Olanzapine-induced restless legs syndrome: Two case reports

Abstract

BACKGROUND

Olanzapine, a second-generation antipsychotic acting as a serotonin-dopamine antagonist, is widely used in the treatment of schizophrenia, bipolar disorder and other psychiatric illnesses. Common adverse effects of olanzapine include somnolence, weight gain, metabolic syndrome, and extrapyramidal symptoms. However, olanzapine-induced restless legs syndrome (RLS) is a rare adverse reaction, with a reported incidence of only 0.5%-2.3% in clinical trials, which is easily overlooked in clinical practice. To date, few case reports have systematically described the clinical characteristics of olanzapine-induced RLS in schizophrenia patients with long-term disease course and multiple comorbidities. I here report two cases of olanzapine-induced RLS, summarize the diagnostic and therapeutic experience, and review relevant literature to improve clinicians’ awareness of this adverse reaction.

CASE SUMMARY

The clinical data of two chronic schizophrenia patients who developed RLS after olanzapine administration in December of the admission year were retrospectively collected and analyzed. Combined with a systematic review of relevant literature, the pathogenesis, differential diagnosis and management strategies of olanzapine-induced RLS were discussed.

CONCLUSION

Olanzapine may induce RLS by interfering with the dopaminergic system and iron metabolism. Clinicians should closely monitor sleep quality and lower extremity discomfort in schizophrenia patients treated with olanzapine, promptly identify RLS and implement individualized interventions to improve treatment adherence and quality of life.

Key Words: Olanzapine; Restless legs syndrome; Schizophrenia; Adverse drug reaction; Case report

Core Tip: Olanzapine-induced restless legs syndrome (RLS) is a rare adverse drug reaction with an incidence of only 0.5%-2.3%, easily ignored in psychiatric practice. This article reports two elderly female schizophrenia patients complicated with multiple physical illnesses who developed typical RLS after olanzapine administration. We analyze its possible mechanisms related to dopaminergic dysfunction and abnormal iron metabolism, summarize individualized dose adjustment and antipsychotic switching strategies, and remind clinicians to actively screen RLS symptoms during olanzapine treatment.

INTRODUCTION

Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a common sensorimotor disorder characterized by an irresistible urge to move the legs, often accompanied by paresthesia such as tingling, crawling, or burning sensations[1]. Symptoms typically worsen at rest or during nighttime sleep, leading to severe sleep disruption and impaired quality of life[2]. The global prevalence of RLS is approximately 5%-10%, with a higher incidence in the elderly and females[3]. Olanzapine, a second-generation antipsychotic acting as a serotonin-dopamine antagonist, is widely used in the treatment of schizophrenia, bipolar disorder and other psychiatric illnesses[4]. Common adverse effects of olanzapine include somnolence, weight gain, metabolic syndrome, and extrapyramidal symptoms[5]. However, olanzapine-induced RLS is a rare adverse reaction, with a reported incidence of only 0.5%-2.3% in clinical trials[6], which is easily overlooked in clinical practice. To date, few case reports have systematically described the clinical characteristics of olanzapine-induced RLS in schizophrenia patients with long-term disease course and multiple comorbidities. This report describes two cases of olanzapine-induced RLS, summarizes the diagnostic and therapeutic experience, and reviews relevant literature to improve clinicians’ awareness of this adverse reaction.

CASE PRESENTATION

Chief complaints

Case 1: The patient gradually developed delusions of persecution and abnormal behavior over 17 years.

Case 2: The patient showed behavioral disturbance and irritability for 1 month, with a total disease duration of over 30 years.

History of present illness

Case 1: The patient had previously received multiple antipsychotics including risperidone, quetiapine, clozapine, perphenazine, amisulpride, and ziprasidone, with partial symptom improvement but frequent relapses due to poor medication adherence. The initial treatment regimen after admission consisted of olanzapine 5 mg once nightly (qn) (for psychiatric symptoms), levothyroxine sodium (for hypothyroidism), metformin (for hyperglycemia), valsartan + levamlodipine besylate (for hypertension), and eszopiclone (for sleep improvement). On the 10^th day after admission (December 9^th), the patient complained of “nocturnal dysesthesia in lower limbs”, accompanied by severe insomnia (no sleep at night and no drowsiness during the day) and obvious anxiety about sleep. Symptom characteristics included discomfort aggravated at rest, temporarily relieved by moving legs or walking, no signs of organic lesions such as redness, swelling, pain, or numbness in the lower extremities. The symptoms fully met the International RLS Study Group diagnostic criteria[7].

