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Med Hypotheses. 2011 May;76(5):717-9. doi: 10.1016/j.mehy.2011.02.003. Epub 2011 Mar 1.

Dextromethorphan as a potential rapid-acting antidepressant.

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Department of Psychiatry and Behavioral Sciences, Mercer University School of Medicine, 1550 College Street, Macon, GA 31201, USA.


Dextromethorphan shares pharmacological properties in common with antidepressants and, in particular, ketamine, a drug with demonstrated rapid-acting antidepressant activity. Pharmacodynamic similarities include actions on NMDA, μ opiate, sigma-1, calcium channel, serotonin transporter, and muscarinic sites. Additional unique properties potentially contributory to an antidepressant effect include actions at ß, alpha-2, and serotonin 1b/d receptors. It is therefore, hypothesized that dextromethorphan may have antidepressant efficacy in bipolar, unipolar, major depression, psychotic, and treatment-resistant depressive disorders, and may display rapid-onset of antidepressant response. An antidepressant response may be associated with a positive family history of alcoholism, prediction of ketamine response, increased AMPA-to-NMDA receptor activity ratio, antidepressant properties in animal models of depression, reward system activation, enhanced erythrocyte magnesium concentration, and correlation with frontal μ receptor binding potential. Clinical trials of dextromethorphan in depressive disorders, especially treatment-resistant depression, now seem warranted.

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