In a recent investigation published in Molecular Psychiatry, researchers reported experimental evidence underscoring ketamine’s inhibitory impact on lipopolysaccharide (LPS)-induced microglial activation and its association with the antidepressant effects of transforming growth factor β (TGF)-β. Additionally, ketamine administration normalizes elevated levels of pro-inflammatory cytokines like interleukin 6 (IL-6) and tumor necrosis factor ⍺ (TNF-⍺) observed in major depressive disorder (MDD) patients.
MDD is a prevalent mood disorder characterized by persistent feelings of sadness and loss of interest, affecting over 300 million individuals worldwide. Unfortunately, around 700,000 MDD patients succumb to suicide annually. The etiology of MDD involves altered neurotrophins levels and monoamine dysregulation. Conventional monoamine antidepressants aim to improve the cognition, sleep, and mood of patients with MDD by targeting the noradrenergic, serotoninergic, and dopaminergic pathways. However, these therapies are only effective in 30-40% of cases. In contrast, ketamine has emerged as a revolutionary breakthrough in the treatment of MDD. It produces rapid antidepressant effects that can be noticed within a few hours after administration, instead of weeks required by conventional antidepressants. Ketamine has shown remarkable results, especially for patients with treatment-resistant depression (TRD), who often respond positively to a single ketamine injection.
The antidepressant mechanisms of ketamine are intricately linked with N-methyl-D-aspartate (NMDA) and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, the opioid pathway, and the mechanistic target of rapamycin (mTOR). Moreover, ketamine exerts regulatory effects on microglia and astrocytes, modulating neuroinflammation markers such as glial fibrillary acidic protein (GFAP) and glutamate transporter-1 (GLT-1).
Granulocyte-macrophage colony-stimulating factor (GM-CSF) levels, elevated in MDD, are significantly downregulated following ketamine treatment, correlating with symptomatic improvement. The involvement of the complement system, particularly components such as C3a, C5a, and C1q, underscores the synaptic plasticity regulation and inflammatory responses associated with MDD and bipolar disorder.
Experimental models reveal the neuroprotective role of C5a against glutamate excitotoxicity-induced apoptosis and its modulation of glutamatergic pathways, similar to ketamine. Ketamine’s activation of mTORC1 via brain-derived neurotrophic factor (BDNF) and NMDA receptors intertwines with complement-mTOR activation, impacting various stress and metabolic pathways.
This study highlights the potential interplay between the complement system and ketamine’s antidepressant effects, suggesting opportunities for further research to enhance MDD treatment outcomes. Ketamine offers a ray of hope in the realm of TRD, paving the way for novel therapeutic approaches in depression management.
Reference
Quintanilla B, Zarate CA, Pillai A. Ketamine’s mechanism of action with an emphasis on neuroimmune regulation: can the complement system complement ketamine’s antidepressant effects? Mol Psychiatry. 2024 Apr 4.