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Association of dopamine D3-receptor gene variants with neuroleptic induced akathisia in schizophrenic patients - A generalization of Steen's study on DRD3 and tardive dyskinesia

Department of Psychiatry, University of Regensburg, Regensburg, Germany.
American Journal of Medical Genetics (Impact Factor: 3.23). 05/2000; 96(2):187-91. DOI: 10.5167/uzh-94558
Source: PubMed

ABSTRACT

Neuroleptic induced akathisia is a common and distressful extrapyramidal side effect of antipsychotic treatment. A significant proportion of the variability of its development has been left unexplained and has to be attributed to individual susceptibility. Since hereditary factors have been discussed in the etiology of acute akathisia (AA), part of the individual susceptibility might be of genetic origin. Moreover, AA is regarded as a forerunner of tardive dyskinesia, a drug-induced chronic movement disorder, which may be associated with homozygosity for the Ser9Gly variant of the DRD3 gene. Considering expression studies, which demonstrated functional variants of DRD3 polymorphisms, we investigated whether homozygosity for the Ser9Gly variant of the DRD3 gene is associated with AA. Homozygosity for the Ser9Gly variant of the DRD3 gene was connected to an 88% incidence of AA as compared with a considerably lower 46.9% incidence of AA in schizophrenic patients nonhomozygous for the 2-2 allele (exact P = 0.0223). Am. J. Med. Genet. (Neuropsychiatr. Genet.) 96:187-191, 2000.

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    • "The most severe symptoms occur with maximal binding of basal ganglia DRD2 (Farde, 1992). Individuals vary in their susceptibility for getting symptoms of akathisia, but hereditary factors are likely to confer risk for this disorder (Eichhammer, et al., 2000) and other key adverse events (Barnes et al., 2011). Because DRD2 are involved in the pathophysiology of akathisia, then DRD2 polymorphisms were reasonable candidates for possible genetic risk. "

    Full-text · Dataset · Dec 2012
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    • "The most severe symptoms occur with maximal binding of basal ganglia DRD2 (Farde, 1992). Individuals vary in their susceptibility for getting symptoms of akathisia, but hereditary factors are likely to confer risk for this disorder (Eichhammer, et al., 2000) and other key adverse events (Barnes et al., 2011). Because DRD2 are involved in the pathophysiology of akathisia, then DRD2 polymorphisms were reasonable candidates for possible genetic risk. "
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    ABSTRACT: Although the advent of atypical, second-generation antipsychotics (SGAs) has resulted in reduced likelihood of akathisia, this adverse effect remains a problem. It is known that extrapyramidal adverse effects are associated with increased drug occupancy of the dopamine 2 receptors (DRD2). The A1 allele of the DRD2/ANKK1, rs1800497, is associated with decreased striatal DRD2 density. The aim of this study was to identify whether the A1(T) allele of DRD2/ANKK1 was associated with akathisia (as measured by Barnes Akathisia Rating Scale) in a clinical sample of 234 patients who were treated with antipsychotic drugs. Definite akathisia (a score ≥ 2 in the global clinical assessment of akathisia) was significantly less common in subjects who were prescribed SGAs (16.8%) than those prescribed FGAs (47.6%), p < 0.0001. Overall, 24.1% of A1+ patients (A1A2/A1A1) who were treated with SGAs had akathisia, compared to 10.8% of A1- (thus, A2A2) patients. A1+ patients who were administered SGAs also had higher global clinical assessment of akathisia scores than the A1- subjects (p = 0.01). SGAs maintained their advantage over FGAs regarding akathisia, even in A1+ patients who were treated with SGAs. These results strongly suggested that A1+ variants of the DRD2/ANKK1 Taq1A allele do confer an associated risk for akathisia in patients who were treated with SGAs, and these variants may explain inconsistencies found across prior studies, when comparing FGAs and SGAs.
    Full-text · Article · Oct 2012 · Journal of Psychopharmacology
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    • "This finding is particularly interesting in that the DAT1 regulates the dopamine turnover and the DRD2 is one of the main molecular targets of antipychotics, the blockage thereof is considered to be central to the development of motoric side effects [11]. Consistently, the Ser9Gly variant of the dopaminergic receptor D3 gene (DRD3) was also found to be involved as a risk factor in the incidence of motoric side effects after antipsychotic treatment [15]. Nevertheless, the role of mutations located in dopaminergic receptors was not confirmed in a large sample of 665 patients [16]. "
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    ABSTRACT: We previously investigated a sample of patients during an active phase of psychosis in the search for genetic predictors of haloperidol induced side effects. In the present work we extend the genetic association analysis to a wider panel of genetic variations, including 508 variations located in 96 genes. The original sample included 96 patients. An independent group of 357 patients from the CATIE study served as a replication sample. Outcomes in the investigation sample were the variation through time of: 1) the ESRS and UKU total scores 2) ESRS and UKU subscales (neurologic and psychic were included) related to tremors and 3) ESRS and UKU subscales that do not relate to tremors. Outcome in the replication sample was the presence vs absence of motoric side effects from baseline to visit 1 (∼ one month of treatment) as assessed by the AIMS scale test. Rs2242480 located in the CYP3A4 was associated with a different distribution of the UKU neurologic scores through time (permutated p = 0.047) along with a trend for a different haloperidol plasma levels (lower in CC subjects). This finding was not replicated in the CATIE sample. In conclusion, we did not find conclusive evidence for a major association between the investigated variations and haloperidol induced motoric side effects.
    Full-text · Article · Oct 2012 · PLoS ONE
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