Page 18 - JCBP-2-3

Journal of Clinical and
Basic Psychosomatics The antidepressant effect of ketamine

found that patients’ glutamate levels in the PFC increase synthesis, lasting until 72 h after ketamine injection.
rapidly after treatment with ketamine. Chowdhury et al. During this period, synaptogenesis is promoted,
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reported that glutamate levels in the PFC increase rapidly especially the maturation and increase in the number
after ketamine infusion in animal models. Research has of neuronal dendrites. 53
reported that glutamate levels in the PFC are significantly (iii) Conflicting evidence has shown that the antidepressant
correlated with the dosage of ketamine. However, a effects of ketamine disappear after the use of an
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negative correlation between ketamine and glutamate has antagonist of the AMPA receptor. 54
been reported in another literature. 47 Another metabolic glutaminergic receptor, mGluR5,
Two main hypotheses for the antidepressant effects was also examined by PET. The ligand binding of mGluR5
of ketamine (the disinhibition hypothesis and the direct significantly decreased and lasted for 24 h after ketamine
inhibition hypothesis) are related to the N-methyl-D- treatment. This finding suggests that the availability of
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aspartate (NMDA) receptor in the glutamate metabolic mGluR5 is modulated by glutamate released after ketamine
pathway. According to the disinhibition hypothesis, injection, which is associated with the antidepressant effect
ketamine acts by binding to NMDA receptors to block of ketamine. A recent study confirmed this observation,
inhibitory interneurons, thereby increasing the firing of demonstrating that ketamine alters the mRNA or protein
excitatory pyramidal neurons. In contrast, the direct expression of mGluR5. 56
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inhibition hypothesis posits that ketamine inhibits NMDA
receptors in the postsynaptic membrane, subsequently 4.2. Monoamine pathway
altering cellular signaling pathways that affect protein The traditional development of antidepressants is based on
expression. The endogenous coagonist of the NMDA the monoamine hypothesis, which posits that the depletion
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receptor, d-serine, plays a key role in NMDA-induced of 5-hydroxytryptamine (5-HT), norepinephrine, and
neurotoxicity, long-term potentiation, neurotransmission, dopamine underlies depression. In addition to affecting
and plasticity. Moaddel et al. applied ketamine to glutamate, ketamine has been shown to indirectly regulate
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treat TRD patients and found that the plasma d-serine monoaminergic neurotransmission. In rodent models, the
concentration at baseline in the remission group was antidepressant effect of ketamine can be blocked through
significantly lower than that in the non-remission group. the consumption of 5-HT by tryptophan hydroxylase;
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Moreover, a low level of d-serine at baseline indicated an ketamine can increase the levels of extracellular
improved antidepressant response. Another regulatory serotonin, dopamine, and norepinephrine in the PFC.
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protein of the NMDA receptor, SHANK3, has also According to a PET study, ketamine can also enhance the
been reported to be involved in the pathophysiology of binding strength of the 5-HT1B receptor and the 5-HT
depression. Ortiz et al. investigated the relationships transporter. Nevertheless, several studies have reported
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between the volume and glucose metabolism of subcortical negative results, which suggest that the antidepressant
nuclei, ketamine efficacy, and SHANK3 levels. They found effect of ketamine was not affected by 5-HT. 60
that a high level of SHANK3 at baseline could predict the Ketamine can effectively improve core symptoms
response to ketamine, enhanced glucose metabolism in of depression and anhedonia, which are usually not
the amygdala and hippocampus, and increased amygdala alleviated by traditional antidepressants. Anhedonia
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volume.
is strongly associated with the dopaminergic reward
Recent intensive research has revealed that the alpha- circuit, suggesting a potential effect of ketamine on the
amino-3-hydroxy-5-methyl-4-isoxazolpropionic acid dopamine pathway. In rodent models, the behavioral
(AMPA) receptor plays a key role in the antidepressant response to repeated administration of ketamine can be
effects of ketamine. As a target of multiple signaling blocked by dopamine receptor antagonists. A recent
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pathways that regulate synaptic plasticity, the AMPA study demonstrated that ketamine could reverse stress-
receptor is primarily responsible for rapid synaptic induced behavioral inhibition in mice, but this effect was
neurotransmission and signal transduction in the brain. blocked by inhibiting dopaminergic signal transduction.
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The findings in this area are as follows: Moreover, the expression levels of dopamine receptors in
(i) Long-term, low-dose ketamine injection increases the the PFC and hippocampus increased following high doses
ratio of AMPA receptors in the hippocampus. 52 of ketamine in a mouse model of schizophrenia, with
(ii) A series of synaptic signaling proteins are activated these increases positively correlated with the injection
2 h after ketamine injection, subsequently activating dose. Iro et al. reported that repeated administration
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the postsynaptic rapamycin target protein molecular of ketamine increased the firing activity of dopaminergic
pathway. This activation triggers synaptic protein and noradrenergic neurons, but not serotonergic neurons.

Volume 2 Issue 3 (2024) 5 doi: 10.36922/jcbp.2596