Neuropsychiatric Disease and Treatment
January 1, 2020
Daphne Voineskos, Zafiris J. Daskalakis, Daniel M. Blumberger
430 citations
Treatment-resistant depression (TRD) is a form of major depressive disorder that does not respond to standard first-line treatments. Although no consensus definition exists, all models require an inadequate response to at least two trials of antidepressant medication. This review compiles meta-analyses, trials, and reviews on TRD challenges and management. It discusses confounds in definitions and staging, difficulties in assessment, and pharmacological augmentation strategies (lithium, triiodothyronine, second-generation antipsychotics, switching antidepressant class). Somatic therapies (electroconvulsive therapy, repetitive transcranial magnetic stimulation, magnetic seizure therapy, deep brain stimulation), psychotherapeutic approaches, and novel treatments (ketamine, psilocybin, anti-inflammatories) are reviewed. The evidence indicates that further large-scale work is needed to understand appropriate treatment pathways and prescribe effective options.
Ther Adv Psychopharmacol
October 16, 2025
Stanley Wong, Brett D. M. Jones, Mathura T. Thiyagarajah et al.
3 citations
A review of nine small clinical trials found that ayahuasca and psilocybin, when used to treat major depressive disorder and treatment-resistant depression, are associated with changes in several biological markers. These include increased serum brain-derived neurotrophic factor, decreased serum C-reactive protein, altered amygdala activation, and changes in functional connectivity between brain regions such as the ventromedial prefrontal cortex, anterior cingulate cortex, and posterior cingulate cortex. These associations suggest potential mechanisms of clinical response, but larger, longer-term studies are needed to confirm these findings.
Journal of affective disorders
January 23, 2026
Reinhard Janssen-Aguilar, Jithin Joseph, Huda Al-Shamali et al.
In a retrospective chart review of 209 adults with treatment-resistant depression treated with intravenous ketamine, depressive and anxiety symptoms improved significantly over four or six infusions, but the improvements were modest and highly variable across individuals. Anxiety symptoms improved more slowly and less robustly than depressive symptoms. End-of-treatment response and remission rates were numerically higher after six infusions than after four, but the difference was not statistically significant. Four distinct patterns of symptom change emerged for both depression and anxiety, highlighting the heterogeneity of treatment response. Durability after six infusions could not be assessed because follow-up data were available only for the four-infusion group.