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Olanzapine-induced restless legs syndrome
Journal of Clinical Neuroscience xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Olanzapine-induced restless legs syndrome Mangsuo Zhao a, Tongchao Geng a, Liyan Qiao a, Mingjie Zhang c, Jie Shi a, Fangjie Huang a, Xianzhong Lin a, Jing Wang a, Huancong Zuo b,⇑ a
Department of Neurology, Yuquan Hospital, Medical Center, Tsinghua University, Beijing, PR China Department of Neurosurgery, Yuquan Hospital, Medical Center, Tsinghua University, NO. 5 Shijingshan Road, Beijing 100049, PR China c School of Medicine, Nankai University, Tianjin, PR China b
a r t i c l e
i n f o
Article history: Received 24 July 2013 Accepted 9 January 2014 Available online xxxx Keywords: Antipsychotic drugs Olanzapine Restless legs syndrome Treatment
a b s t r a c t Only nine patients with olanzapine-induced restless legs syndrome (RLS) have been reported in the literature to our knowledge. We describe two patients with olanzapine-induced RLS treated at our hospital and review the nine reported patients. There were five women and six men aged between 28 and 62 years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20 mg. The symptoms improved in all patients when the dose was reduced and immediately disappeared when the medication was stopped. International Restless Legs Scale (IRLS) scores ranged from 10 to 35. Three patients had a family history of idiopathic RLS. Supplemental drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient, while two patients did not respond to the drug. Propoxyphene effectively relieved symptoms in one patient who did not respond to ropinirole or clonazepam. RLS symptoms did not recur following substitution of other antipsychotic drugs for olanzapine. In conclusion, olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. More than half of the patients experienced severe to very severe symptoms. A dose-dependent relationship was observed between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapine-induced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a strong urge to move the legs during periods of rest or inactivity, which is relieved by movement [1]. As awareness of RLS grows, it has become increasingly clear that certain medications, such as escitalopram, fluoxetine, L-dopa/carbidopa and pergolide, L-thyroxine, mianserin, mirtazapine, olanzapine and tramadol may cause RLS [2]. Nine patients with olanzapineinduced RLS have been reported [3–6]. Here, we report two patients treated in our department and review the nine cases reported in the literature. 2. Methods We report two patients with olanzapine-induced RLS treated in the Neurology Department of our hospital. A literature review was performed using the PubMed database with the search terms ⇑ Corresponding author. Tel.: +86 10 8825 9973; fax: +86 10 8825 5861. E-mail address: [email protected] (H. Zuo).
‘‘restless legs syndrome’’ and ‘‘olanzapine’’ (last performed 1 July 2013). References in the identified papers were scanned for additional relevant articles. 3. Results 3.1. Patient 1 A 59-year-old woman with tension-type headache and generalized anxiety disorder was admitted to the Neurology Department of our hospital. She was started on olanzapine 2.5 mg per night, lorazepam 0.5 mg per night, and citalopram 20 mg per day. On the second day after admission, olanzapine and lorazepam were increased to 5 mg and 1 mg per night, respectively, because the patient had difficulty falling asleep. On day 4 after admission, lorazepam was switched to clonazepam, 1 mg per night. On the sixth day, the patient experienced an uncomfortable tightening sensation in her legs when in bed. The paresthesia was relieved only by moving her legs and she had to walk around the ward during the night. However, the patient did not experience restlessness or demonstrate objective akathisia during the day. Furthermore,
http://dx.doi.org/10.1016/j.jocn.2014.01.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
2
M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
