Genetics of major depressive disorder in treatment resistance and tryptophan depletion

This dissertation is composed of five major chapters. The first is a comprehensive literature review, followed by three chapters of research findings, and a final concluding chapter. Major Depressive Disorder (MDD) is a phenotypically complex and heterogeneous syndrome. This challenge and others faced when investigating the genetic basis for the susceptibility to MDD are discussed, as are tools used to address and overcome these challenges. Included in this review of the literature is a discussion on findings of genome-wide analyses of MDD, as well as candidate genes that may play a role in the susceptibility to major depression. Following the literature review, three chapters of studies are presented. The first one demonstrates that in humans, the actual number of risk genotypes in the serotonin system accounts for over half of the variance in mood response to tryptophan depletion. There was no association between the dopamine system and mood response. The main conclusion from that study is that using a pathway analysis, rather than a single gene approach, may lead to more informative results when studying the genetics of a complex behavior. The next study demonstrates a similar conclusion, however, is not pathway specific. It is shown that in a group of depressed subjects not capable of treatment response, the mean number of risk genotypes is greater than in a group without depression. This supports the thought that treatment resistance may be a more severe form of MDD. This study also presents data on single gene results which demonstrate that the genetic basis for susceptibility to major depression may be different and independent from the genetic basis for the capacity to respond to treatment. Several individual polymorphisms are implicated in each case. The final investigation is a published manuscript refuting the findings of a previously published article on polymorphisms in the TPH2 gene and association with treatment resistance. Many other research groups have also been able to replicate the results demonstrated here. A final chapter discusses the overall conclusions about the three research studies, as well as the field of psychiatric genetics with a focus on the continuing search for the genetic basis of susceptibility to major depressive disorder.