Dextromethorphan for depression?

That dextromethorphan, an antitussive component of over-the-counter cough and cold formulations, may elicit significant antidepressant response in patients whose symptoms of major depressive disorder have responded insufficiently to standard antidepressants, is suggested by a case reported recently by Mercer University School of Medicine’s Edward C. Lauterbach (Psychopharmacology Bulletin 46:2:53-58, 2018).

Lauterbach’s adult patient had failed to respond to coadministered citalopram and vortiexetine and had responded and then relapsed on coadministered fluoxetine and bupropion, was treated with a combination of bupropion (300 mg/day after a one-day challenge with 600 milligrams) and an acute dose of dextromethorphan (60 milligrams orally). The patient reportedly evinced significant improvement within forty-eight hours that persisted for seven days. Rechallenged with dextromethorphan (60 milligrams per day, coadministered with bupropion 300 mg/day), the patient again improved for 20 days, whereupon she again relapsed, despite continued treatment.

Lauterbach attributes his patient’s improvement to dextromethorphan (at high bioavailability enabled by bupropion, a potent inhibitor of CYP2D6, the principal metabolic pathway in dextromethorphan clearance). He likens the antidepressant effect he observed in his patient to that of ketamine, previously reported to exert antidepressant effects by dint of N-methyl-d-aspartate receptor antagonism. (Obiter: Dextromethorphan also is a serotonin reuptake inhibitor and sigma-one opioid agonist, and has been implicated in several reported cases of hyperserotonergic toxicity. As the author asserts, dextromethorphan is an NMDA antagonist and has been associated with short-term dissociative states, as have ketamine and phencyclidine. When accompanied by transient reduction of depression ratings, the dissociative state induced by ketamine has been interpreted as an antidepressant effect. Not yet known is whether ketamine’s (or dextromethorphan’s) putative antidepressant effects may convey more benefit than risk. So far, the published literature pertaining to dextromethorphan comprises more reports of clinically significant adverse effects than of benefit.)





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