Major depressive disorder is a severe mental illness whose current medications often work slowly and cause side effects. The N-methyl-D-aspartate receptor (NMDAR), a type of glutamate-gated ion channel, is linked to depression based on preclinical and clinical research. The NMDAR antagonist ketamine produces rapid and lasting antidepressant effects but has psychotomimetic effects and addiction potential that limit its use. Over the past decade, evidence suggests that enhancing NMDAR function, particularly through positive allosteric modulators (PAMs), may offer antidepressant benefits with improved safety. This narrative review presents that approach as a potential novel strategy for treating depression.
A single injection of S-ketamine (5 mg/kg) reduced mechanical pain sensitivity and anxiety-like behaviors in adult male rats that had been exposed to a single-prolonged stress model of post-traumatic stress disorder. The treatment also lowered pro-inflammatory cytokines (TNF-α, IL-1β) and microglia activation in the dorsal striatum and periaqueductal gray, but not in the anterior cingulate cortex or prefrontal cortex. Phosphorylated NF-κB was elevated in the dorsal striatum and reduced by S-ketamine. The results suggest S-ketamine may alleviate pain and anxiety in PTSD by dampening inflammation in specific brain regions.