Advances in the Management of Major Depressive Disorder - Episode 3

Dextromethorphan-bupropion for Treatment of Major Depressive Disorder

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Dr Greg Mattingly explains the mechanism of action of dextromethorphan-bupropion, a new agent to treat Major Depressive Disorder.


The clinicians discussed limitations of standard antidepressants like SSRIs and SNRIs in treating all symptoms of depression. While effective for core mood symptoms, they do not improve emotional blunting, anhedonia, or cognitive issues, and may worsen cognition by decreasing dopamine. A key limitation is also their delayed onset of action, taking weeks to months to work, whereas patients often need faster relief.

They then covered some newer mechanisms being explored to treat depression more rapidly and effectively, centering around enhancing neuroplasticity. This includes glutamatergic agents, GABA modulation, kappa opioid antagonists, psychedelics, Rexin/orexin pathway agents, and anti-inflammatories.

One glutamatergic agent available now is ketamine, which rapidly increases neural plasticity and connections. Intravenous ketamine has shown profound benefits but limitations around administration and side effects like dissociation. An alternative is intranasal esketamine which also modulates glutamate, but still causes some dissociative and cardiovascular side effects.

A newer oral agent combines dextromethorphan and bupropion. Dextromethorphan is a modest NMDA antagonist like ketamine, and bupropion boosts its levels. Together they modulate glutamate levels enough to enhance neuroplasticity, without causing dissociation or major side effects. Early studies show increased glutamate levels and antidepressant effects within hours/days, but not the problematic side effects of IV ketamine. This offers a potential rapid-acting, oral antidepressant option for a broad range of patients.

Summary was AI-generated and edited for clarity.