Rethinking the Treatment-Resistant Depression.
Advances in experimental medicine and biology 2026 DOI: 10.1007/978-981-95-6872-7_5 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Review Peer reviewed |
|---|---|
| Topics | Ketamine Depression |
| Keywords | Biomarkers Individualized treatment Inflammation Neural regulation Refractory depression |
| Citations | 1 |
| Key findings | Treatment-resistant depression affects about one-third of people with major depression and involves glutamatergic dysregulation, default-mode network hyperactivity, impaired neuroplasticity, chronic inflammation, and epigenetic changes, with distinct subtypes guiding personalized care. |
Abstract
Treatment-resistant depression (TRD) affects about one-third of people with major depression and leads to higher suicide rates, impaired functioning, and increased healthcare use. Originally defined as nonresponse to tricyclic antidepressants, TRD now encompasses inadequate response to multiple antidepressant classes, psychotherapy, and neuromodulation. Inconsistent criteria-varying by agency, required treatment failures, dosage/duration thresholds, and symptom scales-complicate prevalence estimates and clinical decision-making. Differential diagnosis is challenging: many presumed TRD cases actually involve bipolar depression, personality or anxiety disorders, somatic symptom disorders, or early neurocognitive conditions. Neurobiological research identifies glutamatergic dysregulation, default-mode network hyperactivity, impaired neuroplasticity, chronic inflammation, and epigenetic changes as TRD markers. Clinically, TRD patients experience persistent anhedonia, cognitive deficits, somatic complaints, and sleep disturbances. Latent class analysis yields subtypes-anxiety-agitation, cognitive-executive dysfunction, somatic-dominant, and affective-deficit-with distinct treatment responses. Biomarker-driven categories (e.g., high-inflammation profiles, connectivity patterns) and developmental/response-based subgroups (e.g., early-onset, ketamine-responsive) guide personalized care. Future work must standardize definitions, integrate multimodal biomarkers, and validate criteria across cultures to improve early identification, prognosis, and targeted interventions.
Comparable studies
Other narrative reviews on ketamine for depression, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression: An International Expert Opinion on the Available Evidence and Implementation Adults with treatment-resistant depression | 2021 | Review | |
| Ketamine: a paradigm shift for depression research and treatment | 2019 | Review | |
| Rapid‐acting antidepressant ketamine, its metabolites and other candidates: A historical overview and future perspective | 2019 | Review | |
| Ketamine: A tale of two enantiomers | 2020 | Review | |
| Molecular mechanisms underlying the antidepressant actions of arketamine: beyond the NMDA receptor | 2021 | Review |
Citations in the library
Cites 12
- Are “mystical experiences” essential for antidepressant actions of ketamine and the classic psychedelics? European Archives of Psychiatry and Clinical Neuroscience February 27, 2024
- Real world effectiveness of repeated ketamine infusions for treatment-resistant depression with comorbid borderline personality disorder. Psychiatry Research March 5, 2023
- Transformative Therapies for Depression: Postpartum Depression, Major Depressive Disorder, and Treatment-Resistant Depression Annual Review of Medicine November 11, 2024
- Ketamine and its two enantiomers in anesthesiology and psychiatry: A historical review and future directions Journal of Anesthesia and Translational Medicine July 11, 2024
- Functional Dysconnectivity of Frontal Cortex to Striatum Predicts Ketamine Infusion Response in Treatment-Resistant Depression. The International Journal of Neuropsychopharmacology December 29, 2020
and 7 more in the library