Ketamine is a dissociative anesthetic is currently used by physicians and veterinarians to cause fast-acting insensitivity to pain during medical procedures. TIAN ZHENG/THE VARSITY

Content warning: Discussions of suicide in the context of treating major depressive disorder.

Ketamine is a promising medication that brings hope to patients struggling with severe depression, offering potential therapeutic effects for those who are non-responsive to standard antidepressants.

The dissociative anesthetic is currently used by physicians and veterinarians to cause fast-acting insensitivity to pain during medical procedures. It is also used illicitly as a recreational drug, causing feelings of disconnection and relaxation among users.

Yet in controlled settings, ketamine also shows potential as a medication to help patients who are suffering from major depressive disorder. In April, a research review by U of T researchers found that ketamine offers significant effects as an antidepressant.

The lead author of the paper, Dr. Joshua Rosenblat, discussed the review’s findings with The Varsity. As a clinician-scientist in the Department of Psychiatry, Rosenblat is currently studying the antidepressant effects of ketamine.

He explained three major effects that differentiate ketamine from standard antidepressants: a different mechanism of action, a rapid onset of effects, and a response in patients who are not positively affected by commonly prescribed antidepressants.

Ketamine affects depression via a novel mechanism of action

For the past several decades, standard antidepressants have worked by affecting levels of serotonin, norepinephrine, and dopamine, explained Rosenblat.

In generalized terms, serotonin is a chemical messenger thought to regulate mood, while norepinephrine controls alertness and arousal. Dopamine affects attention and emotion.

But ketamine affects the brain differently. Rather than targeting these neurotransmitters, it instead changes levels of glutamate – the main excitatory messenger in the brain.

Ketamine’s unique mechanism of action could therefore explain why it may positively affect patients suffering from treatment-resistant depression, who do not respond to standard antidepressants.

Ketamine could provide a more rapid onset of affects, versus standard antidepressants

Ketamine also provides a rapid onset of effects. Standard antidepressants, said Rosenblat, usually take two months of prescribed usage to take effect.

He explained that with ketamine, alleviation of depressive symptoms can appear within two hours of consumption. This is especially promising as an option for patients suffering from suicidal thoughts.

A decrease in suicidal thoughts can plausibly reduce the number of suicidal attempts; however, Rosenblat noted that the evidence is currently too limited to make a conclusion. He explained that studies are lacking, as only a small percentage of patients affected by such thoughts attempt to commit suicide.

Ketamine could also be used for special applications. Depression is very common among patients facing terminal cancer, explained Rosenblat.

“If you were to start them on an antidepressant and they only have one month left to live, for example, [the patients may] only experience the side effects, and never get the benefits.”

Rosenblat is currently leading a clinical trial at Princess Margaret Hospital to research the use of ketamine for improving the final months of life for patients affected by terminal cancer.

The risks and drawbacks of ketamine as an antidepressant

While the prospect of applying ketamine for treating depression is promising, there are several discouraging factors to its application.

To start, ketamine carries the risk of substance abuse. While ketamine is not strongly addictive, said Rosenblat, recreational users of the drug can develop a dependence.

Ketamine may also be prohibitively expensive for potential patients, as it is not covered by OHIP. Furthermore, as a medicine that is only available for research study or private use, it cannot currently be prescribed by most physicians.

There are also limited studies on the rare side effects of ketamine. In the short-term, the main known side effects are disassociation, a daydream-like state, and nausea which may occur during the administration of ketamine.

“We don’t know what we don’t know,” said Rosenblat. It is unclear whether ketamine may cause rare, adverse reactions in some patients. Long-term side effects of ketamine are also unclear.

Rosenblat therefore does not encourage self-medication for U of T students suffering from mental health challenges, as ketamine is not sufficiently studied.

Only a “very small percentage” would likely positively benefit from ketamine, explained Rosenblat, compared to standard treatment options supported by a much wider body of research.

The future of ketamine research

Although ketamine is not fully studied and is currently only used in special situations, it still brings “a message of hope,” said Rosenblat.

While ketamine is still not approved as an antidepressant, the U.S. Food and Drug Administration has approved esketamine, a structurally similar compound, as a nasal spray antidepressant. This became the first antidepressant of its kind to be used in the United States.

While Rosenblat notes that much more future research needs to be done with ketamine, he agrees that preliminary results are “very promising.” With a new avenue of research in treating severe depression, the future of research in the field seems optimistic.

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