Antidepressant Efficacy of Dextromethorphan in the Forced Swim Test Randy Ellis, Robert P. Vertes, PhD Center for Complex Systems and Brain Sciences

Introduction: Cost to Society Major Depressive Disorder (MDD) costs US employers $24-31 billion a year in employee absenteeism and reduced work performance (Birnbaum et al. 2010).

Introduction: Rule of Thirds Conventional MDD treatments such as SSRIs, MAOIs, DRIs, and NRIs have resulted in a “Rule of Thirds:” One third of patients never respond to treatment, one third respond but subsequently relapse, and the last third experience lasting remission (Foy & Kennedy 2005).

Introduction: Glutamate Glutamate is the most abundant excitatory neurotransmitter in the human nervous system. In the past 15 years ketamine, a drug acting at the glutamate NMDA receptor, has been extensively studied for its potential role in the etiology of MDD along with other psychiatric and neurological disorders (for a review, see Lee et al. 2015).

Introduction: Dextromethorphan Dextromethorphan (DM) and/or its primary metabolite dextrorphan have greater potencies than ketamine for multiple neural mechanisms related to MDD such as NMDA antagonism, σ1 agonism, 5HTT inhibition, and muscarinic antagonism (Lauterbach 2012).

Rationale The goal of this research was to investigate the antidepressant efficacy of dextromethorphan in the most widely used animal model of MDD, the Porsolt Forced Swim Test (Porsolt, Le Pichon, and Jalfre 1977).

Methods: Subjects Male Adult Sprague-Dawley rats (N=8) were allowed access to food and water ad libitum.

Methods: Apparatus Habituation and test trials were conducted in opaque buckets (H: 14.5in, D: 12in).

Methods: Habituation Rats were placed in buckets filled halfway with water for 15 minutes to acclimate to the aquatic environment.

Methods: Drugs and Treatments DM or saline (30mg/kg) was administered intraperitoneally (IP) 23 hours after habituation trials, 1 hour before test trials.

Methods: Test 1 hour after administration, rats were placed in buckets for 5 minutes while being recorded with a Canon Rebel T3i camera.

Methods: Statistical Analysis Immobility data were analyzed by one- way analysis of variance (ANOVA). A Kruskal-Wallis ANOVA was conducted if Levene’s test showed significantly different variances between groups. A Cohen’s D was calculated from means and standard deviations to quantify the effect size.

Results Intraperitoneal administration of dextromethorphan significantly reduced the immobility time of rats compared to saline (F (1-6) = 8.29; p < 0.05). Cohen’s effect size (d = 2.04) indicated a highly significant difference between the two treatment groups.

Results Levene’s test indicated unequal variances between groups (F=8.29, p=.02). Kruskal-Wallis ANOVA also yielded significant differences between groups (H(1) = 4.083; p=0.04).

Effects of acute administration of dextromethorphan (30mg/kg) on the immobility time of rats subjected to the forced swim test. Bars represent means ± S.E.M. of 4 rats. *p < 0.05 vs. saline according to one-way ANOVA

Discussion The present study demonstrated that the acute administration of DM (30mg/kg) decreased the immobility time of rats in the forced swim test.

Discussion Only one other study has demonstrated the antidepressant effects of DM in vivo. This was a forced swim test done in mice that showed σ1 receptors contribute to DM’s antidepressant effects (Matsumoto et al. 2014).

Discussion DM has been shown to be an effective treatment for pseudobulbar affect in the form of Nuedexta (Dextromethorphan + ultra low-dose quinidine). Quinidine prevents the breakdown of DM by inhibiting the cytochrome P450 enzyme 2D6. (Pioro et al. 2010).

Discussion James Murrough, MD of the Mount Sinai School of Medicine is currently conducting Phase 2 trials with Nuedexta for Treatment- Resistant Major Depression. This study is estimated to be completed by June 2015.

Discussion Future research will illuminate whether DM is effective for MDD in the clinical environment. If it proves to be effective, further work will determine how it is to be dosed to maximize safety and minimize adverse effects for patients. Additionally, the roles of NMDA, σ1, and other receptor systems in MDD and other psychiatric disorders will be investigated.

References Birnbaum, Howard G., et al. "Employer burden of mild, moderate, and severe major depressive disorder: mental health services utilization and costs, and work performance." Depression and anxiety 27.1 (2010): Kennedy, Noel, and Kevin Foy. "The impact of residual symptoms on outcome of major depression." Current psychiatry reports 7.6 (2005): Lee, Ellen E., et al. "Ketamine as a Novel Treatment for Major Depressive Disorder and Bipolar Depression: A Systematic Review and Quantitative Meta-Analysis." General hospital psychiatry (2015) Lauterbach, Edward C. "An extension of hypotheses regarding rapid-acting, treatment- refractory, and conventional antidepressant activity of dextromethorphan and dextrorphan." Medical hypotheses 78.6 (2012): Porsolt, Roger D., M. Le Pichon, and Ml Jalfre. "Depression: a new animal model sensitive to antidepressant treatments." Nature (1977): Wu, Dafang, et al. "Effects of route of administration on dextromethorphan pharmacokinetics and behavioral response in the rat." Journal of Pharmacology and Experimental Therapeutics (1995): Nguyen L, Robson MJ, Healy JR, Scandinaro AL, Matsumoto RR (2014) Involvement of Sigma-1 Receptors in the Antidepressant-like Effects of Dextromethorphan. PLoS ONE 9(2): e doi: /journal.pone Pioro, Erik P., et al. "Dextromethorphan Plus Ultra Low ‐ Dose Quinidine Reduces Pseudobulbar Affect." Annals of neurology 68.5 (2010):

Acknowledgements This project was funded by a Florida Atlantic University undergraduate research grant (A14- 10) and my Principal Investigator Robert P. Vertes, PhD. I would like to acknowledge Robert Vertes, Stephanie Linley, and Ceylan Isgor for providing excellent counsel throughout the trajectory of this project; Salome Sanchez for providing the camera and tripod; Michelle Gallo, Tatiana Viena, Carolina Barbeito, Patricia Pinedo, Dylan Bouscher, and Michael Ham for supporting me emotionally and spiritually.

Thank you very much for your attention