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.

Abstract

“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

Notes

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The ‘monoamine hypothesis of depression’ model is outdated and various experiments have shown it to not influence depression as was once thought.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

Summary

Ketamine: a paradigm shift for depression research and treatment

Ketamine is the first rapid-acting antidepressant with efficacy for treatment-resistant symptoms of mood disorders. Its discovery sheds new light on the mechanisms underlying antidepressant efficacy.

The problem: an overly narrow focus on monoamine signaling

Depression is among the most disabling medical conditions, yet few patients respond to antidepressants, and many patients relapse after having achieved response.

The premature conclusion that antidepressants work by ameliorating deficits in monoamine signaling contributed to the failure to identify fundamentally new treatment mechanisms since the discovery of antidepressants in the late 1950s.

The opportunity: a broader circuitry perspective

We wondered, how could we target the non-monoaminergic mechanisms more directly? We decided to explore glutamate synaptic alterations using the response to ketamine as a probe, and used a dose and rate of infusion that produced transient schizophrenia-like symptoms and cognitive impairments without producing delirium or an anesthetized state.

Ketamine produced rapid, profound, and surprisingly durable antidepressant effects in patients that were temporally dissociated from the brief acute behavioral effects of the drug. The antidepressant effects were meaningful clinically, and reduced all symptoms of depression, notably suicidal ideation.

Ketamine is an effective treatment for some patients, but there is great interest in finding a sub-dissociative therapeutic dose. The optimal frequency of ketamine administration is also evolving, with treatment initiated typically twice per week and tapered gradually.

Mechanism of action: ketamine as “the tip of the iceberg”

Ketamine was shown to have antidepressant effects by blocking NMDA receptors. However, ketamine increases neuroplasticity despite blocking NMDA receptors, and it remains unclear whether NMDA receptor antagonist properties will improve efficacy or safety.

Ketamine may contribute to its antidepressant efficacy by stimulating glutamate release, which in turn promotes BDNF release, TrkB receptor stimulation, activation of mTORC1, and stimulation of local protein synthesis. This leads to the rapid proliferation of dendritic spines and restoration of functional connectivity.

Ketamine may affect reward and motivation circuits, and may have effects at sites other than NMDA receptors. It is also possible that different isomers of ketamine may have complementary or even additive antidepressant effects.

Ketamine may serve as a prototype for an entirely new class of antidepressant medications. These medications could increase glutamate release, promote AMPA receptor facilitation, or raise BDNF levels.

Changing expectations

Ketamine’s rapid and profound antidepressant effects revealed how little we understood the most intensively studied class of medications in psychiatry.

Where does ketamine belong in the treatment algorithm for depression?

Ketamine is increasingly being prescribed to patients who have failed two adequate antidepressant treatments. It can be used in urgent care contexts to manage suicide risk and to mitigate or shorten psychiatric hospitalization.

What does long-term ketamine treatment look like?

Ketamine treatment must include protections against abuse liability and management of acute dissociative effects. Home administration by a visiting nurse may be explored.

Could ketamine change what it means to have depression?

Depression is highly stigmatized and ketamine may become a transformative treatment. Ketamine may not only be a source of hope for patients and their families, but also a powerful weapon in the fight against stigma.

Was the discovery of ketamine’s antidepressant serendipitous?

Ketamine was discovered as a treatment for depression. Its discovery was based on a novel mechanistic hypothesis, and the discovery led to more specific mechanistic hypotheses, which are now driving a new generation of human translational neuroscience studies.

Figure 1.

Ketamine was tested in depressed patients for its antidepressant effects and its therapeutic mechanisms of action. The perspective shift in perspective led to the discovery of alterations in glutamate signaling associated with depression. The acute behavioral effects of ketamine are observed in healthy humans and patient populations, whereas the rapidly emerging antidepressant effects of ketamine are observed only in individuals with psychiatric symptoms.

Ketamine has antidepressant effects by blocking postsynaptic NMDA glutamate receptors, which activate eEF2 and depress BDNF levels. This raises BDNF levels and shuttles AMPA glutamate receptors to the synapse, enhancing synaptic efficacy. Ketamine may generate its antidepressant effects indirectly by blocking NMDA receptors on GABA interneurons, which increases stimulation of AMPA glutamate receptors, which in turn activates a signaling cascade that raises BDNF levels, which in turn activates local protein synthesis necessary for increasing dendritic spine formation and restoring synaptic connectivity. Ketamine increased cortical structural connectivity in animals and restored cortical functional connectivity in depressed patients. This increase in connectivity was associated with alleviation of depression symptoms.