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How does ketamine affect “depressive beliefs”?

By Sammy Byron , on November 3, 2022 - 6 minutes to read
Comment la kétamine agit-elle sur les « croyances dépressives » ?

by Hugo Bottemanne, Sorbonne University

What determines what we believe about the world, ourselves, our past, and our future? Cognitive neuroscience suggests that our “beliefs” depend on the activity of our brain, and more precisely on the way it processes sensory information to make sense of our environment.

These beliefs (defined as probability estimates) are at the heart of the predictive brain processes that allow our brain to predict the probabilistic structure of the world around us. These predictions may even be the fundamental building blocks from which our mental states, such as perceptions and emotions, are constructed.

Many psychiatric disorders, such as depression or schizophrenia, are thus characterized by unusual beliefs whose origin is difficult to understand. However, if the cerebral systems underlying them were well identified, they could constitute a major target for therapeutic action to relieve the suffering associated with these disorders.

A better understanding of the mechanisms of beliefs in psychiatry

This is suggested by the study we have just published in the journal JAMA psychiatry. With my team, we explored the effect of ketamine, a dissociative psychotropic drug, on the mechanisms of updating these beliefs (how we modify them following information received) in patients suffering from treatment-resistant depression.

While conventional antidepressants take several weeks to become effective, ketamine, which is an antagonist molecule of the NMDA (N-methyl-D-aspartate) receptors present on neurons, gives initial antidepressant effects within a few hours. During its administration, it also causes a dissociative experience of depersonalization with the sensation of leaving one’s body (or “autoscopy”).

This rapidity of action and these a priori unexpected dissociative effects question the processes involved in its therapeutic effectiveness, and constitute a mystery at the frontier of pharmacology and neuroscience.

Cognitive-affective biases in depression

In France, depression is the most common psychiatric disorder (20% of the population affected at least once in their lifetime) and the leading cause of suicide. Depressive beliefs (pessimism, devaluation, rejection, experience of failure) are one of the most specific symptoms. These negative themes are said to be “mood congruent”, their content being homogeneous with the subject’s affective tone.

These beliefs are crucial because they influence perception and actions, causing a negative self-reinforcement phenomenon. The belief of being “rejected by one’s peers” progressively favors the withdrawal into oneself, consolidating in return the conviction of being “worthless”. Once the loop has closed in on itself, it is difficult to get out of this vicious cycle.

Since the research conducted by psychiatrist Aaron Beck, a large number of studies have suggested that the way in which information is encoded in belief networks according to its valence (its positive or negative character) could be involved in the generation of these depressive beliefs.

These innovative works have indeed shown that we tend to preferentially encode positive information. This phenomenon, called “affective bias”, is at the origin of the generation of beliefs that are slightly more positive than reality: we tend to believe that we are more intelligent, more attractive, better drivers or better lovers than the statistical reality.

In depression, this bias disappears, or is reversed: patients integrate more information of negative valence, generating over time darker beliefs about the world, themselves or the future. This phenomenon of reversal of the affective bias could be one of the keys to understanding the origin of depressive beliefs.

How ketamine affects belief systems

We initiated our study following a surprising clinical finding in our unit at the Pitié-Salpêtrière Hospital (Paris). Patients suffering from resistant depression and receiving ketamine for antidepressive purposes reported a strange sensation: after the treatment, their perspectives on the world seemed to have changed as if their point of view had changed.

The negative beliefs that had accompanied them for several months seemed to fade away. Some patients even expressed a sense of strangeness about these thoughts, as if they had belonged to someone else. More intriguingly, these changes seemed to be directly associated with the antidepressant efficacy of the treatment, although the causality of this relationship was not understood.

Confronted with our patients’ accounts, we suspected an effect of ketamine on the mechanisms of belief updating. In an attempt to understand this phenomenon, we conducted an experiment to assess the effect of ketamine on the way we generate beliefs – in this case a task performed before and after treatment.

In this experimental task, we asked subjects to estimate their probability of experiencing 40 future negative events (e.g., being bitten by a dog or having a car accident) as well as other estimates that might influence the processes under study. We then observed how their estimates about these 40 negative events were impacted, depending on the valence of this information.

Only four hours after ketamine administration, we found a significant decrease in the integration of negative information in belief generation: the affective bias in favor of positive information was restored in patients with resistant depression. More surprisingly, this effect was directly associated with the reduction of depressive symptoms after one week, suggesting that these cognitive changes may precede clinical improvement.

Prospects for future research

Further research is still needed to understand the brain processes associated with these changes, but a large body of evidence points to an involvement of NMDA receptor-mediated signaling. These neuronal receptors are precisely involved in the excitation-inhibition balance of the brain, and they seem to be crucial for predictive processes and brain plasticity.

The direct action of ketamine on the activity of these receptors would thus constitute a direct pharmacological pathway of modulation of predictive mechanisms, explaining both its rapid-acting antidepressant and dissociative effects. By modulating the way the brain uses sensory bricks to build beliefs, ketamine could thus allow to modify the mechanisms at the origin of depressive beliefs.

These hypotheses open up numerous prospects for developing treatments targeting these brain processes, or combining these molecules with augmentative psychotherapy protocols operating specifically on belief systems. This objective is currently at the heart of debates in so-called psychedelic medicine, notably for psilocybin, a hallucinogenic molecule with rapid antidepressant effects like ketamine. Perhaps this is the way forward for the reconciliation of pharmacological and psychotherapeutic approaches in psychiatry?

Read more: This article includes results from the recently published study by Hugo Bottemanne in the journal JAMA Psychiatry “Evaluation of Early Ketamine Effects on Belief-Updating Biases in Patients With Treatment-Resistant Depression”

Hugo Bottemanne, Psychiatrist at the Pitié-Salpêtrière Hospital & researcher at the Brain Institute – Sorbonne University AP-HP, Sorbonne University

This article is republished from The Conversation under a Creative Commons License. Read the original article.

Sammy Byron

After studying as a specialist in investigative journalism across Europe, I decided to start writing for my own community of Internet users. You can also find my most accurate studies and analyses on the latest trends in the United States. If you are interested in an analysis or a study in collaboration with our Experts, do not hesitate to use the dedicated contact form.


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