Ketamine's rapid impact on depression linked to immune system pathways

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In a recent study published in Molecular Psychiatry, researchers review the anti-inflammatory effects of ketamine in the peripheral and central nervous systems. To this end, all relevant articles were obtained from PubMed and Web of Science databases, with both animal and human studies published until September 2023 considered for the analysis.

Study: Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: Can the complement system complement ketamine’s antidepressant effects? Image Credit: Jack_the_sparrow /

Treating major depressive disorder

Major depressive disorder (MDD) is a mood disorder associated with persistent feelings of loss of interest and sadness. Current estimates indicate that over 300 million individuals are affected by MDD globally, about 700,000 of whom commit suicide each year. Altered neurotrophin levels and monoamine dysregulation are both mechanisms that have been attributed to manifestations of MDD.

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

According to the Sequenced Treatment Alternatives to Relieve Depression (STAR*D) study, a significant number of MDD patients do not respond to standard treatment. Patients who fail to respond to two antidepressants of suitable dosage are known to suffer treatment-resistant depression (TRD). 

Racemic (R, S)-ketamine, which is more commonly referred to as ketamine, and (S)-ketamine (esketamine) have shown significant positive effects on MDD. As compared to conventional treatments, ketamine has been shown to exert antidepressant effects within a few hours. Many TRD patients have also responded positively to a single ketamine infusion.

Mechanism of action of ketamine for MDD treatment

The mechanisms that underlie the antidepressant effects of ketamine are associated with the N-methyl-D-aspartate (NMDA) receptor, opioid pathway, 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 exhibit lower levels of glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1). In these patients, an acute administration of ketamine normalized these levels, thus improving their mood. 

In vivo experimental findings have also shown that ketamine has an inhibitory effect in lipopolysaccharide (LPS)-induced microglial activation, which led to improvements in depressive-like behaviors. Rodent studies have also reported that transforming growth factor β (TGF)-β, an anti-inflammatory molecule inhibiting excessive microglial activation, is associated with the differential antidepressant effects of ketamine enantiomers.

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

Patients with MDD exhibit higher interleukin 6 (IL-6) and tumor necrosis factor ⍺ (TNF-⍺) levels than non-depressed individuals. One rodent study revealed ketamine administration 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 twelve days led to symptomatic improvement that was associated with significant downregulation of GM-CSF. 

Ketamine and the immune response

The antidepressant effects of ketamine have been linked with the complement system, which is a vital component of synaptic plasticity. The complement system comprises 30 proteins that are involved in the classical, alternate, and lectin pathways, all of which converge in C3 cleavage, a major complement component.

Complement proteins play a crucial role in the regulation of cell proliferation, maturation, and responsiveness. Activation of the complement system results in the release of complement and immune molecules that are linked with inflammatory responses.

Increased levels of serum complement components C3a and C5a have been observed in bipolar disorder. Similarly, a high concentration of serum C1q levels is found in patients with MDD.

An in vivo experiment with C5a receptor knockout mice highlighted the neuroprotective role of C5a against glutamate excitotoxicity-induced apoptosis through elevated expression and regulation of glutamate receptor subunit 2 (GluR2). Glutamatergic modulation has been established as a mechanistic commonality between the complement system and ketamine. 

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


The current study indicated the potential association between the complement system and the antidepressant effects of ketamine. Nevertheless, additional studies are needed to improve treatment outcomes for MDD using ketamine.

Journal reference:
  • Quintanilla, B., Zarate, C. A., and Pillai, A. (2024) Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: Can the complement system complement ketamine’s antidepressant effects? Molecular Psychiatry; 1-10. doi:10.1038/s41380-024-02507-7
Dr. Priyom Bose

Written by

Dr. Priyom Bose

Priyom holds a Ph.D. in Plant Biology and Biotechnology from the University of Madras, India. She is an active researcher and an experienced science writer. Priyom has also co-authored several original research articles that have been published in reputed peer-reviewed journals. She is also an avid reader and an amateur photographer.


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