Neuropsychological effects of fast-acting antidepressants may explain their clinical benefits, new research suggests

Fast-acting antidepressants, including ketamine, scopolamine, and psilocybin, have been shown to have immediate and lasting positive effects on the mood of patients with major depressive disorder, but how these effects arise is unknown. New research led by the University of Bristol explored their neuropsychological effects and found that these three drugs can modulate affective biases associated with learning and memory.

The document, published in Scientific translational medicine was carried out in collaboration with researchers from Compass Pathways, Boehringer Ingelheim and the University of Cambridge.

Negative affective biases are a core feature of major depressive disorder. Affective biases occur when emotions change the way the brain processes information, and negative affective biases are thought to contribute to the development and persistence of a depressed mood.

The research team used an affective bias test, based on an associative learning task, to study the effects of rapid-acting antidepressants (RAADs) in rats. They found that all treatments were able to reduce negative affective biases associated with past experiences, but that there were additional features of the dissociative anesthetic, ketamine, and the experimental serotonergic psychedelic psilocybin COMP360 (proprietary formulation of Compass Pathways of synthetic psilocybin), which could explain why the effects of a single treatment can be long-lasting.

The findings suggest that these lasting effects are due to adaptive changes in brain circuits that control affective biases, and these may influence how past experiences are remembered. The effects at low doses were highly specific to the modulation of affective biases and were localized in the prefrontal cortex of the brain, a region known to play an important role in mood.

Emma Robinson, professor of psychopharmacology at Bristol’s School of Physiology, Pharmacology and Neuroscience and lead author, said: “Using a behavioral task, we showed that medications thought to have rapid and long-lasting benefits in depressed patients, specifically modulate affective biases. associated with past experiences, which we believe is very important in understanding why they can improve a patient’s mood so quickly.

“We also found differences in how ketamine, scopolamine, and psilocybin COMP360 interact with these neuropsychological mechanisms, which may explain why the effects of a single treatment in human patients can last for several days (ketamine) several months (psilocybin).

“Using an animal model, we were able to study these important interactions with learning and memory processes and neuronal plasticity and propose a two-step model that could explain the effects we observe.”

In this task, each animal learned to associate a specific search material with a food reward under treatment or control conditions. The treatment condition is designed to generate a change in the animal’s affective state and a choice test is used to quantify the affective bias this generates.

Acute treatment with the RAADs ketamine, scopolamine, or psilocybin prevented recovery of the negative affective bias induced in this model. However, the most interesting finding occurred 24 hours after treatment, when low, but not high, doses of ketamine and psilocybin led to a relearning effect where the negatively biased memory was recovered with more affective valence. positive. Only psilocybin, but not ketamine or scopolamine, also positively biased novel experiences.

Further exploring the relearning effects of ketamine in our studies, the researchers found that they were dependent on protein synthesis, localized in the medial prefrontal cortex, and could be modulated by reactivation of signals, which is consistent with their predictions of experience-dependent neuronal plasticity. .

The study results suggest a neuropsychological mechanism that could explain both the immediate and sustained effects of RAADs, potentially linking their effects on neuronal plasticity to mood.