The International SSRI Pharmacogenomics Consortium (ISPC): a genome-wide association study of antidepressant treatment response

Abstract

Response to treatment with selective serotonin reuptake inhibitors (SSRIs) varies considerably between patients. The International SSRI Pharmacogenomics Consortium (ISPC) was formed with the primary goal of identifying genetic variation that may contribute to response to SSRI treatment of major depressive disorder. A genome-wide association study of 4-week treatment outcomes, measured using the 17-item Hamilton Rating Scale for Depression (HRSD-17), was performed using data from 865 subjects from seven sites. The primary outcomes were percent change in HRSD-17 score and response, defined as at least 50% reduction in HRSD-17. Data from two prior studies, the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics Study (PGRN-AMPS) and the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, were used for replication, and a meta-analysis of the three studies was performed (N=2394). Although many top association signals in the ISPC analysis map to interesting candidate genes, none were significant at the genome-wide level and the associations were not replicated using PGRN-AMPS and STAR*D data. Top association results in the meta-analysis of response included single-nucleotide polymorphisms (SNPs) in the HPRTP4 (hypoxanthine phosphoribosyltransferase pseudogene 4)/VSTM5 (V-set and transmembrane domain containing 5) region, which approached genome-wide significance (P=5.03E−08) and SNPs 5' upstream of the neuregulin-1 gene, NRG1 (P=1.20E−06). NRG1 is involved in many aspects of brain development, including neuronal maturation and variations in this gene have been shown to be associated with increased risk for mental disorders, particularly schizophrenia. Replication and functional studies of these findings are warranted.

Pharmacogenomics in the treatment of mood disorders: Strategies and Opportunities for personalized psychiatry

“…A similar polygenicity is expected in drug-response phenotypes of mood disorders [10]. One approach that can assist in translating genomic knowledge into clinical applications is the polygenic score (PGS) method proposed by the International Schizophrenia Consortium [93].…”

“…The treatment response of patients with mood disorders treated by the current approaches of psycho-pharmacotherapy vary widely between individual patients and is unsatisfactory in many cases [10,52,56]. For instance, in patients with MDD, the treatment efficacy of selective serotonin reuptake inhibitors (SSRIs), the most commonly used first-line pharmacological agent [51] varies between 48 and 64% [10,52] and reported remission rates are as low as 23.5% [10,89]. Similarly, patients treated with lithium in BPD are only partially responsive and more than a quarter of them have no clinical response at all [ 5 6 ] .…”

“…The fifth most recent pharmacogenomics study on SSRIs r e s p o n s e r e p o r t e d b y t h e I n t e r n a t i o n a l S S R I s Pharmacogenomics Consortium (ISPC) was also unsuccessful to discover genetic variants associated with SSRIs response and remission in MDD patients after 4 weeks of treatment [10]. Similarly, polygenic approaches that tried to elucidate the overall genome-wide genetic influences on antidepressant treatment response in MDD have failed to predict antidepressant efficacy in It is a highly polymorphic gene that encodes an enzyme in the CYPsuperfamily [121] Polymorphisms in the CYP2D6 gene may influence the metabolism and response of antidepressant response [16,67,90].…”

“…Clinical trials and international consortia with available GWAS data in the field of antidepressant response include, the International SSRIs Pharmacogenomics Consortium (ISPC) study [10], Depression and Sequence of Treatment (DAST) Study, the NEWMEDS consortium [37,57,113], the Pharmacogenomics Research Network Antidepressant Medication Pharmacogenomics (PGRN-AMPS) Study [83], the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) Study [95], GENDEP project, and the MARS project [37, 50, ].…”

“…The first genome-wide association study by this group was published in 2015 [10]. This group has data on 998 MDD patients collected from different countries including in Europe, USA, and Asia.…”