Towards elucidating the molecular modes of action of two types of antidepressant drugs using proteomics

Yan, Yu (2021): Towards elucidating the molecular modes of action of two types of antidepressant drugs using proteomics. Dissertation, LMU München: Faculty of Chemistry and Pharmacy

Abstract

Major depressive disorder (MDD) is a common mental disorder that globally millions of people of all ages suffer from. Despite the large-scale and long-term research that has been carried out, the etiology of MDD has not been fully elucidated. A number of antidepressants have been developed for pharmacotherapy of MDD with considerable efficacy in many patients. Nevertheless, currently used antidepressants are still limited by their undesirable side effects and other drawbacks, including insufficiency in the therapy of treatment-resistant depression (TRD). A comprehensive mechanistic study of the side effects of clinically used antidepressants and the development of novel antidepressants free from these limitations are of importance and in great demand. In my PhD work, I have aimed at elucidating the molecular mechanism of action of two drugs that represent different classes of antidepressants. First, in order to investigate side effects caused by chronic treatment with fluoxetine, one of the most widely prescribed selective serotonin reuptake inhibitors (SSRIs), I subjected brain tissue from juvenile macaques that had been treated with fluoxetine for two years to proteome and phosphoproteome profiling using quantitative mass spectrometry. The proteomics data indicate that GABAergic synapse pathways are associated with the increased impulsivity observed in the juvenile macaques after chronic fluoxetine treatment. In the second study, I attempted to unveil novel protein targets for the fast-acting antidepressant ketamine. Using several mass spectrometry-based strategies to uncover drug-protein interactions, I have identified novel binding partners of ketamine and its metabolites, which includes pyruvate kinase, and implicate the involvement of energy metabolism in ketamine’s mode of action. In summary, this work reveals that GABAergic synapse pathways are affected by fluoxetine treatment in non-human primate macaques, and suggests new protein targets and associated mechanisms of ketamine as an antidepressant. My project data provide leads for pharmacology, and drug targets for the development of novel antidepressants with greater efficacy and fewer side effects.

• Item Type: Theses (Dissertation, LMU Munich)
• Keywords: Major depressive disorder, mass spectrometry, proteomics
• Subjects: 500 Natural sciences and mathematics; 500 Natural sciences and mathematics > 540 Chemistry and allied sciences
• Faculties: Faculty of Chemistry and Pharmacy
• Language: English
• Date of oral examination: 20. September 2021
• 1. Referee: Turck, Christoph
• Signature of the printed copy: 0001/UMC 29071