Ketamine: A Paradigm Shift for Depression Research and Treatment

This review and perspective paper (2019) gives a high-level overview of what we know about ketamine’s effects and how it has changed our perspective on (the treatment of) depression.


“Ketamine is the first exemplar of a rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery emerged from a reconceptualization of the biology of depression. Neurobiological insights into ketamine efficacy shed new light on the mechanisms underlying antidepressant efficacy.”

Authors: John H. Krystal, Chadi G. Abdallah, Gerard Sanacora, Dennis S. Charney & Ronald S. Duman


This paper is included in our ‘Top 12 Articles on on Ketamine for Mental Health

The authors hold various advisory positions, stocks, and more related to ketamine that are linked in the paper.

The authors identify the ever-increasing problem with depression (Our World in Data). It affects a large part of the population, and for many, there is no suitable treatment. For those suffering from bipolar disorder, conventional treatments are even more limited.

The ‘monoamine hypothesis of depression’ model is outdated and various experiments have shown it to not influence depression as was once thought.

The perspective (or paradigm) shift is illustrated in figure 1a and shows that cortical and limbic mechanisms play a role in depression. Specifically that glutamatergic and GABAergic signaling plays a role.

Figure 1c highlights all the different mechanisms that may lead to ketamine’s antidepressant effects. These include AMPA receptors, TrkB receptors, BDNF, and mTORC1. Which in turn can lead to local protein synthesis which leads to dendritic spine formation and the restoration of synaptic connectivity. Or in other words, ketamine leads to some restoration of brain connections.

Replications of the early work by these authors led to confirmation of the antidepressant effects of ketamine. The authors summarize this as follows:

These replications found that a single dose of ketamine produced antidepressant effects that began within hours, peaked within 24 to 72 h, and then dissipated typically within 2 weeks if ketamine was not repeated. Also, the subsequent studies showed that ketamine was effective in antidepressant non-responders, including patients with bipolar disorder. Further, the antidepressant effects of ketamine were meaningful clinically, with one-third of patients with treatment-resistant symptoms achieving remission and ∼50%–75% of patients demonstrating clinical response from a single dose, with higher rates of response and remission with repeated administrations (Wilkinson et al., 2017). Lastly, ketamine reduced all symptoms of depression, notably suicidal ideation (Krystal et al., 2013).

The paper also ponders the different response rates and dosing schedules. As ketamine only seems to work up to two weeks, patients need to come back often or otherwise most fall into remission. The individual dosing is also something that needs to be further studied as some studies show therapeutic effects at non-psychedelic dosages, whilst in other cases the response to a relatively high dose (70mg/70kg) was no better than that of half that dose.

The mechanisms of ketamine are not fully understood and even the plasticity enhancing effects seem paradoxical as the molecule inhibits a receptor normally critical for plasticity. When we learn more about ketamine’s mechanisms, new (and complementary) drugs may be developed that can help alleviate depression. Ketamine’s relative safety and immediate effects will make it one of the options doctors can use/are currently using off-label.

When commenting on the stigma on depression, the authors note: “Ketamine may become a transformative treatment. Transformative treatments have a powerful impact on stigma, as exemplified by the emergence of anti-retroviral treatments for AIDS. Thus, ketamine may be not only a source of hope for patients and their families but also a powerful weapon in the fight against stigma and for parity in the support for depression prevention, treatment, and research.

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Ketamine: A Paradigm Shift for Depression Research and Treatment

Open Access | Google Scholar | Backup | 🕊

Published in
March 6, 2019
113 citations

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