Ketamine is an anaesthetic. It has been used by both doctors and vets since the 1970s to provide safe pain relief, and to anesthetize patients. Unlike most anaesthetics ketamine doesn't impact your ability to breathe, which has made it an incredibly useful drug for emergency treatment before or during transport to a hospital. Around 16 years ago it became apparent that ketamine may also have another feature, the ability to relieve the symptoms of treatment resistant depression. This possibility is now being put to the test in the largest clinical study to date.
The trial, which is based out of the University of New South Wales in Australia, has reached across the Tasman to include the University of Otago. Professor Paul Glue, a psychiatrist in the University's department of Psychological Medicine, was part of the team that received grant funding from the Australian Government to conduct this trial, and is heading up a local centre which offers access to the study treatments.
Professor Glue has a history of prescribing ketamine to individuals who haven't responded to other depression treatments, and after speaking with him it is easy to understand why. “It works for about two thirds of people,” he says, passing me print-outs of graphs showing the extent of the response. The evidence is remarkable. Individuals who have had no relief from depression for years, potentially decades, report a rapid improvement of their symptoms. What strikes me most is the response time. “It takes around an hour before people start feeling better,” he says, “and the effects can last up to a week before their symptoms come back.”
Standard depression medications take weeks or longer before any improvement is noticed, so why does ketamine work so quickly? Professor Glue believes that it is due to a protein called brain-derived neurotrophic factor (BDNF). BDNF is a protein that helps nerve cells in the brain maintain a healthy level of connection with other nerve cells, and allows brain networks to function normally. Network activities are disrupted in depression, possibly because BDNF levels are decreased. When people are given a dose of ketamine there is a rapid increase in available BDNF levels, allowing for a large number of new connections to be made. There isn't conclusive information about where BDNF is having an effect in the brain, but all evidence suggests that it is an important factor. “There appears to be a relationship between BDNF levels and treatment response,” Professor Glue tells me, “the higher the BDNF the better the response, and for those who have little or no BDNF release there may be no response to ketamine.”
I ask him if it works on people who have previously responded to other depression medications, or might not be completely resistant to antidepressant treatments. “We don't know,” he says, “no one has done that research.” In the US, researchers are beginning to ask how treatment resistant a person's depression needs to be before ketamine is an option, but for now the answer to that question is regulatory.
Ketamine is prescribed as an off-label treatment for depression, which means that it is not an approved use of the drug. In order to be prescribed as an approved treatment for depression ketamine would have to go through the registration process, which would require significant financial backing. The data suggests that ketamine is effective, but it just isn't integrated into our medical system.
Financially it doesn't make sense for a pharmaceutical company to cover the costs of ketamine's registration, or the clinical trials necessary to support its use as an anti-depressant. It's a generic drug, so once it is registered as an anti-depressant any pharmaceutical company could produce and sell it in New Zealand. The ease with which that competition could occur means that the original 'registering' pharmaceutical company wouldn't make their money back. As a result, no company has come forward to support it wholesale. However, Janssen, a large US-based pharmaceutical company, are currently testing a ketamine product. The product is a nasal spray, the effectiveness of which has yet to be reported. If these tests prove successful then Janssen will retain rights over the formulation, giving them a financial incentive to register it in New Zealand and other nations.
While the lack of financial backing for ketamine research has meant that the road toward registration has been long, the end is now closer than ever. With new investment by Janssen, and with this Australasian ketamine trial, support is building for the registration of ketamine as an anti-depressant.
However, a significant issue, in terms of making ketamine more available for those who could benefit from it, is its history of abuse. While the rate of abuse in New Zealand is quite low, probably because it is difficult to access, ketamine is abused recreationally in most countries where it's available. At high doses it can cause hallucinations, dissociation, and memory loss lasting for anywhere between five minutes and an hour. Those who abuse it for upwards of a year appear to develop psychological dependence on it. Chronic users of ketamine will snort or inject multiple high doses each day, and over years this level of abuse may also cause urinary tract inflammation and memory problems. The question is, would we be putting people at new or unnecessary risk by widening access to ketamine?
The answer is no, at least for the current study.
When we talk about chronic ketamine abuse we're talking about people ingesting or injecting hundreds of milligrams of ketamine multiple times a day. This requires a quantity of the drug and a freedom of access which will not be available to people with the proposed protocols. Participants in this trial will be given injections of ketamine twice per week. The dosages they'll receive will be between 25 and 50 milligrams, depending on the weight of the individual. Just like the patients Professor Glue currently treats with ketamine, they will have to go to a specific clinic to have their injection; patients would have no direct access to the drug. The limited access and low dosages being made available ensure that the line between treatment and abuse is very clear.
The researchers are hoping to recruit a total of 200 people in Australia and NZ to take part. Half will be assigned to a control group, and the remaining half will receive ketamine. Participants won't know what group they're in when they begin the trial, which helps the researchers to control for expectation or nonspecific effects. The trial goes on for 12 weeks in total: 4 weeks either receiving ketamine or the control treatment, 4 weeks without any treatment, and then a final 4 weeks where any of the 200 participants with remaining symptoms of depression will have access to two ketamine injections per week.
Over the course of the trial researchers will be keeping close tabs on people, measuring everything from their levels of depression to side-effects to liver function. They want to cover all the bases to make sure that at these doses ketamine is both safe and effective. From work which has been published previously, with smaller groups of participants, there is good reason to believe this will be so.
The risks of treating individuals with ketamine has to be compared to the quality of life it could restore to the hundreds of thousands of patients with treatment resistant depression. Treatment resistant depression is not a neutral experience. It is physically, psychologically, and economically detrimental. These individuals, and those who care for them, are suffering and have been for years. This trial is a step toward a new treatment, one which may finally work for these people. We at the BHRC wish Professor Glue and his colleagues luck as their recruitment begins, and we are very much looking forward to seeing the results in the coming years.
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