if RLS occurs. If this is not possible, a trial of low-dose dopamine or benzodiazepine agonist can be used. However, some cases like ours may be refractory, and high-dose narcotics may be an alternative.

DISCLOSURE STATEMENT

This was not an industry supported study. The authors have indicated no financial conflicts of interest.