World Psychiatry
September 15, 2023
Roger S. McIntyre, Mohammad Alsuwaidan, Bernhard T. Baune et al.
712 citations
At least 30% of people with depression meet the common definition of treatment-resistant depression (TRD): inadequate response to two or more antidepressants despite adequate trials and adherence. Many cases are actually pseudo-resistant due to insufficient treatment or non-adherence. No consensus definition with proven predictive utility for clinical decisions exists, leading to varied prevalence estimates and inconsistent care. Intravenous ketamine and intranasal esketamine are effective for TRD. Some second-generation antipsychotics (e.g., aripiprazole, quetiapine XR) help as adjuncts in partial responders, but only the olanzapine-fluoxetine combination has been studied in FDA-defined TRD. Repetitive transcranial magnetic stimulation and electroconvulsive therapy are established effective interventions. Evidence for extending trials, switching, or combining antidepressants is mixed, and manual-based psychotherapies are not effective alone but help when added to antidepressants.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
August 1, 2024
Roger S McIntyre, Istvan Bitter, Jozefien Buyze et al.
30 citations
In the ESCAPE-TRD trial, esketamine nasal spray caused treatment-emergent adverse events more often than quetiapine extended release (91.9% versus 78.0%), but these events were typically mild or moderate and transient: 92.0% resolved the same day, and only 4.2% of patients discontinued esketamine due to adverse events compared with 11.0% for quetiapine. The median proportion of days with adverse events was lower with esketamine (11.9% versus 21.3%). Along with greater efficacy, esketamine's tolerability profile supports its use for treatment-resistant depression.
medRxiv Preprint Server
March 31, 2026
Maia Mallevays, Louise Fuet, Michel Danon et al.
1 citation
preprint
In patients with treatment-resistant depression receiving esketamine, mystical experiences—similar to those induced by classic psychedelics—occurred in 58% of patients, with high variability across sessions. Higher mean and peak scores on the Mystical Experience Questionnaire (MEQ-30) were associated with greater improvement in depression severity, while dissociative or other non-mystical effects were not. Positive mood and mystical dimensions of the MEQ predicted therapeutic outcomes, and baseline spirituality predicted both treatment response and peak MEQ scores in the first week. These findings suggest that psychedelic-like mystical experiences may contribute to esketamine's therapeutic efficacy.
Journal of affective disorders
May 1, 2026
Michel Danon, Gabriela Ostronoff, Anne-Cécile Petit et al.
Regulatory approvals for intranasal esketamine in treatment-resistant depression differ on its indication for suicidal ideation. In a two-center observational study of 261 adults with moderate-to-severe treatment-resistant depression, eight esketamine sessions over four weeks improved both depressive symptoms and suicidal ideation. However, after statistically adjusting for the antidepressant effect, the reduction in suicidal ideation was no longer significant. The findings suggest that esketamine's anti-suicidal effect does not persist independently of its antidepressant effect.