symptoms associated with a high dose of olanzapine, in particular parkinsonian signs, were not present. Ibuprofen (400 mg) administration did not control her symptoms. The patient did not have a personal or family history of RLS. Laboratory investigations including serum iron, ferritin, glucose, thyroid-stimulating hormone, and renal function tests were within normal limits. The neurological examination revealed no abnormalities and nerve conduction velocity (NCV) and electromyogram (EMG) were normal. She showed no clinical evidence of sleep apnea syndrome. The symptoms met the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria: (1) an urge to move the limbs with or without sensation, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night [1]. The patient was diagnosed with RLS associated with olanzapine. Her score on the International Restless Legs Scale (IRLS) [7] was 30. The patient’s condition immediately improved following the reduction of olanzapine to 2.5 mg per night, and her IRLS score decreased to 9. Her symptoms disappeared completely after discontinuation of olanzapine. However, the headaches recurred and the patient agreed to try olanzapine manufactured by a different pharmaceutical company. The initial dose was 2.5 mg per night increased to 5 mg per night 2 weeks later. Her headache markedly improved and the RLS symptoms did recur. She reported no RLS symptoms at 3 month follow-up. 3.2. Patient 2 A 51-year-old man with Meige’s syndrome and insomnia was admitted to our department. The patient was treated with 2.5 mg olanzapine per night, trihexyphenidyl 2 mg twice daily, and alprazolam 0.4 mg per night. He subsequently reported a tightening sensation in his legs when in bed. As he could relieve his paresthesia by moving or massaging his legs, he did not find it necessary to walk around. He experienced no additional symptoms associated with olanzapine; in particular, no parkinsonian signs were present. The patient did not have a personal or family history of RLS. Laboratory investigations including serum iron, ferritin, glucose, thyroid-stimulating hormone, and renal function tests were within normal limits. Neurological examination revealed no abnormalities, with the exception of involuntary eyelid and lower mandible movement, and NCV and EMG were normal. He had no clinical evidence of sleep apnea syndrome. He was diagnosed with RLS associated with olanzapine, and his IRLS score was 10. On the third day after admission, olanzapine was stopped, and his RLS symptoms disappeared immediately. The patient was then administered tiapride 0.2 g three times daily and clonazepam 1 mg per night to control the involuntary movement in his eyelids and lower mandible. He reported no RLS symptoms at 6 month follow-up. 3.3. Literature review We found nine previously reported cases of olanzapine-induced RLS in four published English-language studies (Table 1). Patients 1 and 2 are reported in the present study, Patient 3 was reported by Kraus et al. [6], Patient 4 by Khalid et al. [5], Patient 5–8 were reported by Kang et al. [4], and Aggarwal et al. [3] reported Patient 9–11. 3.4. Clinical features The 11 patients included five women and six men aged between 28 and 62 years. Of these, six patients were diagnosed with schizophrenia and three were diagnosed with bipolar disorder at a psychology department. One patient was diagnosed with tension-type headache and generalized anxiety disorder and one with Meige’s syndrome in our Department of Neurology. The doses of
olanzapine administered varied; however, RLS symptoms appeared between 2.5 and 20 mg. Patient 4 and 9 were diagnosed with akathisia for the first time, but benztropine, diphenhydramine, atenolol, and lorazepam did not control the symptoms. In two patients (Patient 5 and 8), RLS was initially thought to be psychotic agitation, and the olanzapine dose was increased to control the symptoms. The higher dose aggravated the restlessness; however, the RLS symptoms decreased following a reduction in the dose and completely resolved following the discontinuation of olanzapine. Similarly, RLS symptoms improved in the other patients following a decrease in the dose of olanzapine and disappeared immediately upon discontinuation of the drug. IRLS scores of seven patients varied from 10 to 35: one patient had mild symptoms (0–10), no patient scored in the moderate range (11–20), three experienced severe symptoms (21–30), and three patients had very severe symptoms (31–40). IRLS scores of the other four patients were not provided in the published papers. These findings indicate that more than half of the patients had severe to very severe RLS symptoms. No patient had a prior personal history of RLS, and three patients (Patient 5, 7, and 9) had a family history of idiopathic RLS. All patients met the IRLSSG diagnostic criteria for RLS, and no secondary cause of RLS was identified in any patient. 