Pharmacogenomics of treatment response in depression

Genetic predictors of treatment response in depression have been studied for more than 30 years. The first studies included pharmacogenetic variations in the drug metabolizing enzymes, especially cytochrome P450 2D6 (CYP2D6) that is responsible for the metabolism of most of the antidepressant drugs. More than 100 variants of CYP2D6 have been reported in different populations (www.cypalleles.ki.se). Pharmacogenetics-guided dose modifications of tricyclic antidepressants and selective serotonin reuptake inhibitors (SSRIs) have been recommended for different variants of CYP2D6 and 2C19. Beside to genetic variations in drug metabolism, pharmacogenetics of drug disposition and pharmacodynamic factors have been recently studied. Genetic polymorphisms in the upstream regulatory region of the serotonin transporter gene (SLC6A4), 5-HTR2A, BDNF, and GNB3 are other associated polymorphic genes related with the treatment response. The ten million single nucleotide polymorphisms (SNPs) data that is present in human genome databases provide a big source of genetic variation. In the last 10 years, microarray technology has become a widely used molecular biology method in many laboratories. Besides to hundreds of small scale pharmacogenetic studies, however, there are limited number of genome-wide association studies such as ‘STAR*D (Sequenced Treatment Alternatives to Relieve Depression study), MARS (Munich Antidepressant Response Signature study) and GENDEP (Genome-based Therapeutic Drugs for Depression study)’. These studies address novel genes that may be associated with treatment response in depression such as ubiquitin protein ligase E3C, the bone morphogenic protein 7, RAR-related orphan receptor alpha gene. GENDEP study also report novel markers, one in the interleukin-11 gene associated with nortriptyline response and the other one in the uronyl 2- sulphotransferase gene associated with citalopram response. In today’s research, major challenge is to identify the functional importance of these genetic polymorphisms and develop a dose modification strategy considering all these genetic variants. Large prospective studies are warranted for the assessment of role of pharmacogenomics related with drug response in depression.