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A recent study of patients with treatment-resistant depression has found that the response to intravenous ketamine treatment is linked to rapid changes in neuroplasticity. The findings, published in Translational Psychiatry, contribute to our understanding of how ketamine works in the brain to produce its antidepressant effects.
Ketamine is a dissociative anesthetic that has gained attention for its rapid and robust antidepressant effects, even in treatment-resistant patients. The new study aimed to investigate the mechanisms underlying ketamine’s antidepressant action by examining its effects on neuroplasticity in the brains of depressed individuals.
Neuroplasticity refers to the brain’s ability to change and reorganize its structure and function in response to experiences and environmental stimuli. It plays a crucial role in learning, memory, and adaptation. Deficits in neuroplasticity have been observed in depressed individuals, as well as in animal models of depression-like behavior, suggesting that it may be a core mechanism underlying major depressive disorder (MDD).
While previous research had linked ketamine-induced neuroplasticity changes to its antidepressant effects in animals, no one had specifically investigated these effects in humans prior to the current study.
“Ketamine has remarkable fast-acting effects on clinical symptoms among patients. These clinical effects have been strongly supported across numerous clinical trials to date,” explained study author Rebecca B. Price, an associate professor of psychiatry and psychology at the University of Pittsburgh.
“But the vast majority of what we know about how these rapid effects might be achieved stems from research done in animal models. For example, mice are given ketamine and tested for ‘depression-like’ behaviors as a proxy for antidepressant effects. These methods have repeatedly highlighted a key role for rapid changes in the microstructure of the brain in promoting ketamine’s rapid effects on depression-like behavior — for example, the sprouting of new synapses in regions like the medial prefrontal cortex are seen as a critical mechanism mediating behavioral effects.”
“This is thought of as an important and helpful form of ‘neuroplasticity,'” Price told PsyPost. “These experiments in animals are very valuable because they provide the benefit of very tight experimental controls and measurements of impacts on rodents’ brain that are not feasible in human patients; but they cannot necessarily reveal the full story when it comes to antidepressant mechanisms of action, since a mouse ultimately cannot truly experience what we call ‘depression.'”
“There are also other types of hypothesized psychological or cognitive mechanisms in the case of treatments like ketamine which are unique to humans and impossible to measure in non-humans — for example, transformative or ‘mystical’ experiences related to experiencing profound ‘awe,’ connectedness, and other perspective-shifting thought processes during a ketamine infusion.”
“Ultimately, to piece together a full and complete picture of how ketamine works in treating human conditions like depression, it’s important to translate neuroscience insights from animal models back to human patients. This was our goal in this study.”
The researchers aimed to investigate the effects of ketamine in depressed patients by using diffusion tensor imaging, a neuroimaging technique, to indirectly measure neuroplasticity changes in depressed individuals before and after ketamine administration. Specifically, they measured a neuroimaging marker called mean diffusivity.
“In this paper, we were interested to use a research tool that had not been previously used in this context — namely, ‘mean diffusivity,’ a neuroimaging marker of the microstructure in various brain regions, which can shift rapidly in response to environmental inputs — to provide a strong test in depressed patients of whether some of the key findings in the animal models do in fact transfer to being impactful among human patients receiving ketamine,” Price explained.
The study analyzed data from a clinical trial that included 154 adult subjects with moderate to severe depression. These participants had previously failed to respond to at least one FDA-approved antidepressant medication. The subjects were randomly assigned to receive either ketamine or a placebo (vehicle) in a 2:1 ratio.
Depression severity was assessed using the Montgomery-Asberg Depression Rating Scale (MADRS), which was administered by a clinical rater before and 24 hours after the ketamine infusion. Depressive symptoms were also self-reported by the patients using the Quick Inventory of Depressive Symptoms (QIDS-SR). A subset of the participants (31 in the vehicle group and 67 in the ketamine group) underwent neuroimaging scans using diffusion tensor imaging before and 24 hours after the infusion.
The researchers found that changes in mean diffusivity, a marker of neuroplasticity, were associated with the treatment response to ketamine in patients with depression. They observed that reductions in mean diffusivity scores in specific brain regions (indicating increased neuroplasticity) predicted greater improvement in depression scores.
“Our study in depressed patients helps confirm the relevance of some of the key findings from the animal neuroscience literature,” Price told PsyPost. “One of the ways ketamine may be helpful for depressed patients is by rapidly restoring (within 24-hours) a healthy degree of neuroplasticity in key brain regions that are involved in regulating moods, thoughts, and behaviors.”
“This knowledge may help us better understand how to build upon ketamine’s promise — for example, by finding well-matched ways to capitalize on this ‘window of neuroplasticity’ that occurs for some patients following a ketamine administration to create a more lasting impact, or by helping point the way to alternative treatments (e.g., alternative medications, neuromodulation approaches) that might have similar rapid effects on the brain’s microstructure.”
The brain regions showing significant associations were the left and right BA10 (a region involved in reward processing and emotion regulation) and the left amygdala (a region associated with emotional processing). Increased neuroplasticity in these regions were linked to better treatment response in patients receiving ketamine.
Interestingly, in the left and right hippocampus (a region involved in memory and emotion regulation), the results were paradoxical. Higher mean diffusivity scores, suggesting lower neuroplasticity, were associated with greater improvement in depression scores in the ketamine group. The reasons for this inverse relationship are not entirely clear and require further investigation.
“I was surprised that we found a pattern of findings in the opposite direction to hypotheses in one key brain area that has been strongly implicated in depression and in ketamine’s mechanisms — the hippocampus,” Price said. “In this one brain area, we found some evidence that patients did better when they experienced a rapid decrease in microstructural density or ‘neuroplasticity.’ This could be interpreted to mean that there is some sort of healthy down-regulation or pruning of microstructure in this particular brain region that might be correlated with ketamine’s beneficial effects, but we need to confirm this in larger studies.”
The new research also suggests that the neuroplasticity changes associated with ketamine may be a key factor in determining the antidepressant effects in certain patients.
“In the entire group of patients randomized to receive ketamine, ketamine did not impact the neuroimaging marker when compared to those who received saline,” Price explained. “Instead, it was only those specific individuals who experienced a large improvement in depression symptoms who also showed the corresponding shift in our markers of neuroplasticity. This is interesting because it suggests that the impact of a single infusion of ketamine on neuroplasticity is stronger in some patients than others — and only when it’s especially strong do we see a correspondingly strong impact on symptoms of depression.”
But the study, like all research, has some limitations, such as the indirect nature of the neuroplasticity measure and the relatively small sample size. Further research could help to better understand the mechanisms underlying the observed associations and to confirm the findings with larger and more diverse populations.
“A key caveat for all our findings is that the sample should be considered small and scientific findings always need to be replicated before considered conclusive,” Price said.
The study, “Rapid neuroplasticity changes and response to intravenous ketamine: a randomized controlled trial in treatment-resistant depression“, was authored by Jared Kopelman, Timothy A. Keller, Benjamin Panny, Angela Griffo, Michelle Degutis, Crystal Spotts, Nicolas Cruz, Elizabeth Bell, Kevin Do-Nguyen, Meredith L. Wallace, Sanjay J. Mathew, Robert H. Howland, and Rebecca B. Price.