3.5. Drug treatment and replacement Antipsychotic drugs, such as maprotiline, amisulpride, and mirtazapine, were administered to three patients (Patient 3, 8, 10) simultaneously with olanzapine; citalopram was administered in two patients (Patient 1, 10). We found no evidence of a direct correlation between these drugs and RLS because the symptoms decreased or resolved following the discontinuation of olanzapine. Additional drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient (Patient 7) and had no effect in two patients (Patient 4 and 5). Propoxyphene controlled the symptoms in one patient (Patient 4) for whom ropinirole and clonazepam were ineffective. Gabapentin was not effective in Patient 5. Clonazepam in combination with diazepam and zolpidem moderately alleviated the RLS symptoms in Patient 6. Benzodiazepine was not effective in three patients (Patient 5, 7, and 9). Two patients (Patient 1 and 9) agreed to retry olanzapine manufactured by a different pharmaceutical company. RLS recurred in Patient 9 but RLS symptoms did not reappear in Patient 1, in whom olanzapine was gradually increased to 5 mg per night following 2 weeks at 2.5 mg per night. In a number of patients, olanzapine was replaced with another antipsychotic drug to control psychotic symptoms, such as tiapride, clozapine, aripiprazole, amisulpride, haloperidol, or quetiapine. RLS symptoms did not recur in these patients during the follow-up period. 4. Discussion Epidemiological studies indicate that the prevalence of RLS in the general population is 1–15% [8–12], and an estimated 3% of the general population have severe symptoms requiring pharmacological treatment [13]. Yet only 6.2% of patients with RLS symptoms who seek medical help reported being diagnosed with RLS [14]. RLS is widely underdiagnosed or misdiagnosed because the disorder is not well understood [15]. Several medications including olanzapine have been reported to induce RLS, but to our knowledge only 11 patients including the two presented here were found to have olanzapine-induced RLS. Thus, it is likely that olanzapine-induced RLS is also underdiagnosed or misdiagnosed, most likely as akathisia or psychotic agitation. Akathisia can be ruled out on the basis of dysesthesia in the legs rather than
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
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M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx Table 1 Reports of olanzapine-induced restless legs syndrome in 11 patients in the literature Patient
Sex
Age
Dose
Dose response
IRLS
Drug treatment
Drug replacement
1
F
59
5 mg
None
None
M M
51 41
2.5 mg 20 mg
10 Null
None None
Tiapride Clozapine
4
F
54
20 mg
Improve Disappear Disappear Improve Disappear Disappear
30
2 3
2.5 mg Stop Stop 10 mg Stop Stop
36
Aripiprazole
5
F
36
20 mg
30 mg 15 mg Stop
Aggravate Improve Disappear
31
6 7
M F
34 28
15 mg 20 mg
10 mg 15 mg
Improve Improve
27 21
8
M
59
5 mg
M F M
29 62 36
15 mg 2.5 mg 15 mg
Aggravate Disappear Disappear Disappear Improve Disappear
35
9 10 11
20 mg Stop Stop Stop 10 mg Stop
Overall ( ) Ropinirole ( ) Propoxyphene (+) Clonazepam ( ) Carbamazepine ( ) Ropinirole ( ) Gabapentin ( ) Zolpidem ( ) Clonazepam and diazepam and zolpidem (+) Clonazepam ( ) Propranolol ( ) Ropinirole (+) None
Null Null Null
Lorazepam ( ) None None
Amisulpride Haloperidol Clozapine
None None
Haloperidol Quetiapine None Quetiapine Aripiprazole
F = female, IRLS = International Restless Legs Scale, M = male, Null = data not provided by authors, Stop = cessation of olanzapine, (+) = drug treatment effective, ( ) = drug treatment not effective.
internal restlessness, worsening of symptoms at night, accompanying sleep disturbance, and symptom unresponsiveness to empiric treatment including benztropine, diphenhydramine, and atenolol. Olanzapine is generally increased when RLS is misdiagnosed as psychotic agitation, which is likely to aggravate the symptoms. We observed a positive dose-dependent relationship between olanzapine and RLS symptoms, such that RLS symptoms were aggravated at high doses, diminished at lower doses, and completely disappeared when the drug was stopped. In Patient 1, the RLS symptoms did not recur following administration of olanzapine manufactured by a different pharmaceutical company. In this patient, the olanzapine dose was gradually increased from 2.5 to 5 mg over a 2 week period. This finding suggests that a gradual increase in dose may prevent RLS symptoms. However, different ingredients used by different manufacturers cannot be ruled out. Three patients with a family history of idiopathic RLS developed olanzapine induced-RLS, indicating that family history may be a risk factor for the condition; however, the underlying mechanisms are not known. