Major depressive disorder (MDD) is a common mental disorder with a high lifetime prevalence (10–20%), and is a leading cause of disability and mortality. Although antidepressants are often prescribed, the individual response to antidepressants is highly variable, and predictors for treatment efficacy in MDD patients are therefore anticipated to identify the optimal treatment strategy for psychiatrists. Pharmacogenetic and pharmacogenomic (PGx) studies can provide such predictive factors (that is, genetic variants), although none of these have proven useful in the clinical setting for MDD or other psychiatric disorders. One reason for this lack of clinical utility is related to the smaller effect size of each genetic variant on antidepressant (or antipsychotic) efficacy than would be expected in accordance with the pharmacogenetic/pharmacogenomic concept.1 Moreover, recent evidence suggests that the genetic variants associated with treatment response are highly polygenic, and heritability is assumed to be 42%.2 These findings indicate that a large number of subjects, as well as independent replication studies with meta-analyses, will be required to derive meaningful results from screening data sets. To address this issue, in the current study, we performed a validation study on genetic associations using the Japanese population and a meta-analysis of single nucleotide polymorphisms (SNPs) detected in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study,3 which was performed to determine the treatment efficacy of selective serotonin reuptake inhibitors (SSRIs) in MDD.

The sample comprised 224 MDD subjects treated with SSRIs (male=103, female=121, mean age±s.d.=47.1±15.0 years). Detailed information on the clinical phenotypes is described elsewhere.4 In the current study, however, we included only patients with a minimum depression severity score of 14 out of 17 items on the Hamilton Depressive Rating scale (HAM-D) and an age range from 18 to 75 years according to the inclusion criteria of STAR*D.3 Of these patients, 104, 63 and 57 were treated with fluvoxamine, sertraline and paroxetine, respectively, for 8 weeks (monotherapy). The HAM-D scores were assessed in each patient at baseline (0 weeks: mean±s.d.=21.0±4.9) and after treatment (8 weeks: mean±s.d.=10.1±6.1). A responder was defined as a patient who showed a ⩾50%reduction in HAM-D scores (number of responders=129, number of non-responders=95), in accordance with previous studies.3 SNPs were selected from the STAR*D study, in which the authors examined the association of genome-wide SNPs with citalopram (an SSRI) efficacy. In that study, no SNPs showed evidence at the genome-wide significance level, but the top three SNPs in responders (rs6966038, and rs6127921 and rs809736)3 showing a suggestive association with a P-value <1 × 10−5 were analyzed in our current study (genotyped by TaqMan SNP genotyping (Life Technologies, Carlsbad, CA, USA) for rs6966038, and PCR–RFLP for rs6127921 and rs809736. Primer pairs are available on request).

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