“If you take a hundred people with severe depression, 60 per cent are adequately covered by antidepressants. That leaves 40 who aren’t. If ketamine can relieve the suffering of 30 of those 40, that’s a huge amount of suffering that’s being relieved, that’s a huge number of people who are getting their lives back. “
Graham Barnett is a neuroscientist from the University of Melbourne, specialising in the field of neuroplasticity. Until recently, he was also the consulting medical director of the controversial Aura Medical Clinic, which has been prescribing ketamine to treat refractory (the medical term for treatment-resistant) depression since October of last year.
As reported by many studies, including the US National Library of Medicine National Institutes of Health, standard antidepressant medication works by regulating the levels of brain chemicals like serotonin. Ketamine helps regenerate connections between brain cells that have been damaged by stress and depression. It represents an entirely new way of understanding depression and its treatment.
"When I was a medical student, our idea of the brain was that once you reached adulthood your brain had finished its developing. It was hardwired; and from then it was a slow process of gradual attrition," Dr Barrett says.
"We now know that this is absolutely wrong; the brain is constantly reconfiguring itself, rewiring itself; strengthening some circuits and weakening others.
"The most central molecule in this is the NMDA receptor. That is the basis for memory, for learning, for reinforcement. It’s speculation of course, but I think the way that it’s working is enabling people to forget their depression.”
According to the Black Dog Institute, three million Australians are living with depression or anxiety. The cost to the Australian economy has been estimated at $20 billion per year. In this country, around 2500 people die by suicide each year. We have the second highest use of anti-depressants in the OECD, with 89 in every thousand people being prescribed medication for daily use.
Ketamine has been a known drug for over half a century, but first came in to prominence as a general anesthetic during the Vietnam War, and is on The World Health Organisation’s list of essential medicines. In the 80s it gained a reputation as a hallucinogenic recreational drug. Doses for depression are approximately 1 per cent of a recreational dose and 0.02 per cent of a general anesthetic dose.
Anesthesiologist Dr Glenn Z. Brooks has been working with ketamine for 40 years. "It’s not a club drug, it’s not a horse tranquilizer. It’s a general anesthetic, and it’s found in every operating room in the world," he says.
Brooks is the founder of NY Ketamine Infusions, one of the first practices in the United States using ketamine to treat depression. While he has used the drug for decades for anesthesia and the relief of complex neuropathic pain, his recent work with depressed patients is partly inspired by losing a son to suicide at the age of 18 in 1999.
"It’s not a club drug, it’s not a horse tranquilizer. It’s a general anesthetic, and it’s found in every operating room in the world."
"Immediately after his suicide, his mother and I did all the usual things: scholarship funds, money to charities… nobody at that time was using ketamine to treat major depressive disorders. That didn't come for a decade later. The research was going at the time, it has actually just begun. In clinical practice, even as an anesthesiologist, I wasn't aware of its use".
Dr Brooks was working in addiction medicine and administering ketamine for neuropathic pain when he was contacted by a psychiatrist to see if he would be interested in administering a ketamine infusion for a severely depressed patient.
"I remember the patient very well. He had been very depressed, and was suicidal. He was suffering from post-traumatic stress from early childhood trauma, as are most of my patients. The psychiatrist had tried all of the medications that they had available. He had also had electroconvulsive therapy and trans-cranial magnetic stimulation. None of those had been effective. We did our first infusion over 45 minutes. Nothing was noticed immediately, as is usually the case. I checked on him later that evening, and after six hours his suicide ideation completely disappeared. He felt a lightening, like the dread, had been lifted. Colours seemed brighter, music sounded better, he became of aware of things he previously hadn’t noticed. That was his first experience. And luckily he did respond to that first dose, so we knew we were on the right track.
“I was immediately impressed. He was 24 years old. He was my first ketamine experience, and my first 'save'. I couldn’t have been more happy.”
Another of Dr Brooks’ patients is Dennis Hartman. He had suffered from major refractory depressive disorder his entire life, associated with post-traumatic stress disorder which was the result of a childhood of abuse.
"It’s acute misery. Living with my depression feels like pain," he says. "It’s something you can’t show to someone, point to an injury or a wound, but it feels very much like physical pain."
"I was aware I had a problem by the time I was in 7th grade. I had a very traumatic childhood and spent it in a state of intense fear. By the time I reached adolescence I had a pretty good idea that I wasn’t able to do things like other kids were able to do.
"It felt like it was literally a character that I was talking off and hanging in the closet at the end of the day. The character looked happy, and successful, and put together, and confident, but it was being powered by a depressive sufferer who was wracked with anxiety."