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS [16,17]. Furthermore, one study found that loss of BTBD9 significantly disrupted sleep with concomitant increases in waking and motor activity in a Drosophila model [18]. Recently Kang et al. reported that the BTBD9 gene affected susceptibility to antipsychotic-induced RLS [19]. This result is consistent with our finding that patients with a family history of idiopathic RLS were susceptible to olanzapine-induced RLS. Our findings suggest that it is important to increase the dose of olanzapine gradually and be vigilant for RLS symptoms during treatment, particularly in patients with a family history of idiopathic RLS. The pathophysiological mechanisms underlying RLS are not known; however, the observations that dopaminergic agents are an effective treatment [20] and dopamine receptor antagonists aggravate RLS symptoms in some patients, suggest a central role for the dopaminergic system. Ropinirole and pramipexole have been approved by the USA Food and Drug Administration to treat RLS [21,22]. Three patients in our review received ropinirole to control olanzapine-induced RLS symptoms, but the drug was
effective in only one patient. The reason for this is not clear. It may be that olanzapine has a higher affinity for the D2 and D3 receptors than ropinirole, however causative mechanisms other than dopamine depletion cannot be ruled out [5]. Propoxyphene may control olanzapine-induced RLS, though the most effective treatment is cessation of olanzapine or substituting another antipsychotic medication. It is important to note that other antipsychotic drugs such as haloperidol, thioridazine, loxapine, clozapine, risperidone, aripiprazole and quetiapine have been reported to cause RLS [23–27], but seven patients did not suffer RLS symptoms after substitution of one of these drugs in the follow-up period (Table 1). This suggests that even though antipsychotics can precipitate RLS symptoms, the susceptibility to RLS differs between patients. Such susceptibility differences might be attributable to biological factors, including pharmacokinetic factors and genetic vulnerability [4].
5. Conclusions Olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. The symptoms were severe to very severe in more than half of the patients we surveyed. We found a positive dose-effect relationship between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapineinduced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine.
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Acknowledgement This study was supported by the Tsinghua-Yuyuan Medical Science Foundation.
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
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M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
References [1] Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med 2003;4:101–19. [2] Hoque R, Chesson AL Jr. Pharmacologically induced/exacerbated restless legs syndrome, periodic limb movements of sleep, and REM behavior disorder/REM sleep without atonia: literature review, qualitative scoring, and comparative analysis. J Clin Sleep Med 2010;6:79–83. [3] Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with olanzapine: a case series. Curr Drug Saf 2010;5:129–31. [4] Kang SG, Lee HJ, Kim L. Restless legs syndrome and periodic limb movements during sleep probably associated with olanzapine. J Psychopharmacol 2009;23:597–601. [5] Khalid I, Rana L, Khalid TJ, et al. Refractory restless legs syndrome likely caused by olanzapine. J Clin Sleep Med 2009;5:68–9. [6] Kraus T, Schuld A, Pollmächer T. Periodic leg movements in sleep and restless legs syndrome probably caused by olanzapine. J Clin Psychopharmacol 1999;19:478–9. [7] Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003;4:121–32. [8] Chaudhuri KR, Forbes A, Grosset D, et al. Diagnosing restless legs syndrome (RLS) in primary care. Curr Med Res Opin 2004;20:1785–95. [9] Lavigne GJ, Montplaisir JY. Restless legs syndrome and sleep bruxism: prevalence and association among Canadians. Sleep 1994;17:739–43. [10] Oboler SK, Prochazka AV, Meyer TJ. Leg symptoms in outpatient veterans. West J Med 1991;155:256–9. [11] Phillips B, Hening W, Britz P, et al. Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest 2006;129:76–80. [12] Tan EK, Seah A, See SJ, et al. Restless legs syndrome in an Asian population: a study in Singapore. Mov Disord 2001;16:577–9. [13] Serafini A, Lorenzut S, Gigli GL, et al. The use of rotigotine in the treatment of restless legs syndrome. Ther Adv Neurol Disord 2010;3:241–8.
