NZ study throws light on how ketamine works as antidepressant

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 the Royal Society, Health Research Council and Auckland Medical Research Foundation.

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Biological Psychiatry: Cognitive Neuroscience and Neuroimaging - Ketamine enhances visual sensory evoked potential LTP in patients with major depressive disorder