Mr Hartman spent decades working through a roster of medical and therapeutic treatments for depression. "I tried every known depressive therapy, everything that doctors commonly prescribe: SSRIs, SNRIs, tricyclics, benzodiazepines. A lot of my energy in life has been spent trying to find a way to get relief from this pain."
"On my worst days, I lost the energy. I didn’t have the ability or the strength to inhabit that character anymore… I just didn’t see any way around it."
In his mid-40s, Hartman decided to end his life. "The way I thought about it in my own mind is, 'It’s the humane, reasonable thing to do, to end my life'. There’s only so much untreatable suffering that one person can be expected to endure, in their lifetime."
He picked a date several months away in order to get his affairs in order and to avoid causing is nephew trauma during finals. While he was waiting for his date, he heard of an experimental trial using ketamine to treat depression and PTSD. He applied and was immediately accepted.
"The day I received my infusion my symptoms were raging. It was relatively bad - the anxiety, the anhedonia (the inability to experience pleasure), the insomnia.
"They turned on the drip and I was in a dreamlike state, like a spectator watching my thoughts unfold in front of me. Within 15 to 20 minutes of the end of the infusion, I was aware that something was different. They started to ask me questions to monitor my mood, and I had trouble pinpointing my symptoms so I could describe them.
"Within a couple of hours of the infusion I had a clear awareness that there was something missing. It didn’t strike me as a wave of massive relief. It didn’t feel like something was added to be, like I had superpowers. I didn’t have euphoria. It was a gradual realisation over a few hours that something was missing. And what was missing was something horrible."
"The biggest changes for me occurred within 24 hours of my first infusion. If you suffer from lifelong depression as I have, and it’s all you’ve ever known, it becomes part of your identity. You just feel that the world is all about pain. And when I got relief from my first infusion, it was like being emancipated."
Since discovering this treatment, Dennis has become an advocate, establishing and running the Ketamine Advocacy Network which aims to spread awareness of the treatment and connect potential patients with doctors who provide it. There are around thirty clinics in the US offering it openly.
In Australia there is far less awareness, with only Aura making it widely available to the public from their Sydney and Melbourne clinics.
Professor Colleen Loo, a clinical psychiatrist from the University of NSW and the Black Dog institute, is working to change that. She has been running ketamine trials at the Wesley Hospital in Sydney and is considered one of the world's leading ketamine researchers.
Professor Loo first began using trialing ketamine in conjunction with electroconvulsive therapy, hoping that its neuroprotective properties would decrease the side effects of ECT. While there appeared to be little change to the ECT effects, the antidepressive properties of ketamine became apparent. "As is often the case with science, we didn’t find what we thought we’d find, but found something else instead".
"At the same time, were reports coming from the US of remarkable antidepressant effects with ketamine. People in one day could go from being severely depressed to being well. And my initial reaction was, 'I don’t believe it'.
"So we started doing that research and I must say I was astounded by the results. We were seeing exactly what people in the US were seeing.
"It is truly a remarkable treatment. We were seeing people who had been depressed for 10 years who hadn’t got well with other treatments, had tried multiple medications, had a lot of psychological counseling. The kind of people as a clinical psychiatrist you think ‘this is going to be a challenge, because if other people haven’t been able to do it in 10 years, I’m not going to be able to do it overnight,’ but we found with ketamine we were literally able to do it overnight.
"One of the amazing things for me to see as a clinician, as we do the research, has been to see people who are really depressed, we give them the treatment ,and as they walk out the door four hours later, you can see it in their face. Their face is brighter, their whole posture is different, their voice is different, and they actually look better."
Ketamine is currently approved by the Therapeutic Goods Administration for use as a general anesthetic and for complex neuropathic pain, but its use as a treatment for depression remains experimental.
"It is a legal drug in Australia, it’s registered by the TGA, but the use for depression is not yet approved so if you use it for that it’s what we call off label use,” said Professor Loo. "You’re using it outside the approved indication."
Professor Loo is currently seeking research funding for a further round of trials in 2016. Her research focuses on three main areas of study; what the best dosage of ketamine is, how best to administer it, and how to make the effects last. It is this last point which appears to be the most crucial.
"People can get well incredibly quickly with ketamine, but you can also fall back very quickly from being completely well to severely depressed," she says. "We don’t know how to make the effects last. Because whether you’re having one dose, or multiple does, once you stop – what then?"
