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.
Psychedelic Med (New Rochelle)
March 12, 2024
Alexander Wen, Nikhita Singhal, Brett D. M. Jones et al.
36 citations
Blinding is especially difficult in randomized controlled trials of psychedelics because these drugs produce noticeable changes in consciousness. This systematic review of 50 papers from 48 clinical trials published between 1963 and January 2023 found that most studies were double-blinded, used within-subjects designs, and employed inert placebos. The majority did not report on whether blinding procedures were successful, and in those that did, blinding failed. To reduce unblinding and expectancy effects, the authors recommend using active placebos and dose-response or active comparator designs.
EClinicalMedicine
December 1, 2025
Tyler S Kaster, Yi Dai, Fidel Vila-Rodriguez et al.
5 citations
Both repetitive transcranial magnetic stimulation (rTMS) and intranasal esketamine are more effective than starting a new antidepressant medication for treatment-resistant depression. In a secondary analysis of individual patient data from two clinical trials involving 282 matched participants, rTMS reduced depression severity scores by 5.35 points and esketamine by 2.89 points more than medication alone. The difference between rTMS and esketamine was not statistically significant, but the results suggest rTMS may be at least as effective as esketamine. The analysis highlights the need for direct head-to-head trials comparing these two interventions.
Translational Psychiatry
November 17, 2025
Noah Stapper, Lindsay L Benster, Sahit Menon et al.
1 citation
A systematic review of 24 clinical trials examined neurophysiological biomarkers linked to treatment-induced changes in suicidal ideation. Most studies were published within the past five years but showed methodological heterogeneity, including non-randomized designs and concurrent interventions. Despite limitations, findings suggest that the anterior cingulate cortex is involved in the anti-suicidal effects of intravenous ketamine, an effect absent with oral ketamine, possibly explaining intravenous ketamine's superior clinical effects. Improvements in suicidal ideation following electroconvulsive therapy and magnetic seizure therapy were associated with activity in the prefrontal cortex. These patterns may indicate that acute effects of intravenous ketamine and sustained effects of seizure therapies involve differential modulation of these brain regions.
Journal of Affective Disorders
November 1, 2026
Lindsay L Benster, Jordan N Kohn, Benjamin Wade et al.
In a real-world comparison of two FDA-approved treatments for treatment-resistant depression, intranasal esketamine led to faster improvement than repetitive transcranial magnetic stimulation (rTMS). Over 90 days, esketamine patients responded a median of 36 days versus 49 days for rTMS, and suicidal ideation resolved more quickly (median 9 vs. 26 days). However, by about 90 days, overall response and remission rates were similar between the groups (68.8% and 45.2% for esketamine; 59.4% and 40.1% for rTMS), suggesting a difference in speed rather than ultimate effectiveness. For rTMS, slower response was predicted by comorbid anxiety and benzodiazepine use, while former tobacco use predicted faster response. No such predictors were found for esketamine.