The BTBD9 gene may be associated with antipsychotic-induced restless legs syndrome in schizophrenia

Department of Psychiatry, Gachon University, School of Medicine, Incheon, Korea.
Human Psychopharmacology Clinical and Experimental (Impact Factor: 2.19). 03/2013; 28(2). DOI: 10.1002/hup.2287
Source: PubMed


A genome-wide association study and several replication studies have shown significant association between BTBD9 gene single nucleotide polymorphisms and restless legs syndrome (RLS). The aim of this study is to investigate the association between the BTBD9 gene polymorphisms and antipsychotic-induced RLS in schizophrenic patients.

Restless legs syndrome symptoms were evaluated using the diagnostic criteria of the International Restless Legs Syndrome Study Group in 190 Korean schizophrenic patients. We genotyped the rs9357271 and rs3923809 polymorphisms of the BTBD9 gene in schizophrenic patients with (n = 96) and without (n = 94) RLS symptoms.

There was a significant difference in the allele frequency (χ(2) = 8.14, p = 0.004) of the rs9357271 polymorphism between schizophrenic patients with and without RLS symptoms. Significant genotypic association of this single nucleotide polymorphisms with RLS symptoms was also observed for the dominant model (χ(2) = 10.32, p = 0.001) and heterozygous model (χ(2) = 10.9, p = 0.001). When we compared the frequencies of the rs3923809-rs9357271 haplotypes between the two groups, the overall haplotype frequencies were significantly different (permuted p = 0.037), and the A-T haplotype was significantly more frequent in the RLS symptom group than in the no RLS symptom group (0.112 vs. 0.041, permuted p = 0.007).

These data suggest that the BTBD9 gene is associated with antipsychotic-induced RLS symptoms in schizophrenic patients.

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    • "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. "
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    ABSTRACT: 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 62years in the overall group. RLS symptoms emerged at olanzapine doses between 2.5 and 20mg. 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.
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    ABSTRACT: Previous studies have suggested that there is a genetic basis to restless legs syndrome (RLS) development. Occurrence of antipsychotic-induced RLS could also be due to differences in genetic susceptibility. We investigated whether CLOCK and NPAS2 gene polymorphisms are associated with RLS in schizophrenic patients on antipsychotics because RLS symptoms usually manifest during the evening and night. We assessed symptoms of RLS in 190 Korean schizophrenic patients on antipsychotics and divided the subjects into two groups according to the International Restless Legs Syndrome Study Group diagnostic criteria: (i) subjects who met all the criteria and (ii) the remaining subjects who did not meet all the criteria. We found a significant difference in the number of subjects with different genotype and allele carrier frequencies for the CLOCK gene (rs2412646) between the two groups (p = 0.031 and 0.010, respectively). Distribution of CLOCK haplotypes (rs2412646-rs1801260) was significantly different between schizophrenic patients with and without RLS (p = 0.021). However, the distributions of allelic, genotypic, and haplotypic variants of NPAS2 (rs2305160 and rs6725296) were not significantly different between the two groups. Our results suggest that CLOCK polymorphisms are associated with increased susceptibility of schizophrenic patients to RLS. We hypothesize that RLS in schizophrenia patients treated with antipsychotics may be a very mild akathisia that manifests during the night and is under control of circadian oscillation.
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    ABSTRACT: Both subjective and objective assessments of sleep patterns in schizophrenia include a wide range of dyssomnias, with insomnia being the most frequently cited. Early and middle insomnia can range from mild disruption to total sleeplessness. Severe insomnia is a prodromal sign of clinical exacerbation or relapse. In general, most antipsychotic agents (APs) ameliorate this insomnia. However, in some schizophrenics APs can be associated with residual insomnia or with significant daytime somnolence. Furthermore, in some schizophrenics APs can induce or exacerbate comorbid sleep disorders such as restless legs syndrome, sleep-disordered breathing, and parasomnias such as sleepwalking. Copyright Ā© 2015 Elsevier Inc. All rights reserved.
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