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 serotonin1b/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.