Illustration of woman, with string in her brain representing depression.

Ketamine for Depression: The History and Science Behind this Novel New Therapy

The buzz around ketamine for depression is at a fever pitch. The New York Times has called it “The Ketamine Cure,” while the Washington Post labeled it the “Biggest Advance For Depression in Years.” 


Its promise to deliver rapid-response antidepressant effects for people with treatment-resistant conditions has even led to recent approval by the Food and Drug Administration (FDA).


The interesting aspect about all the media hype around ketamine is that there is actually growing peer-reviewed proof behind it. Increasingly, there is robust evidence supporting the use of ketamine for depression and other psychiatric conditions.


The History of Ketamine in Medicine


The history of ketamine began with its initial synthesis in 1962, and its first clinical use started soon after.

In the early days, ketamine showed promise as a novel anesthetic. According to authors Linda Li and Phillip E. Vlissides, who co-wrote “Ketamine: 50 Years of Modulating the Mind,” during the early human trials, “ketamine could rapidly produce profound analgesia with a unique state of altered consciousness and a limited duration of effect that could be safely prolonged with repeated administration.” Moreover, scientists proved it was well tolerated during these investigations, with an impressive safety profile. 


But as research progressed and social familiarity with this drug grew, ketamine began going through several transitions: from a medicine to a party drug and now back to a medicine.


In 1970, the FDA had approved ketamine as an anesthetic. Flash forward to 2019, and the FDA has since also approved a ketamine-based pharmaceutical known as esketamine for treatment-resistant depression. 

The switch from a focus on ketamine as an anesthetic to a psychiatric drug has rapidly developed since 2010. It’s getting a lot of attention thanks to the stark comparison with conventional selective serotonin reuptake inhibitors (SSRIs), the more conventional antidepressants. 


SSRI-style drugs often require weeks or months to take effect, and for a large segment of the population, they don’t work at all. New Frontier Psychiatry suggests that antidepressants don’t provide relief for as many as four million Americans.


Li and Vlissides noted that “[e]ven a single-dose of ketamine may cause rapid antidepressant effects in otherwise treatment-resistant cases of bipolar and major depression.” 


Other recent work has also demonstrated it can cease suicidal ideation, may be more effective than electroconvulsive therapy, and may have applications for post-traumatic stress disorder and other psychiatric conditions. Instead of daily doses of SSRIs, which can have a challenging side-effect profile, ketamine seems remarkably more effective.


Ketamine and the Brain


As New Frontier Psychiatry explained, scientists refer to compounds like ketamine as “dirty drugs,” but not for the reasons you’d assume. From a scientific perspective, the dirty drug label means that it doesn’t just work on a single area of the brain but rather through more than a dozen. This helps to explain why it applies to so many different medical applications, from pain relief to anesthetics to depression.


Ketamine, like THC and many other medicinal compounds, is biphasic. Biphasic describes a duality of effects, depending on dose size. When it comes to ketamine, a large dose essentially turns off the brain (hence why it’s valuable as an anesthetic). In contrast, low doses have psychedelic effects, and may trigger dissociation, which is why it became famous as a party drug.


Although researchers are still investigating the specific neurological pathways through which ketamine works, we do know that it manipulates glutamate. Glutamate is what neurons use to communicate, meaning it’s a profoundly critical component for nervous system function. In the words of the Institute of Medicine, “Glutamate dysfunction has profound effects both in disease and injury.” Depending on the dose, ketamine can block glutamate function or help increase it, helping neurological function return to normal.


There is also increasing evidence demonstrating that ketamine may build new synapses and neurons. However, even this mechanism of action is playing out in surprising ways in the research. For example, Scientific American explained that recent animal models suggest ketamine first improves cognitive function and then stimulates synapse growth a few hours later.


There is so much excitement about ketamine’s synaptogenesis characteristics because chronic stress and depression damage these neurological connections. In particular, the synapse located in the prefrontal cortex takes a hit over chronic stress, leading to memory problems, feelings of guilt and hopelessness, lack of motivation, and other symptoms commonly associated with depression. 


Patients with Depression Pursuing this Novel Treatment


Based on the growing (if still preliminary) body of research, ketamine treatment centers are popping up all over North America. Some are sanctioned by the government, while others not-so-much.


Licensed or not, patients are exploring this novel treatment, often in a desperate or last-ditch effort to find relief from chronic depressive disorders. Many of these anecdotal reports describe overwhelming relief and powerful imagery of recovery.


As only one example, Julian Uzielli, a reporter with the Canadian Broadcasting Corporation, described his experience with ketamine for treatment-resistant depression with a single dose of ketamine and associated therapy.


Five months after his treatment, he was still feeling the positive effects. Uzielli said, “I no longer struggle to get out of bed and I feel motivated to take care of myself. I have a more optimistic outlook, and I’ve been planning for the future — something that once seemed pointless to me. And the people around me have taken notice.” His family was “gobsmacked” by his post-ketamine recovery, and his therapist described it as “miraculous.”


More Research Underway to Move Ketamine Through Next Hurdles


Still, even with the recent FDA approval of a ketamine-based drug for depression, there are a lot of unknowns. While many scientific and anecdotal reports indicate a rapid antidepressant response to a single dose, the effects may wear off over time for some patients. Therefore, patients may need scheduled, ongoing sessions every few months to prevent relapse.


Researchers also need to better understand the “dirty” nature of this substance, meaning its ability to manipulate more than a dozen different neurological receptors. With so many activity channels, ketamine is medically complicated. It’s important we understand all of these interactions in order to predict patient outcomes and minimize adverse events.


Thankfully, the early work with ketamine for depression has put this drug on a scientific fast track. With over 200 trials underway (as per ClinicalTrials.gov), invaluable information will soon be available determining safety profile, counteractions, and applications for psychiatric medicine.

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