Ketamine by Bita Moghaddam

Author:Bita Moghaddam [Moghaddam, Bita]
Language: eng
Format: epub
Tags: Esketamine; Depression; anxiety; neuroscience; psychiatry; antidepressants; PTSD; suicide; PCP; club drug; Prozac; NMDA; Psilocybin., Ketamine
ISBN: 9780262542241
Publisher: MIT Press
Published: 2021-01-22T00:00:00+00:00

Older antidepressants act primarily on proteins that influence the function of serotonin and noradrenaline. Ketamine could be acting on an entirely different neurotransmitter system.

Using state-of-the-art methodologies and mechanistic approaches, neuroscientists have shown that a single dose of ketamine can influence neuronal activity of specific brain regions, alter multiple intracellular signaling systems, and even modify brain morphology. But because of the ubiquitous presence of NMDA receptors throughout the brain, the fact that ketamine or other NMDA antagonists can exert this multitude of effects is not surprising. The challenge has been how to isolate any of these ketamine-induced changes as relevant to antidepressant properties of ketamine.

To address this, laboratories have relied on the effects of ketamine in rodent models that may be relevant to depression. Of course, rodent models have serious limitations in the context of studying depression, which may be a uniquely human illness. But these models rely on two plausible and logical approaches that are related to human depression. The first approach capitalizes on the knowledge that repeated exposure to stress, especially unpredictable stress, often exacerbates and may even cause depression. The second takes advantage of rodent behavioral models that were used successfully decades ago to identify and screen classical antidepressants such as Prozac.

Animal stress models use experimental manipulations that involve repeatedly stressing the animals, such as exposing them to social isolation. A related approach mimics the hormonal effects of stress (instead of manually imposing stress) by injecting them with sustained high levels of the hormone corticosterone. This is the rodent version of the human cortisol that is secreted during stress exposure, among other conditions. The impact of these manipulations is then assessed on various measures of brain function. These could include recording neuronal activity in various brain regions, changes in receptor function or other proteins that are involved in signal transduction in neurons, and morphology of specific subtypes of neurons in regions of the brain suspected to play a role in depression. Then the impact of a single dose of ketamine is measured on these changes. The idea is that if ketamine reverses any of these effects, then that effect is relevant to antidepressant properties of ketamine.

The second approach is to use the so-called rodent behavioral models of depression. This has been a controversial approach because of the implications that they actually model depression. But these models have been quite prevalent in the field of antidepressant research because they were developed to successfully screen older drugs, including SSRIs. These behavioral models generally involve placing rats or mice in an aversive situation where escape may seem possible to them. The animal’s continued mobility is measured as a sign of struggle to escape (“normal” behavior) versus giving up (“depressive” behavior), with the assumption that a lack of motivation to struggle or to escape resembles symptoms of depression. These tests include the forced swim test or tail suspension test.

Using these general approaches, several NMDA-centric theories about ketamine’s antidepressive effects have been proposed. These involve data-supported mechanisms that we will call theories because,

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