The rapid effect of ketamine on depression is related to immune system signaling pathways

The rapid effect of ketamine on depression is related to immune system signaling pathways

In a recent study published inMolecular Psychiatry,Researcher Review the anti-inflammatory effects of ketamine in the peripheral and central nervous systems. For this purpose, all relevant articles were obtained from the PubMed and Web of Science databases, with both animal and human studies published up to September 2023 considered for analysis.

Treatment of major depressive disorder

Major depressive disorder (MDD) is a mood disorder associated with persistent feelings of loss of interest and sadness. Current estimates suggest that MDD affects over 300 million people worldwide, with approximately 700,000 committing suicide each year. Altered neurotrophin levels and monoamine dysregulation are both mechanisms attributed to the manifestations of MDD.

Monoamines, which are associated with noradrenergic, serotoninergic, and dopaminergic activities, can be regulated by certain pharmaceutical agents to improve cognition, sleep, and mood in MDD patients. However, conventional monoamine antidepressant therapy has been shown to be effective in only 30–40% of patients with MDD.

According to the STAR*D (Sequenced Treatment Alternatives to Relief Depression) trial, a significant number of MDD patients do not respond to standard treatment. Patients who do not respond to two antidepressants at appropriate doses are known to suffer from treatment-resistant depression (TRD).

Racemic (R,S)-ketamine, more commonly referred to as ketamine, and (S)-ketamine (esketamine) have shown significant beneficial effects on MDD. Compared to conventional treatments, ketamine has been shown to have an antidepressant effect within a few hours. Many TRD patients also responded positively to a single ketamine infusion.

Mechanism of action of ketamine for MDD treatment

The mechanisms underlying the antidepressant effects of ketamine are related to the N-methyl-D-aspartate (NMDA) receptor, the opioid pathway, the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor and mechanistic target of rapamycin (mTOR).

Various neuronal cells, including microglia and astrocytes, regulate neuroinflammation. Individuals with MDD often have lower levels of glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). In these patients, acute administration of ketamine normalized these values ​​and thus improved their mood.

In vivoExperimental results have also shown that ketamine has an inhibitory effect on lipopolysaccharide (LPS)-induced microglial activation, resulting in improvements in depressive-like behaviors. Studies in rodents have also shown that transforming growth factor β (TGF)-β, an anti-inflammatory molecule that inhibits excessive microglial activation, is associated with the differential antidepressant effects of ketamine enantiomers.

Mouse models have shown that (R)-ketamine, and not (S)-ketamine, ameliorates the stress-induced reduction in the expression of Tgfb1 and its receptors Tgfbr1 and Tgfbr2. Nevertheless, further research is needed to clarify the microglia-based mechanisms underlying the antidepressant effects of ketamine.

Patients with MDD have higher levels of interleukin 6 (IL-6) and tumor necrosis factor ⍺ (TNF-⍺) than non-depressed individuals. A study in rodents found that administration of ketamine normalized these levels and improved MDD symptoms.

Higher levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) have been observed in patients with MDD. Administration of 0.5 mg/kg ketamine infusions for 12 days resulted in symptomatic improvement that was accompanied by significant downregulation of GM-CSF.

Ketamine and the immune response

The antidepressant effects of ketamine have been linked to the complement system, which is an essential component of synaptic plasticity. The complement system includes 30 proteins involved in the classical, alternative and lectin pathways, all of which converge on C3 cleavage, an important component of complement.

Complement proteins play a crucial role in regulating cell proliferation, maturation and responsiveness. Activation of the complement system leads to the release of complement and immune molecules that are associated with inflammatory responses.

Elevated levels of serum complement components C3a and C5a have been observed in bipolar disorder. Likewise, a high concentration of serum C1q level is noted in patients with MDD.

Ain vivoExperiments with C5a receptor knockout mice highlighted the neuroprotective role of C5a against glutamate excitotoxicity-induced apoptosis through increased expression and regulation of glutamate receptor subunit 2 (GluR2). Glutamatergic modulation has been demonstrated to be a mechanistic commonality between the complement system and ketamine.

Ketamine also activates mTORC1 by triggering brain-derived neurotrophic factor (BDNF), tropomyosin receptor kinase B (TrkB), and NMDA receptors. In addition, the C3a ligand C3a receptor in CD4+ T cells leads to the activation of mTOR, which is essential for cell survival. Complement mTOR activation also modulates many stress and metabolic pathways, such as: B. cytokine secretion, oxidative phosphorylation and the activation of inflammasomes.

Conclusions

The current study suggested a possible connection between the complement system and the antidepressant effects of ketamine. Nevertheless, further studies are needed to improve treatment outcomes in MDD with ketamine.

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