[14] Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005;165:1286–92. [15] Hadjigeorgiou GM, Stefanidis I, Dardiotis E, et al. Low RLS prevalence and awareness in central Greece: an epidemiological survey. Eur J Neurol 2007;14:1275–80. [16] Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639–47. [17] Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:1000–6. [18] Freeman A, Pranski E, Miller RD, et al. Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome. Curr Biol 2012;22:1142–8. [19] Kang SG, Lee HJ, Park YM, et al. The BTBD9 gene may be associated with antipsychotic-induced restless legs syndrome in schizophrenia. Hum Psychopharmacol 2013;28:117–23. [20] Hening WA, Allen RP, Earley CJ, et al. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep 2004;27:560–83. [21] Stiasny K, Wetter TC, Trenkwalder C, et al. Restless legs syndrome and its treatment by dopamine agonists. Parkinsonism Relat Disord 2000;7:21–5. [22] Bayard M, Avonda T, Wadzinski J. Restless legs syndrome. Am Fam Physician 2008;78:235–40. [23] Duggal HS, Mendhekar DN. Clozapine-associated restless legs syndrome. J Clin Psychopharmacol 2007;27:89–90. [24] Horiguchi J, Yamashita H, Mizuno S, et al. Nocturnal eating/drinking syndrome and neuroleptic-induced restless legs syndrome. Int Clin Psychopharmacol 1999;14:33–6. [25] Perez-Lloret S, Rey MV, Bondon-Guitton E, et al. Drugs associated with restless legs syndrome: a case/noncase study in the French Pharmacovigilance Database. J Clin Psychopharmacol 2012;32:824–7. [26] Rittmannsberger H, Werl R. Restless legs syndrome induced by quetiapine: report of seven cases and review of the literature. Int J Neuropsychopharmacol 2013;16:1427–31. [27] Wetter TC, Brunner J, Bronisch T. Restless legs syndrome probably induced by risperidone treatment. Pharmacopsychiatry 2002;35:109–11.
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
Contents lists available at ScienceDirect
Journal of Clinical Neuroscience journal homepage: www.elsevier.com/locate/jocn
Clinical Study
Olanzapine-induced restless legs syndrome Mangsuo Zhao a, Tongchao Geng a, Liyan Qiao a, Mingjie Zhang c, Jie Shi a, Fangjie Huang a, Xianzhong Lin a, Jing Wang a, Huancong Zuo b,⇑ a
Department of Neurology, Yuquan Hospital, Medical Center, Tsinghua University, Beijing, PR China Department of Neurosurgery, Yuquan Hospital, Medical Center, Tsinghua University, NO. 5 Shijingshan Road, Beijing 100049, PR China c School of Medicine, Nankai University, Tianjin, PR China b
a r t i c l e
i n f o
Article history: Received 24 July 2013 Accepted 9 January 2014 Available online xxxx Keywords: Antipsychotic drugs Olanzapine Restless legs syndrome Treatment
a b s t r a c t Only nine patients with olanzapine-induced restless legs syndrome (RLS) have been reported in the literature to our knowledge. We describe two patients with olanzapine-induced RLS treated at our hospital and review the nine reported patients. There were five women and six men aged between 28 and 62 years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20 mg. The symptoms improved in all patients when the dose was reduced and immediately disappeared when the medication was stopped. International Restless Legs Scale (IRLS) scores ranged from 10 to 35. Three patients had a family history of idiopathic RLS. Supplemental drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient, while two patients did not respond to the drug. Propoxyphene effectively relieved symptoms in one patient who did not respond to ropinirole or clonazepam. RLS symptoms did not recur following substitution of other antipsychotic drugs for olanzapine. In conclusion, olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. More than half of the patients experienced severe to very severe symptoms. A dose-dependent relationship was observed between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapine-induced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine. Ó 2014 Elsevier Ltd. All rights reserved.
1. Introduction Restless legs syndrome (RLS) is a sensorimotor disorder characterized by a strong urge to move the legs during periods of rest or inactivity, which is relieved by movement [1]. As awareness of RLS grows, it has become increasingly clear that certain medications, such as escitalopram, fluoxetine, L-dopa/carbidopa and pergolide, L-thyroxine, mianserin, mirtazapine, olanzapine and tramadol may cause RLS [2]. Nine patients with olanzapineinduced RLS have been reported [3–6]. Here, we report two patients treated in our department and review the nine cases reported in the literature. 2. Methods We report two patients with olanzapine-induced RLS treated in the Neurology Department of our hospital. A literature review was performed using the PubMed database with the search terms ⇑ Corresponding author. Tel.: +86 10 8825 9973; fax: +86 10 8825 5861. E-mail address: [email protected] (H. Zuo).