“A lot of the safety evaluations have been around giving a single dose, but you can’t assume that if one dose is safe then 10 or 20 or 30 doses are safe. We do know from looking at reports from people who have used ketamine repeatedly and recreationally, that there are some potentially serious side effects. You can get a thickening or inflammation of the bladder. Who is likely to develop this, and is it related to the number of treatments or the dose of each treatment, and if you do develop this is it going to be an ongoing problem… all of these things need to be sorted out."
"People can get well incredibly quickly with ketamine, but you can also fall back very quickly from being completely well to severely depressed."
Professor Loo does not believe the treatment is yet at the level required for use outside the parameters of a clinical trial. "The issue for me is more the monitoring. One is, 'How are you coming out of the depression, and are you OK?’…My worry about sending people home is we need to keep a close eye to track how people are going clinically. That’s so important.”
“People say to me all the time, 'You’ve got this wonderful thing, why aren’t you offering it in research trials to hundreds of people?' I would love to, if I had the funding to do it.”
Barrett believes that despite the drug’s experimental status, it should be available to the public. “I do respect the opinion of the cautious types who say that it’s premature. We don’t know enough about it to let everyone start prescribing it, we’ve got to proceed with care.
“But it’s safe, and it fills a need, and therefore it can be justified to use off label. And by the way, if you took off-label prescribing out of medicine, doctors would be out of business. Off-label use of medications is much more common and frequent that is commonly realized.
There’s now been over 30 studies in the US, and they’re unanimous that ketamine works in 70 per cent of cases of resistant depression. Well, thirty studies is good enough for me.”
As ketamine has been in wide usage for more than 40 years, its patent has long since expired.
"The fact that ketamine is an older drug and its patent has long expired means that there’s nothing in it for the drug companies," Dr Barrett says. "No drug company is going to pick up the tab of going through the extremely expensive process of running the clinical trials that you need in order for the drug to become registered by the TGA. That’s an extremely expensive process and you’ve got to have a pot of gold at the end to induce a drug company to take it. With ketamine there’s no pot of gold.”
“So it’s up to a small number of doctors who are either crusaders or entrepreneurs or a combination of both, who open ketamine clinics and make it available to people.”
“We’ve got a lot of hard research to be done, but I want to find out with ketamine how best to use it. How long does it work for? Do people come resistant to it? Can you give it for long periods of time? Do people develop a dependence on it? These are the questions that are interesting to me.”
“The US have done a lot more work there, way in advance of us. The number of studies done is now quite large, and so far there hasn’t been any significant negative finding. I think that somehow or other we have allowed this party drug stigma to frighten us too much.”
“Patients who have been suffering for twenty-five years, and have tried every antidepressant in the handbook, receive ketamine and get their old life back… their feeling of gratitude and happiness is overwhelmning. They say, ‘why haven’t we been using this before?’ The Americans are doing it, why haven’t we been doing it? And it does come back to the stigma of being associated with a party drug.”
Since October, Australians have been able to access the treatment outside the boundaries of a clinical trial. Aura Medical has been offering standard course of treatment is twelve injections over a six week period, followed by six injections over a further six weeks. Each treatment costs $150.
The clinic has been wracked with controversy, as former patients have claimed that they were not asked for a referral from a previous general practitioner or psychiatrist, were only assessed very briefly prior to receiving treatment, and were not adequately monitored during the course of the treatment. In addition, one patient alleged that they were not properly informed that the treatment was not yet approved by the Therapeutic Goods Administration (TGA) or the Australian College of Psychiatrists. Their website was pulled offline last week.
Barrett has since severed his connection with Aura Medical. He has stated that he still has complete faith in ketamine as a treatment, but had concerns over the profit motive of the operation.
Professor Loo is optimistic that there is a future for ketamine use for depression. “My hope would be that if within the next three to five years, and the evidence is strong enough, and there are no major safety concerns, then it would move in to being an approved treatment.”
Hartman is aware of the risks involved in taking an experimental drug, but firmly believes that the benefits outweigh them. “There aren’t any patients yet who have been on it for years, because it’s so new. My hope is I’ll be able to go longer and longer between treatments, and that eventually my physical symptoms won’t come back, or that I’ll be so much more resilient and healthy that I won’t mind so much when they come back. I don’t know if that’s how it’s going to play out, or whether I’ll choose to get ketamine therapy for the rest of my life. I don’t know yet.”
“People like me deserve a last ditch backstop.”
* Readers seeking support and information about suicide prevention can contact Lifeline on 13 11 14 or Suicide Call Back Service 1300 659 467 or follow @LifelineAust @OntheLineAus @kidshelp @beyondblue @headspace_aus @ReachOut_AUS on Twitter.