The notion that ketamine might have antidepressant effects is not new. Widely stigmatised as a party drug, the compound has nonetheless been the subject of intense scientific scrutiny. Since the 1990s, scientists have been exploring its potential mental health benefits, considering whether it might be helpful for depression, bipolar disorder and obsessive compulsive disorder (OCD).

First synthesised in 1962, ketamine was subsequently approved by the Food and Drug Administration (FDA) as an analgesic and anaesthetic. It appears on the World Health Organization’s List of Essential Medicines, and has both human and veterinary applications.

However, due to its potential for abuse, it is also a controlled substance in many parts of the world. The UK Government, for instance, labelled ketamine a Class C drug in 2006, raising this to Class B in 2014 in light of new evidence about its harmful effects.

All this said, its legal status does not tell the whole story. A growing body of research suggests that, when taken in a controlled context, ketamine has a remarkable effect on lifting mood. It could therefore alleviate various psychiatric disorders where conventional drugs have failed.

Pioneering ketamine studies

Dr John Krystal, now professor and chair of the Department of Psychiatry at Yale University, was a pioneer in this field. In 2000, he published the first ever study implicating ketamine as a treatment for depression.

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“My colleagues and I had spent many years of treating depression with traditional antidepressant medications and waiting for weeks or even months of treatment to see improvement,” he recalls. “The observation that a single dose of a short-acting medication could produce a dramatic improvement in symptoms within 24 hours, that would last from days to weeks in patients who had not previously responded well to medications, seemed like a revelation.

"When taken in a controlled context, ketamine has a remarkable effect on lifting mood."

“This area of research has advanced to the point where clinics around the country are administering ketamine to depressed patients.”

Of course, if ketamine really is a viable depression drug, unregulated infusions in psychiatry clinics are hardly the ideal form of administration. For a number of researchers in the field, the endgame is clear: to learn more about treatment protocols and safety, and ultimately get the drug approved as a standard medication.

Pharmaceutical companies too are keen to explore the potential, and set foot in what could feasibly be quite lucrative terrain. For them, the question is slightly different – would it be possible to synthesise a drug that acted like ketamine, without its dissociative side effects?

RCTs and drug development

In August this year, the largest ever randomised controlled trial (RCT) in ketamine got underway. Led by Professor Colleen Loo of the University of New South Wales (UNSW), the study is taking place in locations across Australia and New Zealand. It will last three years and recruit 200 adult patients with major depression, who have not responded to other medications.

Funded by a $2.1m grant from the National Health and Medical Research Council, the trial will build on five years of UNSW ketamine research.

“[It] will allow us to examine the effects of repeated dosing and whether the positive effects of ketamine on an individual’s depression can be sustained over a longer period,” said Loo.

She slammed off-label ketamine treatments as “premature and irresponsible”, given that the effectiveness and safety of repeat treatments have yet to be established through clinical trials.

Ketamine is an NMDA glutamate receptor antagonist, meaning it works by blocking a brain pathway called NMDA, or N-methyl-D-aspartate. Most researchers in the field, including Loo’s team, attribute its antidepressant properties to this mechanism.

From a pharma standpoint, this creates an obvious target for drug development. So far, more than a dozen companies have attempted to create drugs that inhibit the NMDA receptor.

Most notably, Janssen Pharmaceuticals is developing a nasal spray derived from ketamine, which has received a ‘breakthrough therapy’ designation and could be filed with the FDA as early as 2018. A smaller pharma company, Cerecor, is working on an NMDA antagonist called CERC-301, which would be a ketamine-like antidepressant taken as a pill.

Drugs of this kind may hold more promise than ketamine itself, in that they target the relevant pathways more selectively and won’t lead, for example, to hallucinatory or anaesthetic effects on top of the desired mood enhancement. They would also be convenient to administer and would not require a subcutaneous injection.

A new framework

With studies into NMDA antagonists continuing apace, a team of US researchers is taking a different angle. Their findings, published in Nature in May this year, attributed the antidepressant effects not to the drug itself, but to one of its chemical byproducts.

The byproduct in question – a metabolite called hydroxynorketamine (HNK) – exerts its mood-lifting powers even in the absence of ketamine. And when ketamine is blocked from transforming into HNK, it no longer works as an antidepressant.

“Thus far we have established that production of HNK metabolites of ketamine is both necessary and sufficient for antidepressant effects of ketamine in mice,” says study co-author Dr Todd Gould, of the University of Maryland. “As HNK metabolites do not inhibit the NMDA glutamate receptor, they do not have side effects of ketamine. We have gone up to very high doses in mice, 40-fold the antidepressant relevant dose, without any apparent negative side effects.”

"Janssen Pharmaceuticals is developing a nasal spray derived from ketamine."

If this metabolite is responsible for ketamine’s antidepressant effects in humans, we will have a biochemical explanation for the drug’s quick onset – and long-lasting impact. While ketamine is broken down rapidly, HNK remains in the body for days after the drug is taken.

Gould feels the long-term potential could be significant, with HNK holding promise as a medication in its own right.

“The next steps are the necessary dose-ranging and long-term toxicology studies, for FDA approval for a human phase I and II studies,” he says. “We are confident about its safety because HNK metabolites have been in humans since 1970 as a by product of ketamine, even though the FDA treats them as a new drug entity.”

Benefits vs. risks

Despite seeming radical, Gould’s hypothesis may actually complement, rather than contradict, other work in the field.

“The framework that has emerged from the ketamine studies is not really threatened by the HNK findings as it already has been shown that HNK, through mechanisms that are not yet known, enhances synaptic functional connectivity,” says Krystal. “If it works in humans, it may help to lead scientists to fill new features in this conceptual framework.”

However, as this conceptual framework develops in the year ahead, it seems clear that ketamine holds potential for depression. Although the appropriate form and dosage have yet to be determined, few would now dispute that the drug is a suitable candidate for research.

“It is a medication that must be treated with respect in that it has abuse liability, may produce transient cognitive or perceptual effects, and may produce transient nausea,” says Krystal. “However, its side effects seem to be easily managed. As a result, it seems to me that its benefits clearly outweigh the risks.”