How Does Ketamine Work as an Antidepressant?
Depression can be an almost intolerable burden to live with. While antidepressants help many to soothe its symptoms, many others find no relief in these substances. A decades old drug, ketamine, is now offering hope to many of these people. Ketamine was first discovered in 1962. It was found to be a dissociative anesthetic and was used on the battlefields of the Vietnam war. While it can be used to dull pain at lower doses, at higher doses it can be profoundly hallucinogenic. With the emergence of ketamine as a promising new treatment for depression in recent years, it is now leading the way when it comes to legally available psychedelic therapy.
What is depression?
While we know what depression looks like, there is no currently accepted textbook understanding of what depression really is. Clinically, it is characterized by low mood, a loss of the ability to take pleasure in things, changes in weight and energy levels, negative thoughts about oneself, impairment in thinking and suicidal thoughts. In essence, the psychology of a person with depression is characterised by emotional pain and hopelessness. It is a state of deep stuckness from which there seems no escape. It can feel like being alone at the bottom of the ocean with no way out.
What is treatment resistant depression?
In the 20th century, several treatments for depression were developed, thankfully relieving the suffering of countless people. For many, however, none of these interventions help. These cases are classified clinically as treatment resistant depression and they typically represent the most severe and unrelenting instances of depression. Finding a way to help the group of people in the treatment-resistant class is the holy grail for new antidepressant therapies.
How was ketamine discovered as a treatment for depression?
At the beginning of the 21st century, exciting new therapies emerged that showed promise for helping those with severe, previously untreatable depression. One such therapy is a low-dose intravenous infusion of ketamine. Scientists had previously observed a link between the brain receptor that ketamine targets and schizophrenia, alcoholism and depression. The possibility that this receptor plays a causal role in the origin of multiple mental health issues led scientists to consider whether ketamine might have potential in treating such issues [1]. Researchers found that the antidepressant effects of ketamine kicked in incredibly quickly, within a matter of hours compared to weeks for traditional antidepressant medication. They also found that the effects could last for multiple weeks. A promising new antidepressant therapy had been discovered.
How effective is ketamine as a treatment?
When it comes to suicidality, the rapid onset of ketamine’s effects result in it being able to save lives. The anti-depressant effects are powerful, even helping those with previously untreatable depression. Current evidence suggests that the effects appear to be limited to the short term, however, typically lasting on the order of weeks [2]. Individuals must return for repeated ketamine infusions in order to maintain the positive effect on their depressive symptoms.
A brief tour of the brain
In order to understand how ketamine works, we have to be familiar with some basic of neurobiology. The brain is made of brain cells called neurons which signal to each other via chemicals called neurotransmitters. The cell sending the signal squirts out a chemical substance and the chemical lands on the surface of the cell receiving the signal. This receiving cell has specialized receptors on its surface which the chemicals fit into. When this happens, the signal has been received and it sets in motion the appropriate event in the receiving cell. The main neurotransmitters in the brain uses to transmit and process information are called glutamate and GABA. Glutamate increases activity in the brain while GABA decreases activity. When activation is transmitted through networks of neurons via glutamate, the receiving cells register the presence of this neurotransmitter via multiple types of receptor. One type is the AMPA receptor, which produces activity in the receiving cell. The other major type is the NMDA receptor. When activated, these receptors cause a strengthening of the connection between the two neurons, allowing learning to occur. It is the NMDA receptor that ketamine targets.
How does ketamine work in the brain?
When ketamine gets into our bloodstream, it crosses into the brain and can drift into these NMDA receptors. By imitating glutamate, it can cause activation of neurons and a strengthening of connections in the brain. These processes have the potential to affect mood, perception and patterns of thinking. What’s more, this boost of activity may be only the first step in ketamine's effect. By adding signals of this kind into the brain, the activated neurons may result in the release of other neurotransmitters, producing complex cascading effects. What’s more, ketamine's effects are not just limited to NMDA receptors, it also activates opioid receptors
Why does ketamine have antidepressant effects?
Like most chemical treatments for mental health disorders, the therapeutic effects of ketamine were first stumbled on before we had a good understanding of why it works. Why ketamine produces antidepressant effects is actively being researched. We may not have the definitive answer, but there are promising leads.
A shock to the system
One way of thinking about the possible mechanism behind the anti-depressant effects is that it may operate something like shock therapy. In the 20th century, passing electrical current through the brain was found to have antidepressant effects. Ketamine may also produce additional activation of networks in the brain, albeit via a more targeted chemical route. Since depression is characterized by being stuck in a specific psychological mode, shocks to the system of different kinds may be what the system needs in order to temporarily escape its rut, find relief and hopefully a better equilibrium after. This finding of a new balance is one reason that altered states in general have therapeutic potential.
Brain plasticity
Since ketamine acts on pathways involved in learning, the activation of NMDA receptors that promote brain plasticity may be particularly important, allowing the brain to adapt and flexibly change its perspective. Taken in combination with the change in biochemical state produced by ketamine, the result may be the recruitment of the brain’s natural healing intelligence. Biological systems have a remarkable tendency to move towards health if allowed to. Simulating the system using ketamine combined with the effects of potentially increasing brain plasticity may give the brain a chance to move itself into a healthier state.
Other mechanisms
As well as activating NMDA receptors, ketamine also activates opioid receptors. This is thought to account for its pain-relieving properties. One study found that chemically blocking opioid receptors so that ketamine couldn’t act on them dulled its antidepressant effects [3]. This research provides evidence that opioid receptors at least contribute to the overall therapeutic effects of ketamine. Why this is, we currently don’t know, but it may help to soothe the emotional pain that is a core part of the depressed state. What’s most likely is that a range of mechanisms are involved in the therapeutic effects of ketamine, from soothing psychological pain to providing a shock to the system to increasing brain plasticity.
How does ketamine compare to antidepressant medication?
Traditional antidepressant medications act on the serotonin system and slowly build up their effects over weeks. We still do not know why they can help to soothe the symptoms of depression in some patients. Ketamine has been found to be more effective for patients who receive no benefit from these serotonergic antidepressants. Arguably the most important difference is the time course of the effects. The rapid onset of ketamine's antidepressant effect makes it a potentially life-saving option for those who are suicidal. In both cases, however, long term treatment is typically required, as the symptoms often return without repeated doses.
How does ketamine therapy compare to psilocybin therapy for depression?
Ketamine therapy is the first legal psychedelic therapy. This is thanks largely to ketamine being placed on the World Health Organization’s List of Essential Medicines for its use as anaesthetic. As a result, ketamine hasn't been prohibited as fully as psilocybin, creating fewer legal barriers for doctors to be able to provide this medicine. The antidepressant effects can last for several weeks but further treatments are typically necessary in order to maintain the effect. Psilocybin therapy on the other hand has been found to reduce depressive symptoms for 6 months following a single session. The key difference may be that psilocybin therapy often goes to the emotional root of the depression, while ketamine may act at the level of the symptoms. Without addressing the root cause, the symptoms will gradually return over time.
Where can one receive ketamine therapy?
Legal Ketamine Clinics now exist throughout the United States, a list can be found here [4]. A ketamine nasal spray is also available for depression. Access to this treatment is likely to only increase over time as many more people continue to find relief from their depression through the use of ketamine.
References
[1] https://www.annualreviews.org/doi/pdf/10.1146/annurev-med-053013-062946#article-denial
[2] https://pubmed.ncbi.nlm.nih.gov/31612847/
[3]