Case 2: The patient had previously used antipsychotics including chlorpromazine, clozapine, olanzapine, and sodium valproate. Recently, she took olanzapine 5 mg once daily (qd) + sodium valproate 0.5 g qd at home, but discontinued medication voluntarily, leading to disease exacerbation. Initial treatment after admission was quetiapine, then switched to olanzapine 2.5 mg qn (gradually increased), combined with sodium valproate and haloperidol for symptom control. On the 19^th day after admission (December 9^th), the patient complained of poor nighttime sleep, and “feeling that legs have no place to rest”. The symptom was emphasized again on December 20^th, characterized by aggravation at rest, slight relief after activity, and severe impact on falling asleep. No signs of organic lesions in the lower extremities were found. Symptoms appeared to be correlated with the increase in olanzapine dose (gradually increased to 12.5 mg qd).

History of past illness

Case 1: Past medical history included chronic schizophrenia (chronic persistent type) diagnosed in multiple hospitals since 2007; essential hypertension (grade 3) with stable blood pressure controlled by valsartan and levamlodipine besylate; type 2 diabetes mellitus with stable blood glucose managed by metformin; hypothyroidism treated with levothyroxine sodium tablets.

Case 2: Past medical history included chronic schizophrenia diagnosed in 1995; essential hypertension (grade 3) with blood pressure controlled by levamlodipine besylate and irbesartan; sinus bradycardia; fatty liver; post-cholecystectomy.

Personal and family history

Case 1: No special personal or family history.

Case 2: No special personal or family history.

Physical examination

Case 1: No abnormalities were found on cardiopulmonary and abdominal examinations, normal muscle strength and tone of extremities, and no obvious abnormalities on neurological examination.

Case 2: No abnormalities were found on cardiopulmonary and abdominal examinations; muscle strength and tone of extremities were normal; and there were no obvious abnormalities on neurological examination.

Laboratory examinations

Case 1: Routine blood, urine, stool tests, electrolytes, liver and kidney function, and thyroid function were all within normal ranges. Serum ferritin and transferrin saturation were not detected due to limited preserved inpatient residual blood specimens.

Case 2: Routine blood, urine, and stool tests were normal, random blood glucose was 5.80 mmol/L, and electrolytes (potassium 4.13 mmol/L, sodium 138.9 mmol/L, chloride 102.5 mmol/L, calcium 2.36 mmol/L) were normal. Liver function tests showed elevated levels of alanine aminotransferase 69 U/L, γ-glutamyl transpeptidase 57 U/L, and total cholesterol 5.52 mmol/L. Thyroid function tests revealed elevated levels of anti-thyroglobulin antibody 20.24 KIU/L, and anti-thyroid peroxidase antibody 44.71 KIU/L. Serum ferritin and transferrin saturation were not detected due to limited preserved inpatient residual blood specimens.

Imaging examinations

Case 1: No obvious abnormalities were found.

Case 2: Cardiac color doppler ultrasound revealed mild left ventricular diastolic dysfunction and mild mitral regurgitation, abdominal ultrasound showed fatty liver and senile uterine atrophy, and no abnormalities on lower extremity vascular ultrasound. Electrocardiogram showed sinus bradycardia (52 beats/minute).

FINAL DIAGNOSIS

Case 1

The patient was comprehensively diagnosed with olanzapine-induced RLS, chronic persistent schizophrenia, grade 3 essential hypertension, type 2 diabetes mellitus and hypothyroidism.

Case 2

The final comprehensive diagnoses of this patient included olanzapine-induced RLS, chronic schizophrenia, grade 3 essential hypertension, sinus bradycardia and fatty liver.

TREATMENT

Case 1

December 9^th: Discontinued eszopiclone and Tianmeng Oral Liquid 10 mL twice daily was added for sleep improvement.

December 12^th: Zopiclone 7.5 mg qn was added with no significant improvement in RLS symptoms.

December 14^th: Confirmed olanzapine-induced RLS; a clozapine 25 mg qd, tapering schedule was initiated: Olanzapine was reduced by 2.5 mg every 3 days with gradual clozapine dose escalation.

December 16^th: Clozapine was increased to 50 mg qd, and olanzapine decreased to 5 mg qn.

December 25^th: Olanzapine was discontinued and clozapine adjusted to 75 mg qd. The patient reported complete resolution of lower extremity discomfort and significant improvement in sleep. Psychometric scales: Brief Psychiatric Rating Scale (BPRS) score 45; Positive and Negative Syndrome Scale (PANSS) score 53; RLS Rating Scale (RLSS) score 3. No other adverse drug reactions were observed.

Case 2

December 9^th: Olanzapine was increased to 12.5 mg qd, and lorazepam was decreased to 1 mg qn; the patient also received adjuvant group biofeedback therapy and occupational therapy.

