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.
JAMA Psychiatry
March 25, 2026
Wiesław Jerzy Cubała, Malek Bajbouj, Michael Bauer et al.
3 citations
A single day of treatment with an inhaled synthetic formulation of mebufotenin (GH001) significantly reduced depression symptoms in adults with treatment-resistant depression compared to placebo. In a randomized, double-blind trial of 81 patients, those receiving up to three escalating doses of GH001 showed an average 15.5-point greater improvement on the Montgomery-Åsberg Depression Rating Scale by day 8 than those on placebo. Remission rates were 57.5% for GH001 and 0% for placebo. No severe or serious adverse events occurred. The findings suggest GH001 may be a rapid-acting, well-tolerated treatment option for treatment-resistant depression.
The British Journal of Psychiatry
July 6, 2026
Nick Glozier, Richard W. Morris, Elizabeth Stratton et al.
A 4-week course of subcutaneous racemic ketamine produced short-term clinical benefit in a minority of people with treatment-resistant depression, with response rates declining substantially after treatment cessation. Among 130 participants, 30% responded at treatment end (Montgomery-Åsberg Depression Rating Scale reduction ≥50%), but only 17% remained responders 4 weeks later, and over 50% experienced less than a 25% reduction in depression scores. No difference in response was found between fixed and flexible dosing regimens. Prior ketamine treatment during an earlier randomized trial did not affect later outcomes. No suicides or suicidal behavior requiring admission occurred, and only expected side effects were observed.