Confirmatory factor analyses were conducted of Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) symptoms of common mental disorders derived from structured interviews of a representative sample of 4,049 twin children and adolescents and their adult caretakers. A dimensional model based on the assignment of symptoms to syndromes in DSM-IV fit better than alternative models, but some dimensions were highly correlated. Modest sex and age differences in factor loadings and correlations were found that suggest that the dimensions of psychopathology are stable across sex and age, but slightly more differentiated at older ages and in males. The dimensions of symptoms were found to be hierarchically organized within higher-order "externalizing" and "internalizing" dimensions, which accounted for much of their variance. Major depression and generalized anxiety disorder were substantially correlated with both the "externalizing" dimension and the "internalizing" dimension, however, suggesting the need to reconceptualize the nature of these higher-order dimensions.

Background-Antidepressant response is likely influenced by genetic constitution, but the actual genes involved have yet to be determined. We have carried out a genome-wide association study to determine if common DNA variation influences antidepressant response.

We report a genome-wide association study (GWAS) of major depressive disorder (MDD) in 1,221 cases from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study and 1,636 screened controls. No genome-wide evidence for association was detected. We also carried out a meta-analysis of three European-ancestry MDD GWAS datasets: STAR*D, Genetics of Recurrent Early-Onset Depression (GenRED) and the publicly-available Genetic Association Information Network MDD dataset (GAIN-MDD). These datasets, totaling 3,957 cases and 3,428 controls, were genotyped using four different platforms (Affymetrix 6.0, 5.0 and 500K, and Perlegen). For each of 2.4 million HapMap II SNPs, using genotyped data where available and imputed data otherwise, single-SNP association tests were carried out in each sample with correction for ancestry-informative principal components. The strongest evidence for association in the meta-analysis was observed for intronic SNPs in ATP6V1B2 (P = 6.78 × 10−7), SP4 (P = 7.68 × 10−7) and GRM7 (P = 1.11 × 10−6). Additional exploratory analyses were carried out for a narrower phenotype (recurrent MDD with onset before age 31, N = 2,191 cases), and separately for males and females. Several of the best findings were supported primarily by evidence from narrow cases or from either males or females. Based on previous biological evidence, we consider GRM7 a strong MDD candidate gene. Larger samples will be required to determine whether any common SNPs are significantly associated with MDD.

Several reports have been published investigating the relationship between common variants in serotonin-related candidate genes and antidepressant response, and most of the results have been equivocal. We previously reported a significant association between variants in serotonin-related genes and response to the selective serotonin reuptake inhibitor fluoxetine. Here, we attempt to expand upon and replicate these results by (i) resequencing the exonic and putatively regulatory regions of five serotonin-related candidate genes (HTR1A, HTR2A, TPH1, TPH2, and MAOA) in our fluoxetine-treated sample to uncover novel variants; (ii) selecting tagging single nucleotide polymorphisms (SNPs) for these genes from the resequencing data; and (iii) evaluating these tagging SNPs for association with response to the selective serotonin reuptake inhibitor citalopram in an independent sample of participants who are enrolled in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) clinical study (N=1953). None of the variants associated previously with fluoxetine response were found to be associated with citalopram response in the STAR*D sample set. Nor were any of the additional tagging SNPs found to be associated with citalopram response. An additional SNP in HTR2A (rs7997012), previously reported to be associated with outcome of citalopram treatment in this sample, but not well tagged by any of the other SNPs we studied, was also genotyped, and was associated with citalopram response (P=0.0002), strongly supporting the previous observation in the same STAR*D sample. Our results suggest that resequencing the serotonin-related genes did not identify any additional common SNPs that have not been identified previously. It appears that genetic variation in these five genes has a marginal effect on response to citalopram, although a previously observed association was supported and awaits replication in an independent sample.