December 20^th: Olanzapine-induced RLS was confirmed; olanzapine was adjusted to 5 mg bid, and zopiclone 0.75 mg qn and lorazepam 1 mg qn were added for sleep improvement. One week after adjustment, the patient reported significant improvement in nighttime sleep and obvious relief of lower extremity discomfort. Psychometric scales: BPRS score 38; PANSS score 65; RLSS score 5. No new adverse reactions were observed, and psychiatric symptoms were stably controlled.

OUTCOME AND FOLLOW-UP

Case 1

The patient reported complete resolution of lower extremity discomfort and significant improvement in sleep. Psychometric scales: BPRS score 45; PANSS score 53; RLSS score 3. No other adverse drug reactions were observed.

Case 2

The patient reported significant improvement in nighttime sleep and obvious relief of lower extremity discomfort. Psychometric scales: BPRS score 38; PANSS score 65; RLSS score 5. No new adverse reactions were observed, and psychiatric symptoms were stably controlled.

Table 1 summary of admission course, olanzapine dosage changes, restless legs syndrome onset, interventions and clinical outcomes in two patients with olanzapine-induced restless legs syndrome.

Table 1 Summary of admission course, olanzapine dosage changes, restless legs syndrome onset, interventions and clinical outcomes in two patients with olanzapine-induced restless legs syndrome.

Case	Admission information	Onset and clinical features of RLS	Therapeutic interventions	Improvement of clinical symptoms
1	Hospitalized in late November; RLS occurred on the 10th hospital day (December 9th)	Symptom onset on December 9th; intractable unexplained bilateral lower-extremity discomfort exacerbated at rest and alleviated by limb movement, accompanied by severe insomnia and sleep-related anxiety; baseline RLSS score = 22	December 9th: Eszopiclone discontinued, Tianmeng Oral Liquid 10 mL bid prescribed for insomnia	Complete resolution of lower-extremity discomfort and prominent sleep improvement on December 25th; RLSS decreased to 3; no newly emerging adverse drug reactions
			December 12th: Zopiclone 75 mg qn supplemented
			December 14th: Diagnosis of olanzapine-induced RLS confirmed; antipsychotic switching strategy implemented
2	Hospitalized in mid-November; initial RLS complaint on the 19th hospital day (December 9th), symptom aggravation on December 20th	Initial leg discomfort reported on December 9th and aggravated on December 20th; intolerable in-situ restlessness of lower limbs worsening at rest and partially relieved by physical activity, resulting in obvious sleep-onset difficulty; baseline RLSS score = 18	December 9th: Olanzapine dose elevation, lorazepam reduced to 1 mg qn; adjuvant biofeedback and occupational therapy provided	Markedly improved nocturnal sleep and substantial relief of leg discomfort 1 week after medication adjustment; RLSS declined to 5; psychiatric symptoms remained stable without additional adverse events
			December 20th: Olanzapine downtitrated; zopiclone 0.75 mg qn plus lorazepam 1 mg qn added

qn: Once nightly; bid: Twice daily; RLSS: Restless Legs Syndrome Rating Scale; RLS: Restless legs syndrome.

DISCUSSION

The exact pathogenesis of olanzapine-induced RLS remains unclear. Based on current studies, the following mechanisms are hypothesized: Dopaminergic imbalance is the mainstream RLS pathogenesis[8]. Olanzapine competitively blocks central D2 receptors[9], inhibits nigrostriatal and mesolimbic dopaminergic transmission, breaks monoamine balance between dopamine, serotonin and norepinephrine to induce RLS[10]. High-dose olanzapine (≥ 10 mg/day) correlated with higher RLS incidence in a previous cohort study, confirming dosage-dependent risk[11]. Individual hepatic drug metabolic polymorphism also leads to variable olanzapine blood concentration among patients, partially explaining inter-individual susceptibility discrepancy of drug-induced RLS. Low D2 affinity of clozapine accounts for effective RLS remission after antipsychotic replacement in case 1. Iron is an essential cofactor for tyrosine hydroxylase, the rate-limiting enzyme in dopamine synthesis[12]. Iron deficiency can reduce dopamine synthesis and release in the brain, leading to RLS[13]. Olanzapine may affect iron metabolism through multiple pathways: (1) Inhibiting intestinal iron absorption by altering gastrointestinal motility; (2) Reducing iron transport across the blood-brain barrier by downregulating the expression of iron transporters (such as ferroportin); and (3) Increasing iron storage in hepatocytes, leading to relative iron deficiency in the brain[14]. Previous cross-sectional research verified lower serum ferritin in olanzapine-related RLS patients[15]; our study could not obtain iron metabolism biomarkers due to specimen limitation, which has been listed as a research limitation.

Genetic factors may also contribute to olanzapine-induced RLS. Previous studies have identified several genes associated with primary RLS, including BTBD9, MEIS1, and MAP2K5[16]. Patients carrying these risk gene polymorphisms may be more susceptible to RLS when exposed to olanzapine[17]. Gene detection was not conducted in the current two cases for objective restriction, as relevant discussion remains literature-based.

