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Why Ketamine Treatment Is Not All That New

Ketamine is used for depression, but its target is not different from therapy.

Key points

  • Ketamine is a hallucinogen that has recently been found effective for "treatment-resistant" clinical depression.
  • Treatment using this drug targets the same areas that have been targeted by psychotherapy for more than a century.
  • Saying that depression is "treatment-resistant" may be just one way of saying psychotherapy is not given enough time for most lasting effects.

Ketamine gets a lot of attention lately as an alternative for “treatment-resistant depression.” This is a term for severe depression that does not respond to multiple antidepressants or to psychotherapy. Estimates put the rate of this type of severe depression at about 25 to 30 percent of all depressions.

Concerns Regarding Ketamine Use

Although ketamine research seems promising, there are major concerns regarding its use. Ketamine is allowed by the Food and Drug Administration as anesthesia, but it is likely more famous as a hallucinogen and so-called “party-drug.”

Using a hallucinogen for treating a legitimate psychological condition understandably causes many people concern. Even under the very strict procedures used by clinics and other mental health facilities that administer ketamine, there still are legitimate concerns about what problems can be associated with using this drug.

Ketamine has been shown to impact areas of the brain and neurochemicals active in severe depression. What is not certain is how long these effects last and whether the neural changes are more temporary or permanent. There are also concerns about side effects from using the hallucinogen.

"Fear Extinction"

When considering ketamine, it is useful to note that its impact is primarily in what is called “fear extinction.” It helps alter the connections we as humans make about what frightens us and what we fear is dangerous (Silote, de Oliveira, Ribeiro, Machado, Andreatini, Joca, & Beijamini, 2020).

Fear is something people often associate with anxiety but not depression. It actually does have a role in both depression and anxiety, but the role is different.

Animal Behavior

Studying behavior across animal species (a particular focus of this blog) shows the role fear plays in clinical depression. If you think of what depression looks like in human beings, its most closely related situation in animals would be animals who have been defeated. Animals who have fought other animals and lost very often look like they have clinical depression. They retreat slowly and deliberately, they hold their head down, they do not react to anything afterward, and they show little interest in what is going on around them. They look as if they have been defeated because they have been defeated.

Animal behavior along these lines underlies the “social rank competition” theory of depression (Wetherall, Robb & O'Connor, 2019). Central to this theory is that animals often develop a pattern of showing defeated behaviors even before they actually get into competition. As means of avoiding actual physical confrontation with someone they know is likely to kill or seriously harm them, the individual shows defeated behavior as a way of “giving up” before they have to risk any actual physical harm.

Theories of clinical depression posit that this may be an evolutionary explanation of human depression. People may “give up” on having any success because on some level they fear what will happen if they try. Taking a defeated stance serves the survival benefit of not having to confront what the person knows to be a losing prospect. This is one reason why people with severe depression can be described as looking like they are “defeated by life.”

More than a century ago, psychologists first described a form of severe depression called melancholy. Their idea was that a person falls into belittling and criticizing themselves, often unconsciously, and responds as if they take the criticisms to be true and accurate. Depressed individuals in this way are not worried that the doubts about themselves might be true; they believe they are true and fear having to find out what this means when confronting the world. Since that time, therapy has targeted helping individuals alter their fear that trying to improve their lives is always a losing battle.

Ketamine targets brain areas controlling our fear responses. It may be that the effect weakens the neural networks controlling these responses. But it may be deeper than that as many people describe “spiritual” experiences that change how they perceive the world. These lessen the weight people give to seeing the world as such a dangerous place and change their perception that trying to move forward is always a losing battle.

Giving Psychotherapy More Time

Psychotherapy also targets this way of viewing the world and works to help depressed individuals recognize that trying to improve their lives is not as dangerous as they may perceive. If we recognize this as a legitimate goal to help “treatment-resistant” depression, then it may be important to give psychotherapy more time to work than has become the norm. Expecting that a person’s worldview can be changed in the average psychotherapy span of 15 to 20 sessions sounds unrealistic.

Considering how ketamine works will hopefully bring about a different way of viewing depression treatment. Hopefully, this will include considering that we need to give more time for psychotherapy to work on deep-seated negative beliefs before we say that depression is “treatment-resistant.” If we do that, maybe we can have the treatment benefits of ketamine without worrying about the side effects.


Silote, G. P., de Oliveira, S. F., Ribeiro, D. E., Machado, M. S., Andreatini, R., Joca, S. R., & Beijamini, V. (2020). Ketamine effects on anxiety and fear-related behaviors: Current literature evidence and new findings. Progress in neuro-psychopharmacology and biological psychiatry, 100, 109878.

Wetherall, K., Robb, K. A., & O'Connor, R. C. (2019). Social rank theory of depression: A systematic review of self-perceptions of social rank and their relationship with depressive symptoms and suicide risk. Journal of affective disorders, 246, 300-319.

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