International Journal of Neuropsychopharmacology
March 26, 2023
T. Su, Cheng-Ta Li, Wei-Chen Lin et al.
48 citations
A single low-dose ketamine infusion (0.5 mg/kg) produces an antidepressant effect lasting up to 14 days in outpatients with treatment-resistant depression and prominent suicidal thoughts, compared with a low-dose midazolam control. The antisuicidal effect, however, persists only 5 days. The benefits are most pronounced in patients whose current depressive episode has lasted less than 24 months or who have failed four or fewer prior antidepressants. The treatment is safe and well tolerated.
The international journal of neuropsychopharmacology
December 29, 2020
Mu-Hong Chen, Wan-Chen Chang, Wei-Chen Lin et al.
28 citations
Depression involves disrupted communication between the frontal cortex and striatum. In 48 patients with treatment-resistant depression, those with lower baseline connectivity in these circuits showed greater symptom improvement after a single low-dose (0.2 mg/kg) ketamine infusion, but not after a higher dose (0.5 mg/kg) or placebo. Reduced connectivity between the superior frontal cortex and striatum predicted treatment response. Patients had weaker frontostriatal connections than healthy controls.
Progress in brain research
January 1, 2023
Cheng-Ta Li
25 citations
Treatment-resistant depression (TRD) describes patients with major depressive disorder who do not respond adequately to antidepressant drugs. Compared to those without TRD, affected individuals have lower health-related quality of life, more functional impairment and productivity loss, and higher healthcare costs, imposing a massive burden on individuals, families, and society. A lack of consensus on the definition of TRD limits comparison of treatment efficacy across trials and results in scarce treatment guidelines specifically for TRD. This chapter reviews common issues including definitions of an adequate antidepressant trial and TRD, prevalence and clinical outcomes, staging models, variations in definitions, and up-to-date treatment options such as pharmacological strategies, psychotherapeutic interventions, neurostimulation, glutamatergic compounds, and experimental agents.
Molecular psychiatry
January 1, 2025
Pei-Chi Tu, Wan-Chen Chang, Tung-Ping Su et al.
13 citations
In two clinical trials involving a total of 96 patients with treatment-resistant depression, a single low dose of ketamine altered specific connections between the thalamus and frontal brain regions, measured by resting-state functional MRI three days after infusion. Some thalamocortical connections increased and others decreased in the ketamine groups compared to placebo or midazolam groups. However, these brain connectivity changes were not statistically significantly linked to improvements in depression or suicidal thoughts after correcting for multiple comparisons. The results suggest that while ketamine may modify thalamocortical connectivity, whether these changes underlie its antidepressant and antisuicidal effects remains uncertain and requires further study.
Journal of Psychiatric Research
July 1, 2023
Mu-Hong Chen, Wei-Chen Lin, Cheng-Ta Li et al.
8 citations
In patients with treatment-resistant depression and strong suicidal thoughts, a single low-dose infusion of ketamine did not change blood levels of two proteins—VEGF and MMP-9—compared to a control drug, midazolam. However, patients who had higher VEGF levels before treatment showed greater improvements in depression and suicidal ideation after ketamine. This suggests that baseline VEGF might help predict who will benefit from ketamine, but the drug itself does not alter these protein levels.
Journal of Affective Disorders
August 1, 2023
Mu-Hong Chen, Ya-Mei Bai, Hui-Ju Wu et al.
7 citations
A single low-dose ketamine infusion (0.5 mg/kg) compared to a low-dose midazolam control (0.045 mg/kg) resulted in higher serum levels of the anti-aging hormone klotho three days after treatment in 48 patients with treatment-resistant depression and strong suicidal ideation. However, ketamine did not significantly increase klotho levels from baseline, and changes in klotho were not associated with changes in depressive or suicidal symptoms. Higher baseline klotho levels predicted a poorer antidepressant response to ketamine. The findings suggest klotho may be involved in ketamine's antidepressant mechanism, but further molecular studies are needed.
Psychiatry research
March 1, 2025
Tung-Ping Su, Li-Kai Cheng, Pei-Chi Tu et al.
6 citations
A single low-dose infusion of ketamine (0.5 mg/kg) reduced depressive and suicidal symptoms more than a low-dose midazolam infusion in 43 patients with treatment-resistant depression and suicidal ideation. Brain scans showed that ketamine increased network integrity, specifically degree centrality and clustering coefficient in the angular gyrus and degree centrality in the right thalamus. These changes in the thalamus and default-mode network may underlie ketamine's antidepressant effect.
The Journal of clinical psychiatry
July 8, 2024
Wei-Chen Lin, Mu-Hong Chen, Tung-Ping Su et al.
4 citations
A single low-dose infusion of ketamine (0.5 mg/kg) briefly reduces hopelessness and later lowers suicidal ideation in people with treatment-resistant depression and strong suicidal thoughts. In a randomized trial of 84 patients, those receiving ketamine showed significantly less hopelessness four hours after infusion compared with those receiving a control drug (midazolam). Two days after infusion, the ketamine group had more positive and fewer negative suicidal thoughts. The early drop in hopelessness predicted the later antisuicidal effect. The antihopelessness effect lasted only about four hours, while the antisuicidal effect appeared on the second day.
The British journal of psychiatry : the journal of mental science
April 2, 2025
Wei-Chen Lin, Li-Kai Cheng, Tung-Ping Su et al.
