Relapse is common in remitted major depressive disorder. Arketamine, an (R)-enantiomer of ketamine, has prophylactic actions in an inflammatory model of depression, but the mechanisms are unclear. In mice, a single injection of arketamine (10 mg/kg) blocked lipopolysaccharide-induced increases in spleen genes of the heme biosynthesis II pathway (Alas2, Fech, Hmbs). Expression of these genes correlated with spleen weight and pro-inflammatory cytokines. Spleens from depressed patients showed higher ALAS2 and FECH expression. Pretreatment with a heme precursor (5-aminolaevulinic acid) worsened inflammation and depression-like behavior, while a heme inhibitor (succinyl acetone) had prophylactic effects. The heme biosynthesis pathway may be a target for preventing relapse.
Daily cannabis smoking doubles the risk of developing a psychotic disorder, but specific vulnerability factors have been unclear. Genetic variation may modify this risk. In 442 healthy young cannabis users, those with a particular variation in the AKT1 gene (rs2494732) showed a greater acute psychotic response to cannabis, along with dependence on the drug and baseline schizotypal symptoms. Working memory was worse in females after acute cannabis use, with some indication that a COMT gene polymorphism affected working memory when drug-free. These findings suggest the AKT1 pathway as a potential target for preventing and treating cannabis psychosis.