TUESDAY, JULY 30, 2019
A new University of Auckland-led study provides the most direct evidence yet of how ketamine works as a fast-acting
antidepressant in humans – by increasing the brain’s ability to form new connections.
The new findings demonstrate that ketamine’s antidepressant actions occur after, and appear quite separate from, its
action on the brain that produces ‘highs’.
The research adds further evidence for the clinical benefits of ketamine, especially for people experiencing suicidal
thoughts for whom the usual six- to eight-week lag before classic antidepressants fully kick in can be a highly
vulnerable period.
Ketamine, or ‘special K’ as it’s known in the club scene where it’s used recreationally, was first synthesised in 1962.
It’s already in wide medical use as an anaesthetic, especially for children, and vets use it as a tranquilizer.
Since the early 2000s, scientists have also recognised its potential as an antidepressant. It has been approved as an
intravenous treatment for depression in the UK and, in nasal spray form, in the US. But in some places, including
Aotearoa New Zealand, it remains controversial due to its hallucinogenic properties and the risk of abuse.
“We know that ketamine works as antidepressant in many people, and works fast – reaching its full effect within a day,”
says lead author Rachael Sumner, a postdoctoral fellow in the School of Pharmacy at the University’s Faculty of Medical
and Health Sciences.
“The question is, how? It doesn’t work the way classic antidepressants do – which most often is by raising levels of the
brain chemical serotonin. If we can figure this out, we may also be able to identify other medications that do what
ketamine does but without the high.”
So the research team, led by Associate Professor Suresh Muthukumaraswamy at the School, carried out a clinical trial to
investigate the effects of a single intravenous dose of ketamine in people with major depressive disorder.
The new findings are now published in scientific journal Biological Psychiatry CNNI.
In the study, 30 participants who were moderately to severely depressed, and had not responded to at least two standard
treatments for depression, were given a small dose of ketamine and a placebo on two separate visits. Their depressive
symptoms were measured at different time points, and they were also connected to an electroencephalography (EEG) machine
so researchers could observe changes in electrical activity during a task that measures the ability of the brain to form
new connections.
In line with past research, ketamine reduced symptoms of depression within one day by 50 percent or greater for nearly
three-quarters (70 percent) of participants. But the EEG imaging revealed something that had previously only been shown
in rodents: a rise in neural plasticity during the period the antidepressant response began to emerge, at around three
hours.
“This is exciting, as it provides evidence for a potential mechanism in the brain for ketamine’s antidepressant
properties,” says Dr Sumner. “Neural plasticity is the brain cells’ ability to change and form connections with other
brain cells, and it is reduced in people with depression. This could help explain the observation that ketamine seems to
trigger changes in the brain that remain days after the drug leaves your system.”
Traces of ketamine are eliminated from the body by the next day. Its antidepressant effects emerge around three hours,
stabilise around 24 hours and generally last a week. (In recreational users, any ‘high’, which may involve out-of-body
experiences and perceptual distortions, generally passes within the first hour.)
Researchers stress that people shouldn’t try to self-medicate with ketamine. Ketamine highs can tip people into a
so-called ‘k-hole’ – a distressing sense of being trapped in a void, disconnected from reality, which can render people
unable to control their own bodies and feeling paranoid, and could exacerbate depressive symptoms.
“In a treatment setting and in our study, this was avoided by administering a low, carefully weight-related dose
gradually over 40 minutes and by constant monitoring to minimise any unpleasant drug reactions,” says Dr
Muthukumaraswamy.
“Those benefits are particularly valuable for people suffering acute depression. The findings show that ketamine may
have a place as a brief but effective treatment for depression which has not responded to other treatment, although
longer-term management remains an issue” he says.
The study received funding from New Zealand's Royal Society, Health Research Council and Auckland Medical Research
Foundation.
Journal article:
Key points:
• A University of Auckland-led study provides the most direct evidence yet of how ketamine works as a fast-acting
antidepressant in humans – by increasing the brain’s ability to form new connections.
• Ketamine is already used as an anaesthetic in humans and animals, and many studies have shown it works as an
antidepressant in humans. It’s approved for this use in the UK and US, but not in New Zealand.
• Researchers says this study, taken with other evidence, should reassure clinicians ketamine is a valid, useful
treatment option for depression.
ends