‘‘restless legs syndrome’’ and ‘‘olanzapine’’ (last performed 1 July 2013). References in the identified papers were scanned for additional relevant articles. 3. Results 3.1. Patient 1 A 59-year-old woman with tension-type headache and generalized anxiety disorder was admitted to the Neurology Department of our hospital. She was started on olanzapine 2.5 mg per night, lorazepam 0.5 mg per night, and citalopram 20 mg per day. On the second day after admission, olanzapine and lorazepam were increased to 5 mg and 1 mg per night, respectively, because the patient had difficulty falling asleep. On day 4 after admission, lorazepam was switched to clonazepam, 1 mg per night. On the sixth day, the patient experienced an uncomfortable tightening sensation in her legs when in bed. The paresthesia was relieved only by moving her legs and she had to walk around the ward during the night. However, the patient did not experience restlessness or demonstrate objective akathisia during the day. Furthermore,
http://dx.doi.org/10.1016/j.jocn.2014.01.007 0967-5868/Ó 2014 Elsevier Ltd. All rights reserved.
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
2
M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
symptoms associated with a high dose of olanzapine, in particular parkinsonian signs, were not present. Ibuprofen (400 mg) administration did not control her symptoms. The patient did not have a personal or family history of RLS. Laboratory investigations including serum iron, ferritin, glucose, thyroid-stimulating hormone, and renal function tests were within normal limits. The neurological examination revealed no abnormalities and nerve conduction velocity (NCV) and electromyogram (EMG) were normal. She showed no clinical evidence of sleep apnea syndrome. The symptoms met the International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria: (1) an urge to move the limbs with or without sensation, (2) worsening at rest, (3) improvement with activity, and (4) worsening in the evening or night [1]. The patient was diagnosed with RLS associated with olanzapine. Her score on the International Restless Legs Scale (IRLS) [7] was 30. The patient’s condition immediately improved following the reduction of olanzapine to 2.5 mg per night, and her IRLS score decreased to 9. Her symptoms disappeared completely after discontinuation of olanzapine. However, the headaches recurred and the patient agreed to try olanzapine manufactured by a different pharmaceutical company. The initial dose was 2.5 mg per night increased to 5 mg per night 2 weeks later. Her headache markedly improved and the RLS symptoms did recur. She reported no RLS symptoms at 3 month follow-up. 3.2. Patient 2 A 51-year-old man with Meige’s syndrome and insomnia was admitted to our department. The patient was treated with 2.5 mg olanzapine per night, trihexyphenidyl 2 mg twice daily, and alprazolam 0.4 mg per night. He subsequently reported a tightening sensation in his legs when in bed. As he could relieve his paresthesia by moving or massaging his legs, he did not find it necessary to walk around. He experienced no additional symptoms associated with olanzapine; in particular, no parkinsonian signs were present. The patient did not have a personal or family history of RLS. Laboratory investigations including serum iron, ferritin, glucose, thyroid-stimulating hormone, and renal function tests were within normal limits. Neurological examination revealed no abnormalities, with the exception of involuntary eyelid and lower mandible movement, and NCV and EMG were normal. He had no clinical evidence of sleep apnea syndrome. He was diagnosed with RLS associated with olanzapine, and his IRLS score was 10. On the third day after admission, olanzapine was stopped, and his RLS symptoms disappeared immediately. The patient was then administered tiapride 0.2 g three times daily and clonazepam 1 mg per night to control the involuntary movement in his eyelids and lower mandible. He reported no RLS symptoms at 6 month follow-up. 3.3. Literature review We found nine previously reported cases of olanzapine-induced RLS in four published English-language studies (Table 1). Patients 1 and 2 are reported in the present study, Patient 3 was reported by Kraus et al. [6], Patient 4 by Khalid et al. [5], Patient 5–8 were reported by Kang et al. [4], and Aggarwal et al. [3] reported Patient 9–11. 3.4. Clinical features The 11 patients included five women and six men aged between 28 and 62 years. Of these, six patients were diagnosed with schizophrenia and three were diagnosed with bipolar disorder at a psychology department. One patient was diagnosed with tension-type headache and generalized anxiety disorder and one with Meige’s syndrome in our Department of Neurology. The doses of
