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Antidepressant Efficacy of Dextromethorphan in
the Forced Swim Test
Introduction
o Major Depressive Disorder (MDD) costs US employers $24-
31 billion a year in employee absenteeism and reduced work
performance (Birnbaum et al. 2010).
o 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).
o 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).
o 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).
o 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
o Subjects: Male Adult Sprague-Dawley rats were allowed access
to food and water ad libitum.
o Apparatus: Habituation and test trials were conducted in
opaque buckets (H: 14.5in, D: 12in).
o Habituation: Rats were placed in buckets filled halfway with
water for 15 minutes to acclimate to the aquatic environment.
o Drugs and treatments: DM or saline (30mg/kg) was
administered intraperitoneally (IP) 23 hours after habituation
trials, 1 hour before test trials.
o Test: 24 hours after habituation, rats were placed in buckets
for 5 minutes while being recorded with a Canon Rebel T3i
camera.
o Statistical analysis: Immobility time was scored and differences
between groups were determined by one-way ANOVA. A
Kruskal-Wallis ANOVA was conducted if Levene’s test
showed significantly different variances between groups.
Results
o Intraperitoneal treatment with dextromethorphan at doses of 30mg/kg (M=56.625; SD=35.30)
significantly reduced the immobility time of rats compared to the control group (M=188.25; SD=87.20)
as shown by one-way ANOVA (F(1-6)=7.83; p=0.03; Fig. 1).
o Levene’s test indicated unequal variances between groups (F=7.83, p=.01), and a Kruskal-Wallis
ANOVA also yielded significant differences between groups (H(1) = 4.083; p=0.04).
56.625
188.25
0
50
100
150
200
250
DM Saline
Immobility Time (s)
Saline
DM
*
DM: n=4 Saline: n=4
Fig. 1. 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
o The present study demonstrated that the acute
administration of DM (30mg/kg) decreased the
immobility time of rats in the forced swim test.
o 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).
o 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).
o 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.
o 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
o 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.
o Kennedy, Noel, and Kevin Foy. "The impact of residual symptoms on outcome of major
depression." Current psychiatry reports 7.6 (2005): 441-446.
o 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)
o 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.
o Porsolt, Roger D., M. Le Pichon, and Ml Jalfre. "Depression: a new animal model sensitive
to antidepressant treatments." Nature 266.5604 (1977): 730-732.
o 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.
o 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
o Pioro, Erik P., et al. "Dextromethorphan Plus Ultra Low‐Dose Quinidine Reduces
Pseudobulbar Affect." Annals of neurology 68.5 (2010): 693-702.
Acknowledgements
o 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.
Randy Ellis, Robert P. Vertes, PhD
Center for Complex Systems and Brain Sciences, Florida Atlantic University, Boca Raton, FL, 33431