Grant: Master's Award: Canada Graduate Scholarships

Major Depressive Disorder is a complex syndrome consisting of a number of subtypes, each characterized by a unique combination of symptoms. These differences in symptoms suggest that there are subtle underlying differences in pathology among depressed individuals. It is believed that these differences may help explain why it is difficult to predict how any one individual will respond to treatment. That is, certain subgroups of depressed individuals may respond best to specific therapies because those therapies are best able to target their underlying pathology. It is thus important that we be able to characterize individuals based on their underlying pathology so we can tailor their treatment to them according to the existence of specific biomarkers (biological indications of a disorder or disease). In order to do so; however, there must be a strong understanding of the neural and epigenetic alterations that underlie which symptoms, which environmental conditions are associated with these alterations and which areas of the brain and epigenome can be most affected by which forms of therapy. Epigenetics is defined as the study of inheritable changes in gene expression that do not involve alterations in the DNA sequence itself. In the context of mental illness, much of the epigenetic research has focused on DNA methylation, a dynamic process capable of chemically altering DNA and, ultimately, leading to changes in protein expression. Both animal and human research suggests that stressful life events can actually induce changes in DNA methylation at the serotonin transporter gene, and that these changes are associated with both depression and serotonin synthesis (Wang et al., 2012; Weaver et al., 2004). This raises the question of whether psychotherapy may act by altering methylation levels and if different forms of psychotherapy may alter methylation at different genes or in different regions within a gene. If found to be true, DNA methylation could be used as a biomarker with individual methylation patterns at specific genes being used to assign individuals to specific therapies. In addition to DNA methylation, neural activity may also serve as a useful biomarker to guide treatment. It is well documented that depressed individuals display altered neural activity compared to controls in a number of brain regions, including the prefrontal cortex and amygdala, at rest and during emotional and cognitive tasks. Furthermore, these differences are reduced by pharmacological and psychological therapy. However, these therapies are thought to act differently, with antidepressant therapy directly decreasing amygdalar activity and cognitive therapy increasing prefrontal inhibition of the amygdala. Considering that research suggests that these different forms of therapy target different brain areas, this raises the possibility that with a better understanding of how individual therapies affect neural activity, one could assign treatment based on preexisting neural activity. For my master’s project, I hope to examine the effect of psychotherapies such as cognitive behavioural therapy on the epigenome, the brain and depressive symptoms under the supervision of Dr. Linda Booij at Queen’s University. With this research, I aim to show that early life stress alters DNA methylation at specific candidate genes, and that this in turn alters the development of the brain. Furthermore, I expect to find that psychotherapy acts by reversing these changes in methylation and brain activity. Ultimately, I hope to use data collected before and after therapy to help determine epigenetic and neural biomarkers that predict response to treatment with specific psychotherapies.