olanzapine administered varied; however, RLS symptoms appeared between 2.5 and 20 mg. Patient 4 and 9 were diagnosed with akathisia for the first time, but benztropine, diphenhydramine, atenolol, and lorazepam did not control the symptoms. In two patients (Patient 5 and 8), RLS was initially thought to be psychotic agitation, and the olanzapine dose was increased to control the symptoms. The higher dose aggravated the restlessness; however, the RLS symptoms decreased following a reduction in the dose and completely resolved following the discontinuation of olanzapine. Similarly, RLS symptoms improved in the other patients following a decrease in the dose of olanzapine and disappeared immediately upon discontinuation of the drug. IRLS scores of seven patients varied from 10 to 35: one patient had mild symptoms (0–10), no patient scored in the moderate range (11–20), three experienced severe symptoms (21–30), and three patients had very severe symptoms (31–40). IRLS scores of the other four patients were not provided in the published papers. These findings indicate that more than half of the patients had severe to very severe RLS symptoms. No patient had a prior personal history of RLS, and three patients (Patient 5, 7, and 9) had a family history of idiopathic RLS. All patients met the IRLSSG diagnostic criteria for RLS, and no secondary cause of RLS was identified in any patient. 3.5. Drug treatment and replacement Antipsychotic drugs, such as maprotiline, amisulpride, and mirtazapine, were administered to three patients (Patient 3, 8, 10) simultaneously with olanzapine; citalopram was administered in two patients (Patient 1, 10). We found no evidence of a direct correlation between these drugs and RLS because the symptoms decreased or resolved following the discontinuation of olanzapine. Additional drugs were administered to control RLS symptoms in five patients. Ropinirole was effective in one patient (Patient 7) and had no effect in two patients (Patient 4 and 5). Propoxyphene controlled the symptoms in one patient (Patient 4) for whom ropinirole and clonazepam were ineffective. Gabapentin was not effective in Patient 5. Clonazepam in combination with diazepam and zolpidem moderately alleviated the RLS symptoms in Patient 6. Benzodiazepine was not effective in three patients (Patient 5, 7, and 9). Two patients (Patient 1 and 9) agreed to retry olanzapine manufactured by a different pharmaceutical company. RLS recurred in Patient 9 but RLS symptoms did not reappear in Patient 1, in whom olanzapine was gradually increased to 5 mg per night following 2 weeks at 2.5 mg per night. In a number of patients, olanzapine was replaced with another antipsychotic drug to control psychotic symptoms, such as tiapride, clozapine, aripiprazole, amisulpride, haloperidol, or quetiapine. RLS symptoms did not recur in these patients during the follow-up period. 4. Discussion Epidemiological studies indicate that the prevalence of RLS in the general population is 1–15% [8–12], and an estimated 3% of the general population have severe symptoms requiring pharmacological treatment [13]. Yet only 6.2% of patients with RLS symptoms who seek medical help reported being diagnosed with RLS [14]. RLS is widely underdiagnosed or misdiagnosed because the disorder is not well understood [15]. Several medications including olanzapine have been reported to induce RLS, but to our knowledge only 11 patients including the two presented here were found to have olanzapine-induced RLS. Thus, it is likely that olanzapine-induced RLS is also underdiagnosed or misdiagnosed, most likely as akathisia or psychotic agitation. Akathisia can be ruled out on the basis of dysesthesia in the legs rather than
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
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M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx Table 1 Reports of olanzapine-induced restless legs syndrome in 11 patients in the literature Patient
Sex
Age
Dose
Dose response
IRLS
Drug treatment
Drug replacement
1
F
59
5 mg
None
None
M M
51 41
2.5 mg 20 mg
10 Null
None None
Tiapride Clozapine
4
F
54
20 mg
Improve Disappear Disappear Improve Disappear Disappear
30
2 3
2.5 mg Stop Stop 10 mg Stop Stop
36
Aripiprazole
5
F
36
20 mg
30 mg 15 mg Stop
Aggravate Improve Disappear
31
6 7
M F
34 28
15 mg 20 mg
10 mg 15 mg
Improve Improve
27 21
8
M
59
5 mg
M F M
29 62 36
15 mg 2.5 mg 15 mg
Aggravate Disappear Disappear Disappear Improve Disappear
35
9 10 11
20 mg Stop Stop Stop 10 mg Stop
Overall ( ) Ropinirole ( ) Propoxyphene (+) Clonazepam ( ) Carbamazepine ( ) Ropinirole ( ) Gabapentin ( ) Zolpidem ( ) Clonazepam and diazepam and zolpidem (+) Clonazepam ( ) Propranolol ( ) Ropinirole (+) None
Null Null Null
Lorazepam ( ) None None
Amisulpride Haloperidol Clozapine
None None
Haloperidol Quetiapine None Quetiapine Aripiprazole
F = female, IRLS = International Restless Legs Scale, M = male, Null = data not provided by authors, Stop = cessation of olanzapine, (+) = drug treatment effective, ( ) = drug treatment not effective.
