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