Page 19 - JCBP-2-3

Journal of Clinical and
Basic Psychosomatics The antidepressant effect of ketamine

However, Chang et al. found that esketamine’s effects were thalamic volume was positively associated with the
64
not blocked by dopamine receptor antagonists, suggesting antidepressant response 230 min after ketamine injection
that esketamine might exert its effects independently of in Val/Val homozygous patients but negatively associated
dopamine. with the ketamine antidepressant response in met carriers.
77
4.3. Inflammatory cytokines Ficek et al. applied genome-wide microarray
techniques to analyze numerous genetic transcription
Inflammatory cytokines such as tumor necrosis factor-α, profiles with altered expression in the brain following
C-reactive protein, interleukin (IL)-1β, IL-6, and IL-8 ketamine administration. These transcription profiles
are upregulated in both depressive animal models and reflected the multitarget pharmacological properties of
human patients. Ketamine has been found to exert anti- ketamine. Interestingly, this study revealed similarities in
inflammatory effects. 65,66 For instance, in a mouse model the transcriptional profiles of ketamine and monoaminergic
of ulcerative colitis, ketamine decreased IL-6 levels in the antidepressants, suggesting a degree of convergence of
blood. It also reduced the production of proinflammatory
67
cytokines induced by lipopolysaccharide in mice, thereby their antidepressant effects on the downstream molecules.
68
reducing splenomegaly and cognitive impairment. Ketamine is metabolized through cytochrome enzyme
In addition, ketamine reversed high proinflammatory P450 (CYP450) in the liver. Pharmacogenomic analyses
cytokine levels in female Wistar rats subjected to maternal of the effects of individual genetic variants of CYP450 on
deprivation. In vivo studies have shown that depressed ketamine metabolism might provide evidence for individual
69
women with low IL-8 levels at baseline demonstrate variation in ketamine efficacy. However, evidence on the
enhanced responses to ketamine treatment. These effect of CYP450 gene variants on the ketamine response is
70
studies suggest that ketamine’s ability to regulate immune still inconsistent. A recent study revealed that the activity
inflammation might play a role in its rapid antidepressant of the liver CYP450 subtype contributed to the sustained
effects. The neutrophil-to-lymphocyte ratio, a novel antidepressant effects of ketamine, while another study
78
biomarker of peripheral blood inflammation associated showed that CYP450 polymorphisms could not predict the
with depression, is closely related to the efficacy of clinical response to ketamine. 79
ketamine. In addition, studies have confirmed a link
71
between depression and elevated IL-6, but not between Recently, the effects of several glutamatergic
IL-6 and ketamine. Park et al. examined eight cytokines polymorphisms on the therapeutic effects of ketamine
72
80
and found that only soluble tumor necrosis factor receptor and esketamine in TRD patients were investigated.
1 was associated with depression; the other cytokines were Unfortunately, no positive result was obtained.
unrelated to emotional changes or ketamine, suggesting 6. Other markers
that cytokines are not the primary mechanism of ketamine’s
antidepressant effects. In summary, the neurobiological The main pathway of action of ketamine, the glutamate
mechanisms of depression are not necessarily identical to pathway, functions by increasing BDNF levels, which could
the underlying mechanisms of the ketamine response, but promote synaptic protein synthesis and synaptogenesis,
they can be used as indirect predictors of the response to increase synaptic connectivity, and ultimately play a role
ketamine. as an antidepressant. Substantial evidence indicates that
BDNF is involved in the rapid antidepressant response
5. Genetic markers to ketamine. For instance, Haile et al. reported that
81
Animal research has shown similar transcriptional improvement in depression 4 h after ketamine infusion
responses related to neuroplasticity and the circadian clock was associated with increased BDNF levels. Woelfer
82
in the ACC of sleep-deprived mice after low-dose ketamine et al. investigated the relationships among the ketamine
injection. Cell culture research has indicated that response, BDNF levels, and resting-state functional
73
ketamine alters the expression of clock genes associated connectivity in healthy volunteers. They reported that the
with the internal clock. Researchers believe that the plasma BDNF level in the ketamine group was greater
74
effect of ketamine on synaptic plasticity is mediated by than that in the placebo group after treatment and that
BDNF. Laje et al. reported that the BDNF Val66Met alterations in BDNF levels after ketamine infusion were
75
polymorphism was associated with dysfunction of NMDA associated with increased functional connectivity of the
receptor transmission and hippocampal synaptic plasticity, dorsomedial PFC, reflecting the effect of ketamine on
suggesting that increased BDNF expression might be synaptic plasticity. Zheng et al. discovered that baseline
83
related to increased susceptibility to depression and poor plasma BDNF could predict the antianhedonic effect of
response to ketamine. Niciu et al. found that bilateral repeated doses of ketamine on patients with depression.
76

Volume 2 Issue 3 (2024) 6 doi: 10.36922/jcbp.2596