Suicidal Ideation and Treatment-Resistant Depression: Clinical Endophenotype Characterization and Exploration of Novel Brain Stimulation Interventions

Suicide is a highly stigmatized symptom construct associated with multiple psychiatric conditions. Over 700,000 individuals across the world die by suicide annually. Major depressive disorder (MDD) is the most common co-morbid psychiatric illness in suicide completers. Suicidal ideation (SI) is more prevalent in individuals with treatment-resistant depression (TRD) compared to those with depression who respond to treatment. Given treatment limitations of SI in TRD, novel interventions paired with an improved understanding of the neurobiology of SI are needed. In this thesis I explore the clinical phenotype of the overlap of TRD and SI through a retrospective analysis of the largest clinical trial in depression, the STAR*D trial. Results from this analysis demonstrate the association between SI and TRD. This analysis also confirms that standard antidepressant treatments do not appear to be effective interventions for individuals with TRD and co-morbid SI, suggesting that novel interventions should be developed for patients struggling with this nexus of conditions. In another published report described in this thesis, our group characterizes the placebo response rates of TRD through a meta-analysis. Placebo response rates tended to be lower in TRD then non-TRD depression, and the implications of this finding are discussed. In the remaining four publications in this thesis, I explore novel brain stimulation interventions for the treatment of SI and TRD. Bilateral repetitive transcranial magnetic stimulation (rTMS) and magnetic seizure therapy (MST) are assessed for their efficacy through secondary analyses of large clinical trials. Findings suggest a significant effect of bilateral rTMS over sham for inducing remission of SI, and a potentially even stronger effect for MST for the treatment of SI in both unipolar and bipolar depression. The significance of these findings and the potential neurophysiological mechanisms of action are explored. Finally, this thesis contains an editorial about the promise of accelerated forms of rTMS treatment combined with a personalized medicine approach. I conclude by exploring how this paradigm of intervention could be applied in suicide prevention trials in the future directions portion of this report.

Department dc:contributor.department

Pharmacology

Year dc:date.issued

2024

Author dc:creator

• Weissman, Cory R

Advisor dc:contributor.advisor

• Daskalakis, Zafiris J

• Brain stimulation
• Clinical endophenotype
• Magnetic seizure therapy
• Repetitive transcranial magnetic stimulation
• Suicide
• Treatment-resistant depression

Handle dc:identifier.uri

http://hdl.handle.net/1807/140097

OAI identifier oai:identifier

oai:utoronto.scholaris.ca:1807/140097