About 30% of people treated for a major depressive episode do not achieve remission after two or more trials of first-line antidepressants, a condition known as treatment-resistant depression (TRD). Because the chance of remission declines with each additional medication trial, clinicians need to understand the characteristics, risk factors, and subtypes of major depressive disorder that are less responsive to standard treatments. This article reviews approved treatments for TRD, including esketamine, and the evidence for psilocybin and pramipexole. Although guidelines to help identify person-centered treatments are available, they remain limited in specificity.
Antidepressant, atypical antipsychotic, and hallucinogen drugs act partly through the serotonin-2A (5HT2A) receptor. Hallucinogens like psilocybin bind as agonists at this receptor, altering perception, mood, and cognition. Some hallucinogens are being tested in small Phase 2 studies for depression, alcoholism, smoking cessation, anxiety, and PTSD. However, concurrent use of antidepressants or atypical antipsychotics may attenuate hallucinogens' therapeutic effects because those medications desensitize or down-regulate 5HT2A receptors. This finding has implications for optimizing hallucinogen therapy in psychiatry.
Dextromethorphan (DXM) has been repurposed over seven decades: first as a cough suppressant, then combined with quinidine for pseudobulbar affect, and most recently formulated with bupropion for major depressive disorder. This article describes DXM's history and mechanisms of action for each use, highlighting the uniquely rapid action and safety profile of the oral dextromethorphan-bupropion antidepressant formulation.