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Xian-Zhang Hu, MD, PhD; A. John Rush, MD; Dennis Charney, MD; Alexander F. Wilson, PhD; Alexa J. M. Sorant, MA; George J. Papanicolaou, PhD; Maurizio Fava, MD; Madhukar H. Trivedi, MD; Stephen R. Wisniewski, PhD; Gonzalo Laje, MD; Silvia Paddock, PhD; Francis J. McMahon, MD; Husseini Manji, MD; Robert H. Lipsky, PhD

Arch Gen Psychiatry. 2007;64(7):783-792.

Context  The HTTLPR, a functional polymorphism of the serotonin transporter gene solute carrier family 6 (neurotransmitter transporter, serotonin), member 4 (SLC6A4), promoter, affects transcription and may be involved in antidepressant drug treatment outcome, although response rates with antidepressants can be lower in patients who experience adverse effects.

Objective  To test the hypothesis that HTTLPR is associated with treatment outcome to citalopram.

Design  A clinical effectiveness trial, Sequenced Treatment Alternatives to Relieve Depression, collected DNA samples from outpatients with nonpsychotic major depressive disorder who received citalopram in the first treatment step. The triallelic HTTLPR locus was genotyped in 1775 samples to discriminate between long (L) and short (S) alleles, followed by the A > G substitution. The low-expression S and L_G alleles were grouped together compared with the high-expression L_A allele.

Setting  Eighteen primary care and 23 psychiatric care sites across the United States.

Participants  Ages 18 to 75 years, meeting criteria for single or recurrent nonpsychotic major depression.

Main Outcome Measures  Categorical response, remission, tolerance, and adverse effect burden.

Results  Expression-based grouping produced a significant finding of association between the L_A allele and adverse effect burden in the entire sample (P = .004 [genotype frequency]; P < .001 [allele frequency]). To control for bias from population stratification, a white American subsample was analyzed. A lesser adverse effect burden was associated with L_AL_A genotype frequency (P = .03) or L_A allele frequency (P = .007). These findings in white patients did not hold when the L allele was undifferentiated. No association was observed between treatment outcome phenotypes and HTTLPR. Development of diarrhea and the presence of the low-expression S or L_G alleles were the strongest risk factors associated with adverse effect burden.

Conclusions  The HTTLPR polymorphism is associated with citalopram adverse effects. Because the L_A allele confers increased SLC6A4 transcription, increased serotonin transporter levels in brain and other tissues may lead to fewer adverse effects for antidepressant medications that target the transporter.

Author Affiliations: Section on Molecular Genetics, Laboratory of Neurogenetics, National Institute on Alcohol Abuse and Alcoholism (Drs Hu and Lipsky), and Genetic Basis of Mood and Anxiety Disorders (Drs Laje, Paddock, and McMahon) and Laboratory of Molecular Pathophysiology (Dr Manji), Mood and Anxiety Program, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland; Department of Psychiatry, The University of Texas Southwestern Medical Center, Dallas (Drs Rush and Trivedi); Department of Psychiatry, Mount Sinai Hospital, Albert Einstein School of Medicine, New York, New York (Dr Charney); Genometrics Section, Inherited Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Baltimore, Maryland (Drs Wilson and Papanicolaou and Ms Sorant); Department of Psychiatry, Massachusetts General Hospital, Boston (Dr Fava); and Department of Epidemiology, University of Pittsburgh, Pittsburgh, Pennsylvania (Dr Wisniewski).

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