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.
The Journal of Clinical Psychiatry
April 20, 2020
Ewa Wajs, Leah Aluisio, Richard Holder et al.
288 citations
In a year-long open-label study of 802 adults with treatment-resistant depression, esketamine nasal spray combined with a new oral antidepressant showed a manageable safety profile and sustained improvement in depressive symptoms. Common side effects included dizziness, dissociation, nausea, and headache, mostly mild or moderate and resolving the same day. Two deaths occurred, neither linked to the drug. Cognitive performance remained stable or improved. Depression scores dropped during the first four weeks and stayed lower through the maintenance phase.
The World Journal of Biological Psychiatry
November 3, 2020
Siegfried Kasper, Wiesław Jerzy Cubała, Andrea Fagiolini et al.
84 citations
Esketamine nasal spray, an NMDA glutamate receptor antagonist, offers a fast-acting treatment option for patients with treatment-resistant depression (TRD) who have not responded to several prior therapies. A group of six European experts with clinical experience using esketamine nasal spray developed consensus statements on practical considerations before, during, and after administration. The guidance is based on their experience and available literature, aiming to help clinicians unfamiliar with the treatment. Further real-world use is expected to expand existing knowledge.
Frontiers in Psychiatry
November 23, 2023
Florian Buchmayer, Siegfried Kasper
19 citations
Intranasal esketamine, approved in 2019 and 2020 for treatment-resistant depression, helps more than half of non-responders after 2–4 failed antidepressant attempts. Guidelines recommend starting it as an add-on therapy in a medical setting for dose selection, monitoring, and managing adverse events. Long-term treatment is safe, with very rare severe side effects. This review critically evaluates published articles on preparation, management, and observation of the treatment, noting that psychiatrists face new but manageable procedures compared to standard prescribing.
Cerebral Cortex
September 6, 2018
Gregory M. James, Gregor Gryglewski, Thomas Vanicek et al.
16 citations
The cerebral cortex can be divided into distinct areas based on the density of proteins involved in the serotonin system. Using positron emission tomography in healthy participants, the study quantified serotonin 1A receptors (n = 30), 5-HT2A receptors (n = 22), the serotonin-degrading enzyme monoamine oxidase A (n = 32), and the serotonin transporter (n = 24). Clustering analysis identified five optimal clusters of cortical regions defined by these molecular profiles. These clusters explained the effects of psychotropic drugs acting on serotonin, such as antidepressants and psychedelics, suggesting the method is useful for integrating multimodal imaging data in neuropharmacology and psychiatry.
Wiener klinische Wochenschrift
March 1, 2025
Pia Baldinger-Melich, Marie Spies, Ina Bozic et al.
5 citations
Modern electroconvulsive therapy (ECT) and nasal esketamine have significantly improved treatment for treatment-resistant depression (TRD), defined as non-response to at least two adequate antidepressant courses. This literature review presents evidence on efficacy and safety, comparing advantages, disadvantages, and response rates. Both treatments are highly effective for TRD. The choice between esketamine nasal spray and ECT should consider contraindications, age, severity, psychotic symptoms, patient preference, and accessibility. Pragmatically, esketamine is chosen before ECT when both are indicated, but studies on ECT in ketamine non-responders are missing.
medRxiv Preprint Server
March 21, 2025
Leo R. Silberbauer, Benjamin Eggerstorfer, Paul Michenthaler et al.
1 citation
preprint
Oral ketamine may offer a more accessible alternative to intravenous and intranasal routes for treating depression, as it is easier to administer and has established safety and efficacy for chronic pain patients at home. The text suggests that current delivery methods limit ketamine's availability to specialized centers, but oral administration could expand access to antidepressant therapy.
European Psychiatry
June 23, 2026
Maximilian Preiß, Valentin Popper, Luna Helene Charlotte Faber et al.
No Summary
International journal of psychiatry in clinical practice
April 29, 2026
David Eckert, Siegfried Kasper
A narrative review presents a decision-making framework for three pharmacological augmentation strategies for treatment-resistant depression: lithium, quetiapine, and esketamine. The agents differ in pharmacological profile, monitoring requirements, and clinical application, though their mechanisms appear to converge on neuroplasticity pathways. Treatment selection may be guided by psychiatric presentation, somatic comorbidity, and practical feasibility. Validated predictive markers for differential response are currently lacking.
The world journal of biological psychiatry : the official journal of the World Federation of Societies of Biological Psychiatry
January 22, 2026
David Eckert, Siegfried Kasper
For treatment-resistant depression, lithium, quetiapine, and esketamine are all effective augmentation options. A systematic review of head-to-head studies found only four trials: three comparing lithium and quetiapine, and one comparing esketamine and quetiapine. The evidence suggests a descriptive superiority of esketamine over quetiapine and of quetiapine over lithium. However, because the three drugs have fundamentally different properties, side effects, and contraindications, the choice should be made in a comprehensive clinical context. The findings argue for re-evaluating existing treatment algorithms in guidelines.
European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology
July 17, 2026
Mauro Scala, Enrico Magrini, Ivana Leccisotti et al.
Suicide remains a leading cause of early death worldwide, and current treatments are limited by slow onset, short durability, or poor tolerability. This narrative review of 34 studies over the past decade examined pharmacological and neuromodulation interventions for suicidal ideation or suicide attempt that are not yet approved for these uses. Across controlled trials, suicidal ideation commonly improved within days to weeks. Some trials reported reductions in suicidal ideation beyond changes in depression scores, suggesting partial independence, though evidence remains inconsistent. Encouraging results were reported for NMDA-related drugs, opioid-system modulation, ayahuasca, and certain neuromodulation techniques, while non-medical cannabis use was associated with worse suicidal ideation trajectories.