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The Super Antidepressant Ketamine

The ambush happened on October 17th, 1971 [1]. Mike Troyer, who was then the acting squad leader within the Delta Company, was clearing a semi-open field with his squad as that was necessary for the US troops to cut-off the supply chain of the resilient Viet Cong fighters of Communist North Vietnam. What mattered on that terrible day was whether you were in the shade or sunlight. Crouching for cover behind an anthill, Troyer stayed out of light and hopelessly watched his more exposed comrades get shot. After what seemed an eternity, Troyer crawled out only to find a couple of men alive and multiple severely hurt. The protocol was clear - he has to call the helicopter medics for pick-up and immediate assistance.


A military-level chopper landed in Troyer’s location in about 15 minutes. In these sorts of situations most do not make it due to severe blood loss, while the lucky ones need an immediate operation. Yes, operation on that same unstable, constantly moving helicopter that was also supposed to withstand Vietnamese bullets and air turbulence. Troyer could only watch as the paramedics would set up their surgical equipment and pull out their most prized helper- ketamine.


Ketamine was approved by the Food and Drug Administration (FDA) in 1970. One of its main perks was the unusual state, sometimes referred to as “dissociative anesthesia”, which is produced. In this state patients might appear awake and have preserved airway reflexes and respiratory drive, but they would be otherwise not responding to sensory input. Ketamine is excellent for general analgesia not only because it allows for painless surgeries, but also because it is very safe to administer [2]. Ketamine is an ideal anesthetic for warlike operations where surgeries have to be performed in complicated and surgery-unfriendly environments.


Quite quickly after its approval by the FDA, the US military started using ketamine in its war in Vietnam. The dissociative anesthesia would allow paramedics to operate in helicopters without massive respiration-supporting machines. The sensory deprivation blurs the exact moments of life-changing operations that would often come to haunt maimed soldiers (for example loss of limb). In the end, only a small part of Mike Troyer’s squad lives to see another day, while the ones that survived were alive in no small part thanks to ketamine.


Ketamine is a pretty well-known drug in society. Some people know the drug as a famous horse anesthetic (which, by the way, is not true [3]), while others know it for its popularity in the clubbing scene. No matter how you call it, “special K”, “Rhino smasher”, “Wonk”[4] or simply, “ketamine dreams” [5], one can not deny the rise to prominence of ketamine as it enters the domain of public knowledge. However, another quite prominent development in the use of ketamine recently happened in the depression field.


In 2019, FDA approved a new nasal spray medication for treatment-resistant depression called Spravato (or by its scientific name, esketamine) [6]. This important acknowledgement is a culmination of the last 2 decades of clinical studies investigating the rapid-acting antidepressant effects [7]. There are two reasons why ketamine is a revolutionary antidepressant for the treatment of depression [8]. Firstly, the most commonly used antidepressant medication called selective serotonin reuptake inhibitors (SSRIs) does not work for every depressed patient. The famous drug fluoxetine known by its commercial name Prozac falls in this category. When one SSRI does not work, a patient has to switch to a different SSRI medication. After trying multiple different options and combinations, almost 70% of depressed patients achieve remission. That other 30% is what is called treatment-resistant depression. Ketamine does wonders as the last line of defence in these treatment-resistant cases. Secondly, ketamine induces its antidepressant effects significantly faster than conventional SSRIs. SSRIs usually take up weeks or months to begin taking effect, while a single therapeutic dose of ketamine can produce effects in as little as a few hours with effects lasting one week after the single treatment. You might ask: “Why does it matter how fast an antidepressant works?” The short answer is that there are significant comorbidities associated with waiting longer for antidepressant effects such as cessation of the treatment altogether.


How exactly does ketamine work? What's the neuroscience behind this “super antidepressant”? First, let me explain the pharmacological mechanism of ketamine. Well, ketamine acts on a brain structure called lateral habenula. Lateral habenula is a pea-sized complex of cells next to the limbic system that is implicated in motivation-processing (remember that I covered this system in my blog post on drug addiction [9]). This tiny structure is the anti-reward center of the brain that is activated by negative emotions. These negative emotions look like an animal expecting a specific outcome after being conditioned to expect it (for example, an orange juice for following a dot with eyes [10]), but it did not get what it wanted (for example, reward is omitted). An animal is disappointed. You should think of lateral habenula as being activated when you are disappointed.


