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Journal of Clinical and
Basic Psychosomatics The antidepressant effect of ketamine

The kynurenine (KYN) pathway plays an important has significantly influenced awareness of antidepressant
role in depression, according to many investigations. treatments and greatly expanded the medication options
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KYN is a major regulator of glutamate and 5-HT. Both for patients with TRD and depression at risk of suicide.
the metabolic enzymes and metabolites of KYN are Investigating biomarkers related to the rapid-acting
involved in the antidepressant mechanism of ketamine. antidepressant effects of ketamine will be extremely
Moaddel et al. applied ketamine to TRD patients beneficial for early intervention, rapid onset of therapeutic
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and found that plasma KYN levels decreased 4 h after effects, and predicting treatment outcomes in depression.
ketamine infusion in the remission group. Kadriu et al. In this review, we summarize a number of biomarkers
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reported that ketamine could reduce the levels of KYN, (Table 1) that can predict and modulate ketamine efficacy.
a metabolizing enzyme, and a toxic metabolite of KYN, Although research in this area is still in its infancy, it
quinolinic acid, but increase the levels of a protective is helpful for clinicians to identify TRD patients who
metabolite, kynureric acid, in depressed patients. They are suitable candidates for ketamine treatment, thereby
also found that proinflammatory cytokines at baseline alleviating the burden on these patients and society.
were associated with alterations in the KYN pathway To date, the majority of biomarkers are still in the
after ketamine treatment, suggesting that KYN might preclinical exploratory stage, and existing findings
be involved in the immune inflammatory response are limited. To realize the clinical application of these
to depression. A recent study also confirmed that biomarkers, future studies should combine different
ketamine could rapidly increase the serum kynurenic types of biomarkers to investigate their relationships
acid concentration in depressed patients, and the level of and interactions. This approach could optimize clinical
kynurenic uric acid at 24 h could predict the sustained outcomes by enhancing the involvement of biological
antidepressant effects of ketamine at 13 and 26 days. The targets in new models. Cross-modal research on
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above evidence suggests that the KYN pathway is involved biomarkers has been carried out consecutively and is
in the immunological, monoaminergic, and glutamatergic extremely valuable for optimizing neurobiological signals-
mechanisms of depression. The key neuroactive factors assisted diagnosis and treatment.
in the KYN pathway, including metabolic enzymes and
metabolites, can be used not only as new therapeutic Table 1. Neurobiological markers underlying ketamine’s
targets to intervene in depression but also as biomarkers rapid-acting antidepressant effects
to detect the efficacy of ketamine.
Neurobiological markers Biomarkers and reference
Recent animal studies have reported a number of novel Neuroimaging markers
protein or molecular markers associated with ketamine. For Brain morphology Increase hippocampal volume 5,6
instance, Klotho has been reported to be associated with
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the antidepressant effect of low-dose ketamine. Higher Reduce the volume of the left nucleus
accumbens
6
vascular endothelial growth factor levels at baseline were
associated with greater antidepressant and antisuicidal Decrease the density of bilateral insula,
right caudate, and bilateral dlPFC and
effects after ketamine infusion. In addition, ketamine increased density in the bilateral post-
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promoted the differentiation of oligodendrocyte precursor central gyrus, sgACC, thalamus, and
cells and increased myelin formation, contributing to its cerebellum 7,8
antidepressant role. 90 Increase FA of the cingulum, forceps
minor, and uncinate fasciculus 9,10
Ma et al. reported that ketamine acts as a special
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use-dependent trapping blocker (activity-dependent Brain metabolism and Decrease the metabolism of the right
insula, habenula, ventrolateral, and
hemodynamics
trapping blocker). It only blocks NMDA receptors that dorsolateral PFCs 11
enter the open state, after which it remains in the NMDAR Increase metabolism of the right ventral
channel and dissociates at a certain rate. In vivo, ketamine striatum 12
dissociates gradually, and the retained dose is free from the Increase glucose metabolism in the PFC 13
action of metabolic enzymes, thereby blocking the channel Increase dorsal ACC glucose uptake 14
for a long time and continuing to exert its inhibitory effects.
Increase CBF of the posterior cingulate
7. Conclusion cortex, thalamus and visual association
regions
15,16
Psychiatry is gradually shifting toward a paradigm of Decrease CBF in the bilateral
early identification and intervention. As a result of this hippocampus and right insula 15
paradigm shift, the rapid-acting antidepressant ketamine (Cont'd...)

Volume 2 Issue 3 (2024) 7 doi: 10.36922/jcbp.2596