Variation in the Gene Encoding the Serotonin 2A Receptor Is Associated with Outcome of Antidepressant Treatment

Abstract

Depressive disorders account for a large and increasing global burden of disease. Although the condition of many patients improves with medication, only a minority experience full remission, and patients whose condition responds to one medication may not have a response to others. Individual variation in antidepressant treatment outcome is, at present, unpredictable but may have a partial genetic basis. We searched for genetic predictors of treatment outcome in 1,953 patients with major depressive disorder who were treated with the antidepressant citalopram in the Sequenced Treatment Alternatives for Depression (STAR*D) study and were prospectively assessed. In a split-sample design, a selection of 68 candidate genes was genotyped, with 768 single-nucleotide-polymorphism markers chosen to detect common genetic variation. We detected significant and reproducible association between treatment outcome and a marker in HTR2A (P range 1 x 10(-6) to 3.7 x 10(-5) in the total sample). Other markers in HTR2A also showed evidence of association with treatment outcome in the total sample. HTR2A encodes the serotonin 2A receptor, which is downregulated by citalopram. Participants who were homozygous for the A allele had an 18% reduction in absolute risk of having no response to treatment, compared with those homozygous for the other allele. The A allele was over six times more frequent in white than in black participants, and treatment was less effective among black participants. The A allele may contribute to racial differences in outcomes of antidepressant treatment. Taken together with prior neurobiological findings, these new genetic data make a compelling case for a key role of HTR2A in the mechanism of antidepressant action.

Pharmacogenetics Studies in STAR*D: Strengths, Limitations, and Results

“…Novel associations with citalopram response were reported within HTR2A (the gene that encodes the serotonin 2A receptor) (32) and GRIK4 (encodes the KA1 subunit of the glutamate-kainate receptor) (35). The KCNK2 gene (encodes a potassium channel of the K subfamily) was associated with treatment resistance (31).…”

“…This phenotype used the relative change in QIDS-C score between baseline and endpoint to define a percentage of improvement or worsening. The goal for such stringent phenotype definition was to guarantee, to the extent possible, that nonresponders would have had a fair chance to respond to the drug, achieving at least six weeks of treatment at a therapeutic dosage (32). …”

“…The first pharmacogenetics results from STAR * D were reported by McMahon and colleagues in 2006 (32), who sampled 768 SNPs in 68 candidate genes. To address the issue of multiple testing, a split-sample design was used.…”

“…Three phenotypes were tested: response, remission, and QIDS-C change from baseline to endpoint as described above (NIMH phenotype definitions). Results of the primary analysis showed two associated markers: one located in the second intron of the HTR2A gene (rs7997012) and the other located in the GRIK4 gene (rs1954787) (32,35) (Tables 1 and 2). The homozygous carriers of both the HTR2A and GRIK4 response-associated alleles were 23% less likely to be citalopram nonresponders than participants with none of these marker alleles.…”

“…One further limitation in the STAR * D genetic data set is the difference between individuals who participated in the genetics study and the STAR * D cohort as a whole, which is discussed in detail elsewhere (32). Because the genetics portion of the study was added after study initiation, participants in that portion would be skewed toward those who entered the study later (which should not introduce bias) and those who remained in the study longer (either because of good treatment response and participation in follow-up or because of poor treatment response leading to continued participation in subsequent levels (which could well introduce bias).…”