Association of the RGS2 gene with extrapyramidal symptoms induced by treatment with antipsychotic medication.
OBJECTIVE
To investigate the role of genes encoding regulators of G protein signaling in early therapeutic response to antipsychotic drugs and in susceptibility to drug-induced extrapyramidal symptoms. As regulators of G protein signaling and regulators of G protein signaling-like proteins play a pivotal role in dopamine receptor signaling, genetically based, functional variation could contribute to interindividual variability in therapeutic and adverse effects.


METHODS
Consecutively hospitalized, psychotic patients with Diagnostic and Statistical Manual of Mental Disorder-IV schizophrenia (n=121) were included in the study if they received treatment with typical antipsychotic medication (n=72) or typical antipsychotic drugs and risperidone (n=49) for at least 2 weeks. Clinical state and adverse effects were rated at baseline and after 2 weeks. Twenty-four single nucleotide polymorphisms were genotyped in five regulators of G protein signaling genes.


RESULTS
None of the single nucleotide polymorphisms were related to clinical response to antipsychotic treatment at 2 weeks. Five out of six single nucleotide polymorphisms within or flanking the RGS2 gene were nominally associated with development or worsening of parkinsonian symptoms (PARK+) as measured by the Simpson Angus Scale, one of them after correction for multiple testing (rs4606, P=0.002). A GCCTG haplotype encompassing tagging single nucleotide polymorphisms within and flanking RGS2 was significantly overrepresented among PARK+ compared with PARK--patients (0.23 vs. 0.08, P=0.003). A second, 'protective', GTGCA haplotype was significantly overrepresented in PARK--patients (0.13 vs. 0.30, P=0.009). Both haplotype associations survive correction for multiple testing.


CONCLUSIONS
Subject to replication, these findings suggest that genetic variation in the RGS2 gene is associated with susceptibility to extrapyramidal symptoms induced by antipsychotic drugs.
Greenbaum
Lior
L
Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah-Hebrew University Medical Center, Ein Karem, Jerusalem, Israel.
Strous
Rael D
RD
Kanyas
Kyra
K
Merbl
Yifat
Y
Horowitz
Anat
A
Karni
Osnat
O
Katz
Elena
E
Kotler
Moshe
M
Olender
Tsviya
T
Deshpande
Smita N
SN
Lancet
Doron
D
Ben-Asher
Edna
E
Lerer
Bernard
B
D000328:Adult; D000483:Alleles; D014150:Antipsychotic Agents / Q000009:adverse effects* / Q000493:pharmacokinetics; D005116:Extrapyramidal Tracts / Q000187:drug effects; D005260:Female; D006239:Haplotypes; D006801:Humans; D008297:Male; D008875:Middle Aged; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020710:RGS Proteins / Q000235:genetics*; D018967:Risperidone / Q000009:adverse effects / Q000493:pharmacokinetics; D012559:Schizophrenia / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism
D014150:Antipsychotic Agents; D020710:RGS Proteins; C087182:RGS2 protein, human; D018967:Risperidone