Pharmacogenetics of Antidepressants in Major Depressive Disorder

Author: Ma-Li Wong

Wong, Ma-Li, 2015 Pharmacogenetics of Antidepressants in Major Depressive Disorder, Flinders University, School of Medicine

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In this PhD by publication thesis has been to advance the understanding of the genetic basis for antidepressant drug response. Currently, MDD is conceptualized as a gene-environment disorder of polygenic nature, its underlying biology implicates central nervous system alterations in limbic system circuits that instigate depressed mood and regulate the stress response, body weight, endocrine rhythms, and immune function. We studied 284 individuals with MDD (112 and 120 patients completed treatment with fluoxetine and desipramine, respectively) and 331 controls recruited from the same Mexican American community of Los Angeles, USA. Depressed individuals were enrolled in an outpatient randomized clinical trial (RCT), an 8-week double-blind pharmacogenetic study of treatment response to daily treatment with desipramine or fluoxetine. Six reprints were included in this thesis. In reprint 1 we reported increased response to antidepressants in highly anxious patients homozygous for the GAG haplotype of the CRHR1 gene had a greater reduction in depressive symptoms scores when compared to heterozygous; however, in patients with low anxiety levels, these associations were not present. In reprint 2 we reported that polymorphisms in the PDE11A gene were significantly associated with the diagnosis of MDD and remission to antidepressants. In reprint 3 we reported the association of MDD to two genes vital to T-cell function, PSMB4 (Proteasome ß4 subunit) and TBX21 (T-box 21 or TBET). We found the nominal association between SNPs in genes that support the role of T cell [CD3E (CD3e molecule, epsilon), PRKCH (Protein kinase C substrate 80K-H), PSMD9 (Proteasome 26S subunit, Non-ATPase 9) and STAT3 (Signal transducer and activator of transcription 3)] and HPA axis (UNC3, urocortin 3) functions to antidepressant response.

In reprints 4 and 5 we re-sequenced 8 genes relevant to pharmacokinetics and pharmacodynamics of antidepressant drugs, including the BDNF (brain derived neurotrophic factor gene), ABCB1 (ATP-binding cassette, sub-family B gene, MDR/TAP), SLC6A2 [Solute carrier family 6 (Neurotransmitter transporter), member 2 gene/Norepinephrine transporter gene, NAT1/NET1], SLC6A3 [Solute carrier family 6 (Neurotransmitter transporter), member 3 gene/dopamine transporter gene, DAT1], SLC6A4 [Solute carrier family 6 (Neurotransmitter transporter), member 4 gene/serotonin transporter gene, 5HTT/SERT/5-HTTLPR], CREB1 (cAMP responsive element binding protein 1 gene), CRHR1 and NTRK2 (Neurotrophic tyrosine kinase, receptor, type 2) genes. We identified many novel SNPs, almost doubling the number of SNPs reported for those genes and found that in the BNDF gene 6 SNPs (rs12273539, rs11030103, rs6265, rs28722151, rs41282918, and rs11030101) and 2 haplotypes were significantly associated with MDD; and one SNP (rs61888800) was associated with antidepressant response. In reprint 6 we examined the role of whole-exome functional gene variants in antidepressant response and found that exm-rs1321744 achieved exome-wide significance (1.98 x 10-06) for treatment remission; this variant is located in a brain methylation site, which suggests its involvement in epigenetic regulation of neuronal gene expression.

This body of work has increased knowledge of pharmacogenomics of antidepressant drugs in major depressive disorders, identified brain pathways involved in MDD and antidepressant response. Current work in our lab aims to expand and replicate these findings.

Keywords: randomised clinical trial, corticotrophin releasingi hormone receptor 1, Phosphodiesterase 11 A, Proteasome beta 4 subunit, T-box 21, Brain derived neurotrophic factor, Neurotrophic tyrosine kinase receptor type 2, brain methylation site.

Subject: Psychiatry thesis, Medicine thesis

Thesis type: Doctor of Philosophy
Completed: 2015
School: School of Medicine
Supervisor: Professor Malcolm Battersby