Neuropsychological effects of rapid-acting antidepressants may explain their clinical benefits

Rapid-acting antidepressants may work through changes in how the brain updates and retrieves emotional memories. Research using an affective bias test in rats found that ketamine, scopolamine, and the serotonergic psychedelic COMP360 psilocybin can reduce negative affective biases linked to past experiences. The drugs differ in timing and in which aspects of learning and memory they affect, potentially explaining why clinical benefits can last from days to months after a single dose. At 24 hours, low-dose ketamine and psilocybin showed a re-learning effect: previously negative memories were retrieved with a more positive affective valence. Only psilocybin also shifted responses toward new positive experiences. The proposed mechanism links sustained mood effects to adaptive brain circuit changes involving learning and memory, with low-dose effects localized to the prefrontal cortex and ketamine re-learning shown to depend on protein synthesis in region-specific neural plasticity.