The antidepressant effects of (R,S)-ketamine, a mixture of (R)-ketamine and (S)-ketamine, are a major advance in mood research. Off-label use for treatment-resistant depression has grown in the US, and in 2019 the FDA and European authorities approved (S)-ketamine nasal spray for this condition, but only in certified medical settings. Preclinical evidence indicates that (R)-ketamine may be more potent and longer-lasting as an antidepressant than (S)-ketamine, with fewer side effects. Clinical trials of (R)-ketamine in humans are now underway. This article reviews the history of these compounds and discusses the mechanisms behind ketamine's antidepressant actions.
In mice susceptible to chronic social defeat stress, removing the spleen reduces arketamine's antidepressant-like effects. RNA sequencing of the prefrontal cortex revealed that the oxidative phosphorylation (OXPHOS) pathway mediates this effect. Inhibiting OXPHOS with oligomycin A reversed the spleen removal's suppressive effect. Specific OXPHOS genes—COX11, UQCR11, and ATP5e—may be involved. Transforming growth factor β1 (TGF-β1) and COX11 appear to modulate the suppression; activating the TGF-β1 receptor with SRI-01138 alleviated it. Cutting the subdiaphragmatic vagus nerve also counteracted the inhibitory effect of splenectomy. These results suggest that arketamine's antidepressant-like effects involve the OXPHOS pathway and TGF-β1 in the prefrontal cortex, communicated through a spleen-brain axis via the vagus nerve.
The spleen filters blood and supports the immune system. New evidence shows it also influences brain function in health and disease through immune modulation. In mice, systemic inflammation or chronic social defeat stress causes spleen enlargement (splenomegaly). The antidepressant arketamine can reverse both splenomegaly and depression-like behaviors in stressed mice. A direct brain-to-spleen pathway exists: neurons in the paraventricular nucleus and central amygdala regulate humoral immune defense. Vagal nerve signaling also contributes to brain-spleen communication. This review summarizes recent findings on the brain-spleen axis.