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

2. 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).

3. 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).

4. 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).

5. 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).

6. 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).

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

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

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

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

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

12. 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.

13. 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.

14. 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).

15. 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
56.625 181.5

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

17. 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).

18. 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).

19. 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.

20. 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.

21. 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): 78-89.
• Kennedy, Noel, and Kevin Foy. "The impact of residual symptoms on outcome of major
depression." Current psychiatry reports 7.6 (2005): 441-446.
• 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): 693-702.
• Porsolt, Roger D., M. Le Pichon, and Ml Jalfre. "Depression: a new animal model sensitive
to antidepressant treatments." Nature 266.5604 (1977): 730-732.
• Wu, Dafang, et al. "Effects of route of administration on dextromethorphan
pharmacokinetics and behavioral response in the rat." Journal of Pharmacology and
Experimental Therapeutics 274.3 (1995): 1431-1437.
• 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): e89985. doi: 10.1371/journal.pone.0089985
• Pioro, Erik P., et al. "Dextromethorphan Plus Ultra Low‐Dose Quinidine Reduces
Pseudobulbar Affect." Annals of neurology 68.5 (2010): 693-702.

22. 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.

23. Thank you very
much for your
attention