Ketamine for depression could be effective in 40 minutes and last for weeks, although safety issues remain.
Ketamine — sometimes known as a ‘horse tranquiliser’ or club drug — is not a new drug, although its use for those with depression is relatively new.
Recent studies have found that it can lift depression in as little as 40 minutes and treat people for a week or longer.
The fact that ketamine for depression works so quickly, and on one of the most resistant forms of depression, has many researchers fascinated.
Traditional antidepressants can be slow to work — if they work at all.
The problem with using ketamine as a treatment for depression is that it gives people an addictive high.
Similar drugs to ketamine, though, without the side-effects, which act on the same chemical pathways, are also being developed.
These could provide hope for those who suffer some of the most debilitating types of depression.
How ketamine for depression treatment works
Research has provided a critical insight into how ketamine works — and possibly a way to side-step its addictive properties (Zanos et al., 2016).
Scientists at the National Institutes of Health (NIH) have found that it is not the ketamine itself that causes the antidepressant effect.
Instead, it is another substance into which ketamine is broken down by the body that provides the effect (a metabolite).
Dr Carlos Zarate, one of the study’s co-authors, said:
“This discovery fundamentally changes our understanding of how this rapid antidepressant mechanism works and holds promise for development of more robust and safer treatments.
By using a team approach, researchers were able to reverse-engineer ketamine’s workings from the clinic to the lab to pinpoint what makes it so unique.”
Although previous research has been carried out on humans, the new study tested ketamine for depression in mice.
It found that the mechanism of action was not what many had assumed.
Instead it works through a glutamate receptor: α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)
With this information the scientists were able to make an antidepressant which worked on the mice without the side-effects.
Dr Todd Gould, one of the study’s authors, said:
“Now that we know that ketamine’s antidepressant actions in mice are due to a metabolite, not ketamine itself, the next steps are to confirm that it works similarly in humans, and determine if it can lead to improved therapeutics for patients.”
70 percent respond to ketamine for depression
Fully 70 percent of people in one study who were given the drug responded to it — despite previously not improving with other standard depression treatments (Tiger et al., 2020).
Ketamine increases the brain’s production of dopamine.
Dopamine is involved in how we process rewards: when we eat delicious foods, help others, exercise and fall in love, the brain produces dopamine.
One of the key symptoms of depression is finding it difficult to seek out and experience rewards — people feel there is nothing to look forward to.
Dr Mikael Tiger, the study’s first author, said:
“In this, the largest PET study of its kind in the world, we wanted to look at not only the magnitude of the effect but also if ketamine acts via serotonin 1B receptors.
We and another research team were previously able to show a low density of serotonin 1B receptors in the brains of people with depression.”
The study included 30 people with depression that had not responded to other treatments.
They were given either a dose of ketamine for depression or a placebo.
Brain scans revealed that ketamine operates through serotonin 1B receptors.
The effect is to reduce the release of serotonin, but increase the release of another neurotransmitter called dopamine.
Dopamine is part of the brain’s reward system, which helps to attract people to positive experiences.
Those who wished to continue, received ketamine for a further two weeks, twice a week.
The results showed that over 70 percent responded to the treatment.
Dr Johan Lundberg, study co-author, said:
“We show for the first time that ketamine treatment increases the number of serotonin 1B receptors.
Ketamine has the advantage of being very rapid-acting, but at the same time it is a narcotic-classed drug that can lead to addiction. So it’ll be interesting to examine in future studies if this receptor can be a target for new, effective drugs that don’t have the adverse effects of ketamine.”
Esketamine for depression as a nasal spray
Researchers have been examining different ways to administer ketamine and in different forms.
A nasal spray containing a form of ketamine for depression — a type of anaesthetic — can help severely depressed and suicidal people, research finds (Canuso et al., 2018).
The form of ketamine works quickly, and on one of the most resistant forms of depression.
When people are severely depressed there is a critical window when they need rapid relief from suicidal thoughts.
While antidepressants can be beneficial in the long-run, they cannot help people when they are at highest risk because they take too long to kick in.
The study tested a nasal spray containing esketamine — a part of the ketamine molecule — on 68 people experiencing severe depression and suicidal thoughts.
Half received treatment as normal plus a placebo and the other half received treatment as normal plus the nasal spray.
The results showed that the nasal spray was effective in rapidly reducing suicidal feelings within 40 minutes of being administered.
The effects were still being seen after 24 hours, in comparison to those receiving a placebo.
The more esketamine people were given, the longer its effect.
The drug has now been approved by the FDA in the US.
The problem with using ketamine as a treatment for depression is that it gives people an addictive high, so safety issues will need to be explored.
The study’s authors conclude:
“These preliminary findings indicate that intranasal esketamine compared with placebo, given in addition to comprehensive standard-of-care treatment, may result in significantly rapid improvement in depressive symptoms, including some measures of suicidal ideation, among depressed patients at imminent risk for suicide.”
Ketamine treatment for bipolar disorder
Ketamine and similar drugs are also being tested for the relief of other mental health problems.
One example is bipolar disorder.
When depressed, bipolar patients find it difficult to seek out and experience rewards — they feel there is nothing to look forward to.
Ketamine works by changing how people think about rewards, a study finds (Lally et al., 2014).
Dr. Carlos Zarate, who led the study, said:
“Our findings help to deconstruct what has traditionally been lumped together as depression.
We break out a component that responds uniquely to a treatment that works through different brain systems than conventional antidepressants — and link that response to different circuitry than other depression symptoms.”
In the study, 36 patients with bipolar disorder who were currently depressed were given either ketamine or a placebo.
They were then asked about their depression and symptoms of anhedonia, the inability to experience pleasure.
The first effect of the drug was to reduce patients’ anhedonia within 40 minutes: they could once again anticipate and experience pleasure.
After two hours, the drugs anti-depressant effects were also felt.
This reduction in anhedonia was still detectable two weeks after the single dose.
Brain scans revealed that the drug likely works by changing the way the motivational parts of the brain respond to imagining and taking part in pleasurable experiences.
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