Objective-Because previous preclinical and clinical studies have implicated the endogenous opioid system in major depression and in the neurochemical action of antidepressants, the authors examined how DNA variation in the μ-opioid receptor gene may influence population variation in response to citalopram treatment. Method-A total of 1,953 individuals from the Sequenced Treatment Alternatives to RelieveDepression (STAR*D) study were treated with citalopram and genotyped for 53 single nucleotide polymorphisms (SNPs) in a 100-kb region of the OPRM1 gene. The sample consisted of NonHispanic Caucasians, Hispanic Caucasians, and African Americans. Population stratification was corrected using 119 ancestry informative markers and principal components analysis. Markers were tested for association with phenotypes for general and specific citalopram response as well as remission.Results-Association between one SNP and specific citalopram response was observed. After Bonferroni correction, the strongest finding was the association between the rs540825 SNP and specific response. The rs540825 polymorphism is a nonsynonymous SNP in the final exon of the μ-opioid receptor-1X isoform of the OPRM1 gene, resulting in a histidine to glutamine change in the intra-cellular domain of the receptor. When Hispanic and Non-Hispanic Caucasians were analyzed separately, similar results in the population-corrected analyses were detected.Conclusions-These results suggest that rates of response to antidepressants and consequent remission from major depressive disorder are influenced by variation in the μ-opioid receptor gene as a result of either an effect on placebo response or true pharmacologic response.Antidepressant response rates in the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study averaged <50% for treatment with citalopram (level 1 treatment condition), with only approximately 30% of subjects remitting from major depressive disorder (1).Address correspondence and reprint requests to Dr. Hamilton, University of California, San Francisco, Department of Psychiatry, 401 Parnassus Ave., San Francisco, steveh@lppi.ucsf.edu. Previously presented at the Annual Meeting of the National Institute of Mental Health New Clinical Drug Evaluation Unit, June 11-14, 2007, Boca Raton, Fla.; and the Annual Meeting of Pharmacogenetics in Psychiatry, April 13-14, 2007, New York. Preliminary analyses were also presented in Psychiatric Times (April 15, 2008, vol. 25, no. 5).ClinicalTrials.gov registry number, NCT00021528. NIH Public Access Author ManuscriptAm J Psychiatry. Author manuscript; available in PMC 2010 June 15. NIH-PA Author Manuscript NIH-PA Author Manuscript NIH-PA Author ManuscriptInterindividual differences, such as genetic distinction, may contribute to this variation in response to antidepressant treatment, and two genes have already been identified in two studies (2,3). In the present study, we add to the findings of these investigations and show that the μ-opioid receptor gene is associated with antidepr...

Genome-wide association studies (GWAS) have failed to replicate common genetic variants associated with antidepressant response, as defined using a single endpoint. Genetic influences may be discernible by examining individual variation between sustained versus unsustained patterns of response, which may distinguish medication effects from non-specific, or placebo responses to active medication. We conducted a GWAS among 1,116 subjects with Major Depressive Disorder from the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) trial who were characterized using Growth Mixture Modeling as showing a sustained versus unsustained pattern of clinical response over 12 weeks of treatment with citalopram. Replication analyses examined 585 subjects from the Genome-based Therapeutic Drugs for Depression (GENDEP) trial. The strongest association with sustained as opposed to unsustained response in STAR*D involved a single nucleotide polymorphism (SNP; rs10492002) within the acyl-CoA synthetase short-chain family member 3 gene (ACSS3, p-value = 4.5 × 10-6, odds ratio = 0.61). No SNPs met our threshold for genome-wide significance. SNP data were available in GENDEP for 18 of the top 25 SNPs in STAR*D. The most replicable association was with SNP rs7816924 (p = 0.008, OR = 1.58); no SNP met the replication p-value threshold of 0.003. Joint analysis of these 18 SNPs resulted in the strongest signal coming from rs7816924 (p = 2.11 × 10-7), which resides in chondroitin sulfate N-acetylgalactosaminyltransferase 1 gene (CSGALNACT1). An exploratory genetic pathway analysis revealed evidence for an involvement of the KEGG pathway of long-term potentiation (FDR =.02). Results suggest novel genetic associations to sustained response.

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Purpose: To study the brief and reversible mood response to acute tryptophan depletion (ATD) as a trait marker in subjects considered at risk for major depressive disorder (MDD). Procedures: ATD was administered to 64 subjects (54 European-Americans and 10 from other races) with a personal and family history of MDD. They were in remission and had been medication-free for at least 3 months. Subjects were randomly assignment to an active or sham condition in a double-blind crossover design. They were genotyped for serotonin-related candidate genes, and mood response was quantified with the Hamilton Depression Rating Scale (HDRS). Data were analyzed using Poisson regression with repeated measures and latent trajectory models. Results: Compared to the sham controls, active ATD caused modest depressive changes showing significant main effects of test condition (χ² = 5.14, d.f. = 1, p = 0.023) and time (χ² = 12.22, d.f. = 3, p = 0.007), but no significant interaction of time and test condition. Latent trajectory analysis revealed two groups, identified as depletion responders and non-responders. Those with the HTR2A rs6313 CC genotype had significantly higher HDRS scores during ATD (χ² = 11.72, d.f. = 1, p = 0.0006). Conclusions: ATD may help identifying the biological subtypes of MDD. These data are consistent with imaging reports implicating 5-HT_2A receptor function in ATD phenotypes.