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It would be beneficial to find genetic predictors of antidepressant response to help personalise treatment of major depressive disorder (MDD). Rare copy number variants (CNVs) have been implicated in several psychiatric disorders, including MDD, but their role in antidepressant response has yet to be investigated. CNV data were available for 1565 individuals with MDD from the NEWMEDS (Novel Methods leading to New Medications in Depression and Schizophrenia) consortium with prospective data on treatment outcome with either a serotonergic or noradrenergic antidepressant. No association was seen between the presence of CNV (rare or common), the overall number of CNVs or genomic CNV 'burden' and antidepressant response. Specific CNVs were nominally associated with antidepressant response, including 15q13.3 duplications and exonic NRXN1 deletions. These were associated with poor response to antidepressants. Overall burden of CNVs is unlikely to contribute to personalising antidepressant treatment. Specific CNVs associated with antidepressant treatment require replication and further study to confirm their role in the therapeutic action of antidepressant. [ABSTRACT FROM AUTHOR]

Suicidal thoughts during antidepressant treatment have been the focus of several candidate gene association studies. The aim of the present genome-wide association study was to identify additional genetic variants involved in increasing suicidal ideation during escitalopram and nortriptyline treatment. A total of 706 adult participants of European ancestry, treated for major depression with escitalopram or nortriptyline over 12 weeks in the Genome-Based Therapeutic Drugs for Depression (GENDEP) study were genotyped with Illumina Human 610-Quad Beadchips (Illumina, San Diego, CA, USA). A total of 244 subjects experienced an increase in suicidal ideation during follow-up. The genetic marker most significantly associated with increasing suicidality (8.28 × 10−7) was a single-nucleotide polymorphism (SNP; rs11143230) located 30 kb downstream of a gene encoding guanine deaminase (GDA) on chromosome 9q21.13. Two suggestive drug-specific associations within KCNIP4 (Kv channel-interacting protein 4; chromosome 4p15.31) and near ELP3 (elongation protein 3 homolog; chromosome 8p21.1) were found in subjects treated with escitalopram. Suggestive drug by gene interactions for two SNPs near structural variants on chromosome 4q12, one SNP in the apolipoprotein O (APOO) gene on chromosome Xp22.11 and one on chromosome 11q24.3 were found. The most significant association within a set of 33 candidate genes was in the neurotrophic tyrosine kinase receptor type 2 (NTRK2) gene. Finally, we also found trend for an association within genes previously associated with psychiatric phenotypes indirectly linked to suicidal behavior, that is, GRIP1, NXPH1 and ANK3. The results suggest novel pathways involved in increasing suicidal ideation during antidepressant treatment and should help to target treatment to reduce the risk of this dramatic adverse event. Limited power precludes definitive conclusions and replication in larger sample is warranted. [ABSTRACT FROM AUTHOR]

The article discusses the highlights of the 8th Annual Pharmacogenetics in Psychiatry Meeting held in New York City. An association study of candidate genes with obesity phenotypes in schizophrenics was presented by Yvon Chagnon. Daniel Mueller of the University of Toronto provided data on the cannabinoid-1 receptor and dopamine receptor gene on weight gain. Meanwhile, Holly Garriock of the University of California presented a genome-wide study of intolerance to citalopram in the Sequenced Treatment Alternatives for Depression sample of individuals.

Genome-wide association studies have generally failed to identify polymorphisms associated with antidepressant response. Possible reasons include limited coverage of genetic variants that this study tried to address by exome genotyping and dense imputation. A meta-analysis of Genome-Based Therapeutic Drugs for Depression (GENDEP) and Sequenced Treatment Alternatives to Relieve Depression (STAR*D) studies was performed at the single-nucleotide polymorphism (SNP), gene and pathway levels. Coverage of genetic variants was increased compared with previous studies by adding exome genotypes to previously available genome-wide data and using the Haplotype Reference Consortium panel for imputation. Standard quality control was applied. Phenotypes were symptom improvement and remission after 12 weeks of antidepressant treatment. Significant findings were investigated in NEWMEDS consortium samples and Pharmacogenomic Research Network Antidepressant Medication Pharmacogenomic Study (PGRN-AMPS) for replication. A total of 7062 950 SNPs were analyzed in GENDEP (n=738) and STAR*D (n=1409). rs116692768 (P=1.80e-08, ITGA9 (integrin α9)) and rs76191705 (P=2.59e-08, NRXN3 (neurexin 3)) were significantly associated with symptom improvement during citalopram/escitalopram treatment. At the gene level, no consistent effect was found. At the pathway level, the Gene Ontology (GO) terms GO: 0005694 (chromosome) and GO: 0044427 (chromosomal part) were associated with improvement (corrected P=0.007 and 0.045, respectively). The association between rs116692768 and symptom improvement was replicated in PGRN-AMPS (P=0.047), whereas rs76191705 was not. The two SNPs did not replicate in NEWMEDS. ITGA9 codes for a membrane receptor for neurotrophins and NRXN3 is a transmembrane neuronal adhesion receptor involved in synaptic differentiation. Despite their meaningful biological rationale for being involved in antidepressant effect, replication was partial. Further studies may help in clarifying their role.

There is substantial inter-individual variation in response to antidepressants, and genetic variation may, in part, explain these differences. For example, there is evidence to suggest that variation in the serotonin transporter gene (SLC6A4) predicts response to selective serotonin reuptake inhibitors (SSRIs). Environmental factors such as the occurrence of stressful life events before treatment may also be important. One prior report suggests that both factors interact in predicting response to antidepressants. GENDEP, a prospective part-randomized pharmacogenomics trial, collected longitudinal data on the outcome of 811 patients with major depression undergoing treatment with either an SSRI (escitalopram) or a tricyclic antidepressant (nortriptyline). Life events experienced over 6 months preceding treatment were measured using a List of Threatening Experiences Questionnaire, and several polymorphisms in the serotonin transporter gene (SLC6A4) have been genotyped including the serotonin transporter-linked polymorphic region (5-HTTLPR). Stressful life events were shown to predict a significantly better response to escitalopram but had no effect on response to nortriptyline. Variation in the 5-HTTLPR and another polymorphism in the gene, STin4, significantly modified these effects. Gene-environment interactions including life events may therefore be important not only in the aetiology of depression, but also in predicting response to antidepressant medication.