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Ketamine may overturn insensitivity to prediction error in depression

When it comes to understanding depression, there is no shortage of theories as to why we become depressed. Currently, the guiding directive in scientific depression studies encourages researchers to seek to identify a biochemical origin of the disease, as opposed to theories that emphasize psychological or situational causes. From a research standpoint--and from a patient standpoint--the idea that the causes of depression are biologically based is a realistic working theory because one: researchers are better able to study causative groups, and two: patients can draw some comfort in knowing that depression is not their fault.

Ketamine may overturn insensitivity to prediction error in depression

There are strong bodies of evidence that suggest depression is the result of biological causes such as nutritional deficiencies, hypothyroidism, genes, neural abnormalities, and more. Notwithstanding, there is logic in the fact that situational causes are part of the equation. For many patients, biological factors are at play creating a predisposition for depression that presents itself amid or after a situational cause. We see this most often in cases where major trauma has occurred such as the loss of a loved one, war-time combat, and abuse. However, the situational cause explanation becomes flawed when we encounter the patient that has not suffered a major trauma but suffers from major depression? This question lends greater reason to think that depression is biochemical in origin. In this line of thinking, we can target and study abnormalities more effectively. For example, from a biochemical standpoint, we recently discovered that ketamine may overturn insensitivity to prediction error in depression. So, what in the world does that mean? Let me explain.


European researchers recently produced a promising study titled "Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors" published in in European Neuropsychopharmacology. It is a mouthful, I know but bear with me! This important study demonstrates ketamine’s ability to reverse a particular neural abnormality known as prediction error. This is important because, as the researchers argue, “Major depressive disorder negatively impacts the sensitivity and adaptability of the brain's predictive coding framework.” In their study, they “investigated the downstream effects of ketamine on predictive coding and short-term plasticity in thirty patients with depression." Okay…so what does that mean?


First, let us understand more about our brain's predictive coding and short-term plasticity features.

  • Predictive coding: A theory of brain function in which the brain is constantly generating and updating a mental model of the environment. The model is used to generate predictions of sensory input that are compared to actual sensory input.

  • Short-term plasticity: A phenomenon in which synaptic efficacy changes over time in a way that reflects the history of presynaptic activity. To add on, synaptic plasticity is the ability of synapses to strengthen or weaken over time, in response to increases or decreases in their activity.

If you have battled depression for a long-time, you have probably come across an explanation that depression has something to do with our patterns of thinking—and to overcome depression—you have to "retrain" the patterns, usually with the help of a therapist. Predictive coding and short-term plasticity get at the roots of the mechanisms behind retraining your brain.


What the researchers found is that “electrophysiological brain signals associated with neural plasticity could help explain the rapid, antidepressant effects of the drug ketamine. The findings indicate that ketamine could reverse insensitivity to prediction error in depression. In other words, the drug may help to alleviate depression by making it easier for patients to update their model of reality. That is huge!


While typical antidepressants focus on increasing serotonin levels, ketamine works to increase neural plasticity. This is significant because neural plasticity deals with the brain’s ability to form new connections between neurons and ultimately underlies learning and memory in the brain.


In rodent studies, scientists have consistently shown that ketamine increases neural plasticity within 24 hours, but translating that across patient studies is challenging.


However, this most recent study shows strong potential. The study results are based on a double-blind, placebo-controlled study including 30 participants with major depressive disorder who had not responded to at least 2 recognized treatments for depression. Seven in 10 participants demonstrated a 50% or greater decrease in their depression symptoms one day after receiving ketamine.


The study also found that “just 3 hours after receiving ketamine, the brains of people with moderate to severe depression became more sensitive to detecting errors in its predictions of incoming sensory information.”


Now we can better understand predictive coding at play. The authors indicate, “The brain creates models or predictions about the world around it and what is most likely to come next. This is largely thought to be because it is an efficient way to deal with the massive amount of information hitting our senses every moment of the day. When something is constant and stable in the world these models can become very rigid. It has been suggested that these models can become too rigid and unchanging, underlying negative ruminations and self-belief that people with depression often report.”


“As an example of how this might look in depression — it is often easy for friends and family to point out to their loved one errors or the harm in their thought patterns,” researchers explained. “A counsellor will often work with a person to change their harmful ruminations or beliefs, such as with cognitive behavioral therapy (CBT). However, the person experiencing depression may find this difficult to see, or to take on because of how rigid their models (belief about themselves, the world around them, and their future) have become.”


That is exactly right! For patients battling depression, awareness is only half the battle. Understanding one’s own thought patterns in the context of therapy can feel somewhat abstract to a depressed patient undergoing counseling, but when coupled with scientific explanation and ketamine’s ability to target root causes, those suffering from treatment-resistant depression stand a much greater chance of remission.


To learn more about ketamine for the treatment of depression, we invite you to visit our blog for more information.


If you would like to learn more about Avesta Ketamine and Wellness, please review our About Us page our Ketamine For Mood Disorders page. Also, follow us on our new Facebook page for updates, tips, ideas and more.


Works Referenced

Rachael L. Sumner, Rebecca McMillan, Meg J. Spriggs, Doug Campbell, Gemma Malpas, Elizabeth Maxwell, Carolyn Deng, John Hay, Rhys Ponton, Frederick Sundram, Suresh D. Muthukumaraswamy, Ketamine improves short-term plasticity in depression by enhancing sensitivity to prediction errors, European Neuropsychopharmacology, Volume 38, 2020, Pages 73-85.

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