New research sheds light on the neuropsychological mechanisms behind rapid antidepressants

Scientists have discovered that rapid-acting antidepressants, such as ketamine, psilocybin, and scopolamine, are capable of altering negative mood biases, a common symptom in depressive disorders, in rodent models. This finding opens new avenues for understanding and treating major depressive disorder, a condition affecting millions worldwide. The research was published in Science Translational Medicine.

Major Depressive Disorder is a common but serious mental health condition that negatively affects how a person feels, thinks, and acts. It is characterized by persistent feelings of sadness and loss of interest in previously enjoyable activities. Individuals with MDD may experience a range of emotional and physical problems, such as changes in appetite, sleep disturbances, lack of energy, and difficulty concentrating.

“Depression is such an important illness and cause of suffering in modern society. Current treatments do not work for some people and even those who do get some benefit, can still experience problems and side effects from the treatments,” said study author Emma S. J. Robinson (@psychopharmbris), a professor of psychopharmacology at the University of Bristol.

Researchers have been particularly interested in psilocybin, ketamine, and scopolamine due to their unique and rapid effects on mood disorders like Major Depressive Disorder, which can be resistant to traditional antidepressants. Unlike conventional treatments that typically take weeks or even months to take effect and work through serotonin pathways, these substances act much faster and through different mechanisms.

Psilocybin is a naturally occurring psychedelic compound produced by more than 200 species of fungi, commonly known as “magic mushrooms.” It is known for its hallucinogenic properties, which can induce profound changes in sensory perception, mood, and thought when consumed. In recent years, psilocybin has gained attention in the scientific community for its potential therapeutic effects.

Ketamine, originally developed as an anesthetic, is a medication primarily used for starting and maintaining anesthesia. It induces a trance-like state while providing pain relief, sedation, and memory loss. In recent years, ketamine has emerged as a promising treatment for Major Depressive Disorder, particularly in individuals who have not responded to other treatments. Its unique mechanism of action in the brain, which involves the N-methyl-D-aspartate (NMDA) receptor, differentiates it from other antidepressants and contributes to its rapid efficacy.

Scopolamine, also known as hyoscine, is a medication traditionally used to prevent motion sickness and nausea. It is an anticholinergic drug, which means it blocks the action of the neurotransmitter acetylcholine in the brain. In recent years, scopolamine has garnered interest in psychiatric research due to its rapid antidepressant effects.

“I have been interested in doing research into depression since my PhD but it is a challenging topic and difficult to study in patients. Our research uses animal models and we have spent the last 15 years developing and validating new approaches to model a specific part of human depression in rats. We have been able to develop a behavioural test where we investigate how emotions affect memories.”

“We think the neuropsychological processes we are studying are important in depression and that treatments which can interfere with these processes can have antidepressant effects. In this recent work, we were investigating a group of drugs know as rapid-acting antidepressant to try to understand why they have rapid and sustained effects on mood in some patients.”

The study involved ten separate groups of male Lister Hooded rats, with each group comprising 11 to 16 rats. The primary tool used in the research was an affective bias test. Here, the rats were trained to associate different digging substrates in bowls with a food reward. Over several sessions, they learned that digging in the right substrate would lead to a reward, establishing a memory associated with each substrate.

To simulate an emotionally negative state, some rats were given drugs like corticosterone or FG7142, known to induce stress or anxiety-like effects. Then, the rapid-acting antidepressants – ketamine, psilocybin, and scopolamine – were administered either one hour or 24 hours before a choice test. This test involved presenting the rats with the two substrates they had learned to associate with rewards, and their choices were recorded.

When administered either one hour or 24 hours before the choice test, the antidepressants significantly reduced the negative emotional biases created by the stress-inducing drugs. Remarkably, in some cases, they also induced positive biases – a shift towards selecting the substrate associated with a more positive emotional state. This finding was particularly pronounced with ketamine and psilocybin, suggesting these drugs could not only dampen negative emotional memories but also enhance positive emotional learning.

“People with depression tend to think and remember things in a negative or pessimistic way and this contributes to their low mood and may perpetuate the illness. We think that treatments for depression might affect the way the brain generates this negative thinking. What we found is that both ketamine and psilocybin can change the way experiences on a ‘bad day’ are remembered. Shortly after the drug is given, the effect of the bad day is prevented and looks like experiences from a ‘neutral day.’

“As the effects of ketamine and psilocybin are long lasting and continue after the drug has left the body, we also looked at what would happen the day after the animals were given the treatment. To our surprise the memory was now retrieved as if it had been learnt on a ‘good day’ and we could also change this effect depending on which memory we triggered the animal to retrieve.”

“We think this could explain why these drugs can have long-lasting effects on mood after a single treatment. What we have seen with these next day effects suggests the bad day experiences can be re-learned and the emotional effects at the time they were first learnt can be changed. In patients with depression, this effect might help to reverse the effects on memory which the depressed mood has caused making people more positive. It may also be important for disorders such as PTSD and help reduce the strong negative emotions patients experience with these traumatic memories.”

To ensure these effects were specific to emotional biases and not a result of general memory impairment, the researchers conducted a reward learning assay. This test, similar to the affective bias test but focusing on memory associated with different reward values, confirmed that the rats’ learning and memory capabilities remained intact under the influence of low doses of these antidepressants.

“What is exciting about our finding is that it is specific to the emotional part of the memory but doesn’t have effects on other memory processes.”

Furthermore, the study delved into the role of specific brain regions in these processes. For instance, when ketamine was infused directly into the medial prefrontal cortex – a brain region implicated in mood regulation – it replicated the effects observed with systemic administration, implicating this area in the modulation of emotional biases.

Perhaps one of the most significant findings was the sustained nature of these effects. The modulation of emotional biases by rapid-acting antidepressants appeared to last well beyond the drugs’ active presence in the body, hinting at long-lasting changes in neural plasticity.

“At this time point, the drug has stopped having any direct effects and so what we are seeing is the result of some kind of adaptation. When we investigated this further, we found that there was a re-learning effect which was mediated by the drug and enabled past experiences to be remembered but then re-learnt with a relatively more positive emotional association. We don’t yet know whether there are adaptive changes in the brain circuits which generate these emotional effects, but we think this may be possible and it is an exciting prospect for the field and something we are now investigating.”

While the study marks a significant advance in our understanding of rapid-acting antidepressants, it is not without limitations. The study’s focus was primarily on reward-related learning and memory, leaving open questions about how these findings might generalize to other cognitive domains or to aversive memories.

“I think it is important to recognize that we have only looked at a component of depression and the disease in patients is more complex than we are modelling. Although our findings are an important development for the field, there are lots more experiments now needed, including studies in humans. It can be difficult to isolate the different effects of treatments like ketamine and psychedelics in patients and so we will continue to use our animal model. One thing we are now trying to understand is whether these dissociative or hallucinogenic effects involve the same or different underlying mechanisms and whether it might be possible to have rapid-acting antidepressants without these other effects.”

The study was conducted in collaboration with experts from Compass Pathways, Boehringer Ingelheim, and the University of Cambridge.

“This work was only possible because of the brilliant team of people who did all the hard work and the financial support we have received from the UK Research and Innovation Department and industry collaborators.”

The study, “Rapid-acting antidepressant drugs modulate affective bias in rats“, was authored by Justyna K. Hinchcliffe, Sarah A. Stuart, Christian M. Wood, Julia Bartlett, Katie Kamenish, Roberto Arban, Christopher W. Thomas, Aslihan Selimbeyoglu, Shaun Hurley, Bastian Hengerer, Gary Gilmour, and Emma S. J. Robinson.

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