Patients with treatment-resistant depression (TRD) show elevated levels of the pro-inflammatory cytokine interleukin-6 compared to healthy controls, supporting the immune hypothesis of depression. Analysis of 41 cytokines, chemokines, and growth factors in blood samples from 26 healthy controls and 33 unmedicated TRD patients revealed a unique pattern of increased inflammatory mediators, chemokines, and colony-stimulating factors. Following a single intravenous infusion of ketamine (0.5 mg/kg), several cytokines showed transient changes, but none correlated with treatment response. Low pretreatment levels of fibroblast growth factor 2 were associated with ketamine treatment response, suggesting novel treatment targets for TRD patients with dysregulated immune functioning.
Severe stress during pregnancy in mice alters the expression of two brain receptors linked to schizophrenia: serotonin 5-HT2A increases and metabotropic glutamate mGlu2 decreases in the frontal cortex. These changes correspond to behavioral differences in adult offspring, such as a heightened response to a hallucinogenic drug and reduced antipsychotic-like effects of a mGlu2/3 agonist. Cross-fostering ruled out maternal care as a cause, and similar effects appeared after prenatal immune activation. The findings support the idea that early neurodevelopmental disruptions contribute to schizophrenia risk.
Psychedelic substances like LSD and psilocybin show potential for treating neuropsychiatric disorders, primarily acting through the serotonin 5-HT2A receptor. However, 5-HT1A also contributes to the effects of tryptamine hallucinogens, especially 5-MeO-DMT from Colorado River toad toxin. Using cryo-EM structures, medicinal chemistry, and mouse behavior, researchers mapped how 5-MeO-DMT engages 5-HT1A. They characterized molecular determinants of signaling potency, efficacy, and selectivity at both 5-HT1A and 5-HT2A. A 5-HT1A-selective analogue of 5-MeO-DMT lacked hallucinogenic effects but retained anxiolytic-like and antidepressant-like activity in socially defeated animals, uncovering molecular aspects that may aid developing new neuropsychiatric medications.