Illustration 1: Lateral habenula

It turns out that in depressed mice, lateral habenula is hyperactive - the neurons are firing at a more frequent pace than in non-depressed mice. Think about it this way - in depression, lateral habenula always “thinks” that you are disappointed and not getting your orange juice all the time. Ketamine though “calms” these neurons and restores a normal firing pattern, which makes the animal less “depressed”. Okay, I can already hear what you are going to say: “But, Matas, how do we even know that a mouse is depressed?”


The extent of depression in mice can be measured in two ways: the forced swim test and the sucrose preference test. In the first test, scientists measured the behavioral despair of mice - a depressed mouse is more likely to give up on swimming and become immobile than its non-depressed counterpart. The sucrose preference test quantified another aspect of depression - the inability to feel pleasure. A depressed mouse was likely to not care whether it was drinking sucrose liquid or water. Interestingly, the injection of ketamine to the depressed mice returned its bursting electrical impulse pattern in the "anti-reward center" back to the normal state indicating that ketamine has some kind of an effect on it. The mice who got ketamine will not give up on swimming so easily and will still choose sucrose way more than water.


Illustration 2. Forced Swim Test and Sucrose test

So why is ketamine more effective than the conventional SSRIs? To be more exact, why is it more immediate? The main reason is that conventional antidepressants like Prozac change the monoamine concentrations in the brain in a rather indirect way. Serotonin is this feel good molecule that has been found to be lacking in depressed patients. Conventional antidepressants try to mess with the reabsorption of serotonin which is not completely understood. Ketamine, on the other hand, is more direct. By inhibiting the neuronal firing in lateral habenula, ketamine also inhibits inhibitory neurons.


Let’s get back to humans. Esketamine, the ketamine “version” that is now legal in the U.S., still has some side effects such as bladder dysfunction, dizziness, dissociation, nausea, headache. However, it has been pointed out that the drop-out rate in ketamine treatments is very low indicating that the positive effects of the treatment vastly outweigh side effects [11]. In the end, ketamine's fast antidepressant mechanism and outstanding clinical results are the beacon of hope for thousands of people around the world who's depression was resistant to other types of antidepressants. For them, ketamine is a super drug.



The article was prepared on behalf of INA by Matas Vitkauskas


Sources:


[1] https://www.pbs.org/wgbh/americanexperience/features/two-days-in-october-enlisted-men-vietnam/

[2] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5126726/

[3] https://www.drugfoundation.org.nz/matters-of-substance/february-2009/ketamine-not-just-for-horses/

[4] https://www.youtube.com/watch?v=XfmPu8l24wY&t=22s&ab_channel=VICE

[5] https://www.youtube.com/watch?v=DRfidJNts6U&ab_channel=Partiboi69

[6] https://www.fda.gov/news-events/press-announcements/fda-approves-new-nasal-spray-medication-treatment-resistant-depression-available-only-certified

[7] https://sitn.hms.harvard.edu/flash/2019/fda-approves-first-ketamine-based-antidepressant/

[8] https://www.sciencedirect.com/science/article/abs/pii/S0006322399002309

[9] https://www.integrativeneuroscience.org/post/morning-coffee-science-7?lang=en

[10] https://www.nature.com/articles/nature05860

[11] https://www.globenewswire.com/news-release/2019/05/08/1819624/0/en/Crossing-the-Goal-Line-Bringing-Ketamine-Treatments-to-the-Clinic-A-Free-Webinar-from-the-Brain-Behavior-Research-Foundation.html



Sources of images:


Cover image https://www.axios.com/diving-ketamine-wonder-antidepression-drug-d35421cf-543d-4f00-b8bb-4edb045f1936.html

Illustration 1 https://www.youtube.com/watch?v=ckeq-dGmpmk&t=90s&ab_channel=WorldEconomicForum

Illustration 2 https://www.youtube.com/watch?v=ckeq-dGmpmk&t=90s&ab_channel=WorldEconomicForum