2 citations
Dysfunction in the default mode, salience, and frontoparietal networks—the triple network model—may underlie treatment-resistant depression. Analyzing resting-state functional connectivity MRI data from two clinical trials, researchers found that a single low-dose ketamine infusion altered network properties. In one trial, ketamine changed degree centrality and cluster coefficient in the right posterior cingulate cortex (default mode network) and cluster coefficient in the right supramarginal gyrus (salience network), compared to saline. In another trial, ketamine altered characteristic path length in the left posterior cingulate cortex (default mode network) compared to midazolam. A time effect on cluster coefficient in the right dorsolateral prefrontal cortex (frontoparietal network) appeared for both ketamine and saline. These findings suggest the triple-network model helps explain ketamine's antidepressant effects.
Journal of psychopharmacology (Oxford, England)
March 24, 2025
Chung-Feng Kao, Shih-Jen Tsai, Tung-Ping Su et al.
1 citation
Low-dose ketamine, an N-methyl-D-aspartate receptor antagonist, has an antidepressant effect in treatment-resistant depression that may involve multiple monoamine neurotransmitter systems beyond glutamate. In a trial with 65 patients, those receiving 0.5 mg/kg or 0.2 mg/kg ketamine were compared with those receiving normal saline. Genetic analysis of 50 monoamine-related genes found that variants in the cholinergic, dopaminergic, serotonergic, opioid, cannabinoid, and σ1 receptor systems were associated with ketamine's antidepressant effect. The neuroactive ligand-receptor interaction pathway played a key role. The findings suggest that ketamine's effects involve serotonin, dopamine, and other monoamine systems.
Pharmacopsychiatry
December 20, 2024
Mu-Hong Chen, Tung-Ping Su, Wei-Chen Lin et al.
1 citation
Low-grade inflammation (LGI) is linked to poor response to standard antidepressants, but its role in ketamine treatment for treatment-resistant depression (TRD) was unclear. In 167 patients with TRD, 46 had LGI (C-reactive protein ≥3 mg/L) and 121 did not. A single low-dose ketamine infusion improved depressive symptoms only in patients without LGI, showing no significant antidepressant effect in those with LGI. However, ketamine reduced suicidal thoughts in both groups. The placebo response was notably greater in patients with LGI, which may explain the lack of observed ketamine effect in that group. Further research is needed to confirm these findings.
Scientific reports
May 20, 2026
Guan-Jie She, Wei-Chi Li, Chun-Hsiang Chou et al.
Ketamine infusion alters brain activity patterns in people with treatment-resistant depression, specifically in regions involved in sensory-cognitive integration, mood regulation, and cognitive control. In a study of 45 patients, those receiving ketamine showed changes in the timing and shape of hemodynamic responses in the bilateral olfactory cortex and right inferior parietal gyrus, compared to those receiving midazolam. Improvements in suicidal thoughts were linked to changes in the thalamus and superior frontal gyrus. Ketamine responders also had reduced time-to-peak in the left precuneus. These findings suggest ketamine's effects on suicidal ideation may involve neurovascular coupling dynamics.
The international journal of neuropsychopharmacology
May 3, 2026
Kuan-I Liu, Wei-Chen Lin, Cheng-Ta Li et al.
Intravenous ketamine rapidly reduces depressive symptoms in treatment-resistant depression, but its effects vary by symptom. In a pooled analysis of two randomized controlled trials involving 154 adults, ketamine significantly improved total depression scores and seven individual symptoms, including suicidal thoughts. However, the degree of treatment resistance, measured by the Maudsley Staging Method, moderated improvements in apparent sadness and inner tension: patients with higher resistance showed less benefit. In contrast, the anti-suicidal effect of ketamine remained robust regardless of resistance severity. These exploratory findings suggest that symptom-specific treatment strategies may be needed, with ketamine potentially serving as an acute intervention for suicidal crises across resistance levels, while highly refractory patients may require augmentation for certain affective symptoms.
Pharmacopsychiatry
February 26, 2026
Ping-Chung Wu, Wei-Chen Lin, Tung-Ping Su et al.
A combination of clinical markers better predicts which patients with treatment-resistant depression and suicidal thoughts will respond rapidly and durably to a single low-dose ketamine infusion than any single marker alone. The markers include mild or moderate depression severity, a shorter current episode, no more than four prior antidepressant failures, low or moderate current suicide risk, and a history of suicide attempts. The analysis of 67 patients from previous trials used a decision-tree model to identify these predictors. Clinicians can use these findings to select patients most likely to benefit, though further confirmation is needed.
arXiv Preprint Archive
May 29, 2018
Zehong Cao, Chin-Teng Lin, Weiping Ding et al.
In a randomized, double-blind, placebo-controlled trial, 55 outpatients with treatment-resistant depression received either 0.5 mg/kg ketamine, 0.2 mg/kg ketamine, or saline. Using a wearable forehead EEG device, responders to ketamine showed weaker theta power at baseline and increased alpha power with lower alpha asymmetry and theta cordance after treatment compared to non-responders. A baseline EEG predictor classified responders and non-responders with 81.3% accuracy, 82.1% sensitivity, and 91.9% specificity. The rapid antidepressant effects of mixed ketamine doses are linked to prefrontal EEG patterns, which may help identify likely responders before treatment.