The two cases in this study share several common clinical characteristics: (1) Both patients were middle-aged and elderly females, which is consistent with the epidemiological characteristics of RLS (higher incidence in females and the elderly)[3]; (2) Both had long-term chronic schizophrenia with multiple prior antipsychotic treatments, suggesting that patients with long-term psychiatric illness may be more vulnerable to drug-induced RLS; (3) RLS symptoms occurred after olanzapine administration and were correlated with dose adjustment, which is a key clue for diagnosing drug-induced RLS; (4) Symptoms were typical of RLS (aggravation at rest, relief after activity, sleep disturbance) and responded well to olanzapine dose adjustment or replacement; and (5) No obvious abnormalities were found on physical examinations and laboratory tests, excluding organic causes.

The differences between the two cases mainly lie in: (1) Comorbidities: Case 1 had multiple comorbidities including diabetes mellitus and hypothyroidism, while case 2 had sinus bradycardia and fatty liver, indicating that comorbid somatic diseases may complicate the clinical manifestations of RLS; and (2) Treatment strategies: Case 1 was switched to clozapine due to poor olanzapine efficacy and obvious RLS symptoms, while case 2 only required olanzapine dose adjustment and adjuvant symptomatic treatment due to stable psychiatric symptom control.

Distinctive features of the present cases: Both patients experienced over 15 years of chronic schizophrenia accompanied by multiple age-related chronic internal diseases; comorbid physical disorders interfere with the clinical identification of RLS vs neuropathy/akathisia; individualized regimens verified feasible for the comorbid elderly population, providing new real-world clinical data to supplement existing published case reports.

Based on these two cases and the relevant literature, the clinical management of olanzapine-induced RLS should follow the following principles.

Clinicians should routinely assess sleep quality and lower extremity discomfort in schizophrenia patients treated with olanzapine, especially during dose adjustment. The International RLS Study Group diagnostic criteria[7] and RLSS score[18] can be used to confirm the diagnosis. Differential diagnosis should exclude primary RLS, organic diseases (lumbar spine lesions, peripheral neuropathy, vascular diseases), electrolyte disturbances, and RLS induced by other drugs.

Individual intervention measures include the following: (1) Dose adjustment: If psychiatric symptoms are stably controlled, reducing the olanzapine dose may relieve RLS symptoms[19]. For example, in case 2, RLS symptoms improved after olanzapine was adjusted from 12.5 mg/day to 10 mg/day; (2) Drug replacement: If dose adjustment fails to relieve symptoms or psychiatric symptoms worsen, switching to antipsychotics with low affinity for dopamine D2 receptors (such as clozapine, quetiapine) may be considered[20]. Selection of clozapine requires strict routine blood surveillance due to agranulocytosis risk. Existing meta-analyses show a lower RLS incidence under clozapine and quetiapine vs olanzapine, summarized in this paragraph. Case 1 achieved good results after switching from olanzapine to clozapine; and (3) Adjuvant symptomatic treatment: Dopaminergic agonists (such as pramipexole, ropinirole) are first-line drugs for RLS treatment[21], but should be used with caution in schizophrenia patients due to the risk of worsening psychiatric symptoms. Benzodiazepines (such as zopiclone, lorazepam) can improve sleep and relieve anxiety associated with RLS[22], as used in case 2. Iron supplementation may be effective if iron deficiency is confirmed (serum ferritin)[23].

Comprehensive management includes the following: (1) Monitoring somatic conditions: Regularly check routine blood, liver and kidney function, electrolytes, thyroid function, and iron metabolism indicators to avoid aggravation of RLS due to comorbidities; (2) Health education: Inform patients and their guardians about the symptoms of RLS and the importance of medication adherence, and advise them to promptly report any discomfort; and (3) Non-pharmacological interventions: Encourage moderate exercise (such as walking, stretching), avoid caffeine and alcohol intake, and maintain a regular sleep schedule, which can assist in relieving RLS symptoms[24].

CONCLUSION

Olanzapine-induced RLS is a rare but clinically significant adverse reaction. The pathogenesis may be related to dopaminergic system dysregulation and iron metabolism abnormalities. Clinicians should be alert to RLS symptoms in schizophrenia patients treated with olanzapine, conduct timely diagnosis and differential diagnosis, and implement individualized interventions such as dose adjustment, drug replacement, and adjuvant symptomatic treatment. Future studies should focus on exploring the exact pathogenesis of olanzapine-induced RLS and optimizing treatment strategies to improve the prognosis of patients.

ACKNOWLEDGEMENTS

I thank the medical staff of the Department of Psychiatry, Jurong Mental Hospital for their assistance in data collection.