internal restlessness, worsening of symptoms at night, accompanying sleep disturbance, and symptom unresponsiveness to empiric treatment including benztropine, diphenhydramine, and atenolol. Olanzapine is generally increased when RLS is misdiagnosed as psychotic agitation, which is likely to aggravate the symptoms. We observed a positive dose-dependent relationship between olanzapine and RLS symptoms, such that RLS symptoms were aggravated at high doses, diminished at lower doses, and completely disappeared when the drug was stopped. In Patient 1, the RLS symptoms did not recur following administration of olanzapine manufactured by a different pharmaceutical company. In this patient, the olanzapine dose was gradually increased from 2.5 to 5 mg over a 2 week period. This finding suggests that a gradual increase in dose may prevent RLS symptoms. However, different ingredients used by different manufacturers cannot be ruled out. Three patients with a family history of idiopathic RLS developed olanzapine induced-RLS, indicating that family history may be a risk factor for the condition; however, the underlying mechanisms are not known. Genome-wide association studies have identified a polymorphism in an intronic region of the BTBD9 gene on chromosome 6 that confers substantial risk for RLS [16,17]. Furthermore, one study found that loss of BTBD9 significantly disrupted sleep with concomitant increases in waking and motor activity in a Drosophila model [18]. Recently Kang et al. reported that the BTBD9 gene affected susceptibility to antipsychotic-induced RLS [19]. This result is consistent with our finding that patients with a family history of idiopathic RLS were susceptible to olanzapine-induced RLS. Our findings suggest that it is important to increase the dose of olanzapine gradually and be vigilant for RLS symptoms during treatment, particularly in patients with a family history of idiopathic RLS. The pathophysiological mechanisms underlying RLS are not known; however, the observations that dopaminergic agents are an effective treatment [20] and dopamine receptor antagonists aggravate RLS symptoms in some patients, suggest a central role for the dopaminergic system. Ropinirole and pramipexole have been approved by the USA Food and Drug Administration to treat RLS [21,22]. Three patients in our review received ropinirole to control olanzapine-induced RLS symptoms, but the drug was
effective in only one patient. The reason for this is not clear. It may be that olanzapine has a higher affinity for the D2 and D3 receptors than ropinirole, however causative mechanisms other than dopamine depletion cannot be ruled out [5]. Propoxyphene may control olanzapine-induced RLS, though the most effective treatment is cessation of olanzapine or substituting another antipsychotic medication. It is important to note that other antipsychotic drugs such as haloperidol, thioridazine, loxapine, clozapine, risperidone, aripiprazole and quetiapine have been reported to cause RLS [23–27], but seven patients did not suffer RLS symptoms after substitution of one of these drugs in the follow-up period (Table 1). This suggests that even though antipsychotics can precipitate RLS symptoms, the susceptibility to RLS differs between patients. Such susceptibility differences might be attributable to biological factors, including pharmacokinetic factors and genetic vulnerability [4].
5. Conclusions Olanzapine can induce RLS, particularly in patients with a family history of idiopathic RLS. The symptoms were severe to very severe in more than half of the patients we surveyed. We found a positive dose-effect relationship between olanzapine and RLS symptoms. A gradual increase in dose may prevent olanzapineinduced RLS. The optimal treatment for olanzapine-induced RLS is discontinuation of olanzapine.
Conflicts of interest/disclosures The authors declare that they have no financial or other conflicts of interest in relation to this research and its publication.
Acknowledgement This study was supported by the Tsinghua-Yuyuan Medical Science Foundation.
Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007
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M. Zhao et al. / Journal of Clinical Neuroscience xxx (2014) xxx–xxx
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Please cite this article in press as: Zhao M et al. Olanzapine-induced restless legs syndrome. J Clin Neurosci (2014), http://dx.doi.org/10.1016/ j.jocn.2014.01.007