Linda Nguyen

Date of Graduation

2015

Document Type

Dissertation

Degree Type

PhD

College

School of Pharmacy

Department

Pharmaceutical Sciences

Committee Chair

Rae R Matsumoto

Committee Co-Chair

Han-Ting Zhang

Committee Member

Patrick J Marshalek

Committee Member

Paola Pergami

Committee Member

David P Siderovski

Abstract

Depression affects more than 350 million people and is the leading cause of disability worldwide. Major challenges in the management of depression remain the 4-12 weeks of delayed efficacy and 30% of patients who are resistant to the therapeutic effects of current pharmaceutical treatments. We herein examined whether dextromethorphan (DM) may be able to take on these challenges, because 1) it has overlapping pharmacology with ketamine, which has shown rapid (within 24 hours) antidepressant effects, even in treatment-resistant individuals; 2) unlike ketamine with its notable abuse liability and adverse effects, DM is an over-the-counter antitussive with a high safety margin; and 3) DM binds to several protein targets which are similar to conventional medications as well as distinctive from them, affording possibilities of efficacy in treatment-refractory depression (TRD). The antidepressant-like effects of DM were determined in mice in the forced swim test (FST) and tail suspension test (TST), the two most validated animal models for predicting antidepressant actions. Next, the role of sigma-1 and AMPA receptors in the antidepressant-like effects of DM was examined because mounting evidence suggests that these novel mechanisms contribute to a faster onset of antidepressant efficacy. We also assessed in vivo and in vitro whether DM can promote neural adaptations, which is thought to be a final common pathway for fast acting and conventional antidepressants. Finally, since DM undergoes substantial first-pass metabolism to active metabolites, we evaluated the impact of metabolism on the antidepressant-like effects of DM to determine whether the DM effects are likely mediated through itself or its major metabolites. Our results revealed that DM produces antidepressant-like actions in both the FST and TST, similar to the fast acting and conventional antidepressant controls represented by ketamine and imipramine. Whereas the antidepressant-like effects of DM were blocked by pretreatment with a sigma-1 receptor antagonist (BD1063) or AMPA receptor antagonist (NBQX), the antidepressant-like effects of ketamine were blocked with only NBQX; neither antagonists attenuated the antidepressant-like effects of imipramine. This indicates while only AMPA receptors may play a significant role in mediating the antidepressant-like behaviors of ketamine, both AMPA and sigma-1 receptors may have pivotal roles for DM. Moreover, ketamine rapidly increased hippocampal pro-BDNF levels (within 40 minutes), whereas DM and imipramine did not alter pro-BDNF or BDNF levels in mouse hippocampus or frontal cortex, two key brain regions implicated in depression, in the same time frame. In an in vitro model of neurite growth, however, all three drugs potentiated NGF-induced neurite outgrowth, suggesting DM may work through other trophic factors (e.g., NGF) to facilitate antidepressant-relevant neural adaptations. Lastly, slowing down the metabolism of DM potentiated its antidepressant-like effects, indicating DM rather than its metabolites is the primary mediator of the antidepressant-like effects observed herein. Overall, our results indicate DM produces antidepressant-like effects through mechanisms that overlap in part with ketamine. Taken together with a recent clinical report of DM's efficacy (some within 1-2 days) for treatment-resistant bipolar depression, these data suggest DM may not only elicit antidepressant effects faster than the currently approved medications, but also have efficacy in TRD.

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