The International Journal of Neuropsychopharmacology

Table of Contents - 2005 - Volume 8, Issue 03  


Combined analysis of 635 patients confirms an age-related association of the serotonin 2A receptor gene with tardive dyskinesia and specificity for the non-orofacial subtype 1

Bernard Lerer a1c1, Ronnen H. Segman a1, Ene-Choo Tan a2, Vincenzo S. Basile a3, Roberto Cavallaro a4, Harald N. Aschauer a5, Rael Strous a6, Siow-Ann Chong a7, Uriel Heresco-Levy a8, Massimiliano Verga a4, Joachim Scharfetter a5, Herbert Y. Meltzer a9, James L. Kennedy a3 and Fabio Macciardi a3a10
a1 Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah – Hebrew University Medical Center, Jerusalem, Israel
a2 Defence Medical and Environmental Research Institute, DSO National Laboratories, Singapore
a3 Centre for Addiction and Mental Health (CAMH), Clarke Division, Department of Psychiatry, University of Toronto, Canada
a4 IRCCS H San Raffaele, Universita Vita e Salute, Department of Psychiatry, Milan, Italy
a5 Department of General Psychiatry, University Hospital for Psychiatry, Vienna, Austria
a6 Beer Yaakov Mental Health Center, Sackler Faculty of Medicine, Tel Aviv University, Israel
a7 Institute of Mental Health and Woodbridge Hospital, Singapore
a8 Herzog Hospital and Department of Psychiatry, Hebrew University – Hadassah Medical School, Jerusalem, Israel
a9 Vanderbilt University Medical Center, Psychiatric Hospital at Vanderbilt, Nashville TN, USA
a10 Department of Medical Genetics, University of Milan

Article author query
lerer b   [PubMed][Google Scholar] 
segman rh   [PubMed][Google Scholar] 
tan ec   [PubMed][Google Scholar] 
basile vs   [PubMed][Google Scholar] 
cavallaro r   [PubMed][Google Scholar] 
aschauer hn   [PubMed][Google Scholar] 
strous r   [PubMed][Google Scholar] 
chong sa   [PubMed][Google Scholar] 
heresco-levy u   [PubMed][Google Scholar] 
verga m   [PubMed][Google Scholar] 
scharfetter j   [PubMed][Google Scholar] 
meltzer hy   [PubMed][Google Scholar] 
kennedy jl   [PubMed][Google Scholar] 
macciardi f   [PubMed][Google Scholar] 

Abstract

Tardive dyskinesia (TD) is an important limiting factor in the use of typical antipsychotic drugs. Genetic variability in the serotonin 2A (5-HT2A) receptor may influence risk for TD but the results of prior studies are not confirmatory. The objective of this study was to determine association of T102C and His452Tyr polymorphisms in the 5-HT2A receptor gene (HTR2A) with TD in a large, multicentre patient sample. The design employed case-control analysis controlling for possible confounders using pooled, original data from published and available unpublished samples and employing logistic regression, analysis of variance and meta-analysis. The study sample consisted of 635 patients with schizophrenia or schizoaffective disorder (256 with TD and 379 without TD) drawn from five research centres, divided into six groups based on population origin. The main outcome measure was association of a categorical diagnosis of TD based on the Research Diagnostic Criteria for TD with HTR2A T102C and His452Tyr genotypes and haplotypes. The findings indicate significant association of TD with HTR2A T102C genotype (p=0.002) over and above the effect of population group, also when controlling for age and gender (p=0.0008), but not with His452Tyr genotype. The T102C genotype was significantly associated with TD in older (>median age 47 yr, p=0.002) but not younger patients and in patients with non-orofacial (limb-truncal) (p=0.001) but not orofacial TD. By meta-analysis the Mantel–Haenszel (M-H) pooled odds ratio (OR) across all the available data was 1.64. A T102C-His452Tyr haplotype was significantly associated with TD (p=0.0008). These findings confirm that genetic variability in HTR2A contributes a small but significant degree of risk for the expression of TD, particularly in older patients and specifically for the non-orofacial (limb-truncal) type. Together with other genetic variants associated with TD the findings could be used to assess risk in patients who are candidates for treatment with typical antipsychotic medications.

(Received December 31 2004)
(Reviewed January 7 2005)
(Accepted January 10 2005)


Key Words: Antipsychotic drugs; molecular genetics; pharmacogenetics; pharmacogenomics; serotonin 2A (5-HT2A) receptors; schizophrenia; single nucleotide polymorphism; tardive dyskinesia.

Correspondence:
c1 Biological Psychiatry Laboratory, Department of Psychiatry, Hadassah – Hebrew University Medical Center, Ein Karem, Jerusalem 91120, Israel. Tel.: +972-2-6777185 Fax: +972-2-6439294 E-mail: lerer@cc.huji.ac.il

Footnotes

1 This work was presented at the 42nd Annual Meeting of the American College of Neuropsychopharmacology, San Juan, Puerto Rico, December 2003.


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