You always remember the day your life changed. John, an engineer, was at work. 
There was an explosion. That’s all he’ll say about it. It’s all he needs to say. He hasn’t been the same since.

The accident was 10 years ago. He kept working, pulling 14-hour days, trying to bury the horror of what he’d witnessed. But he couldn’t forget. One day he woke up in tears with a splitting headache.

“In the old days, it would have been called a nervous breakdown,” says the slightly built father-of-two. “I just couldn’t face it anymore.”

Diagnosed with post-traumatic stress and a major depressive disorder, what followed were countless visits to the psychologist, rounds of cognitive behavioural therapy, daily doses of antidepressants and even a course of electro-convulsive therapy (ECT). But nothing could lift his depression. That’s why John finds himself in a drab, messy treatment room at Australia’s Wesley Hospital. He’s hoping that today his life might change again.

The 48-year-old sits nervously in a large cream armchair next to a plastic Christmas tree. A psychiatric nurse is dabbing a spot on his abdomen with antiseptic. Then, quickly and without fuss, she clasps a syringe and injects his pale belly fat with a clear solution. It could be a placebo. Or, John hopes, it could be something most people might associate with strobe-lit dance parties. It could be ketamine.

A powerful anaesthetic used on humans and animals, on the street the drug nicknamed Special K is renowned for inducing vivid 
hallucinations and out-of-body feelings that neuroscientists refer to as dissociative 
dysphoria. You might call it “tripping”.

But what if it could do far more than that? In this trial, researchers aim to prove that ketamine can haul the most deeply troubled minds out of clinical depression, freeing 
millions of people like John from the grey 
fog that clouds their existence and takes 
away any possibility of enjoyment in life.

If they’re right, it could have implications not only for those mired in the depths of 
despair, but for all of us who struggle to ride life’s peaks and troughs. Why? Because it raises the possibility that after years spent focusing on the role that neurotransmitters like serotonin and noradrenaline play in depression, 
scientists may have identified a more direct lever for mediating the illness.

If that’s the case, a better understanding of how the brain works could open up new pathways for treatment and increase the potential for you to protect yourself. Pretty special, huh?

Don’t call it a comeback. Just how did a drug used by human and animal doctors to sedate their patients, and by clubbers to disappear into psychedelic “K-holes”, become one of the most exciting developments in the treatment of mental illness? One that researchers 
in the journal Science have hailed as “the biggest breakthrough in depression research in 
a half century”.

The first pointer that ketamine might be able to mend minds, as well as morph them, was its use treating chronic pain. Suddenly released from perpetual agony, patients taking the drug were also cheerier than they’d been in years. Later, there were anecdotal reports of the drug being successfully used on suicidal patients in US emergency departments.

A small number of clinical trials have 
followed, including one conducted at the 
Connecticut Mental Health Centre that found 70% of depressed patients who failed to 
respond to years of treatment on traditional antidepressants improved within hours of receiving a single dose of ketamine.

Results like these sparked the interest of Dr Colleen Loo, a professor of psychiatry at the University of New South Wales and the study leader of John’s trial. A friendly, fast-talking clinician and researcher with a background in deep-end-of-the-pool physical treatments for depression, such as transcranial magnetic stimulation and ECT, Loo was intrigued by the strength and speed of the drug’s response.

“I was thinking, ‘My goodness, for the first time, here’s a medication that’s in the ballpark of effectiveness of ECT,’” she says, as we chat in her office at the Black Dog Institute in Sydney. “This is unheard of.”

Loo’s trial, the first in the world to be 
placebo controlled, began at the start of 2012 and has treated nine patients. Results have been impressive. Two-thirds of the group responded within three days of a single treatment. Changes in mood have often been 
noticeable within hours, but peak improvement has usually been seen within one to two days, with the effects lasting from three days up to a week. It’s a remarkable result for a single dose of a drug, reckons Loo.

“When it works, the patients just think it’s amazing,” she says. “A lot of them say they haven’t felt this well for five or 10 years.”

There are probably days when you don’t want to get out of bed. It’s a figure of speech, of course. Only for some unfortunate guys out there, it’s not.

Take Nathan, a 38-year-old spray painter, who’s also undertaking the trial. Ever since his father died in 1990, his mind has been held hostage by thoughts of death and mortality.

When things get really bad, he might only shower every few days. The rest of the time he’s simply trying to sleep his way through a nightmare.

“I didn’t think life could get that bad,” he says. “It was too painful to be awake. It was easier just to play dead.” What was he hiding from? “I didn’t feel like I had a soul anymore, 
I was that empty,” he says. “I looked at my wife and kids and felt nothing. Complete emptiness.”

Clearly, what Nathan is experiencing is more than a case of the blues. The problem with depression is that it’s a catch-all term that can describe a variety of mood states. “When we talk about depression, we’re talking about 10 different things,” says Loo. “Some people become depressed due to life circumstances, some due to excessive vulnerabilities.”

Those who possess the resilience and self-esteem to cope with setbacks and change their circumstances can often bounce back quickly. Others, though, aren’t as equipped to deal with life’s slings and arrows. A serious disappointment, like losing a job or a messy divorce, plunges them into blackness. Ketamine is 
targeted squarely at the latter. People, like John and Nathan, who have tried everything else and seen no relief.

In the treatment room, John is trying to read an iPad without much success. “Waste of time,” he mutters. It’s about an hour after he was injected and things are getting a little fuzzy. “It’s like if you’d drank a six-pack of beer,” he says, looking around the room. “Your eyes are a little bit behind your brain.”

It could, of course, be the placebo midazolam, a Valium-like substance, that’s causing these symptoms. Of the six treatments John will receive over a six-week period, five will be ascending doses of ketamine and one will be the placebo.

The ketamine dose varies from 0.1 to 0.5 milligrams per kilo of body weight – around one-tenth to one-fifth of an anaesthetic dose, according to lead specialist anaesthetist Dr John Leyden. Recreational doses are generally above 0.5mg, he says. “That’s where you get that stupor and the disassociation where they’re basically tripping off their heads.”

Recreational users also get a rush. Taken intravenously or nasally, your brain’s neurons and receptors are deluged like a Joburg summer cloudburst. One of the reasons John was injected into the subcutaneous fat in his stomach is to slow the absorption rate. Previous trial patients who were injected intravenously had complained of excessive “side effects”.

A slower absorption method produces a more controlled release, reckons Leyden. The hope is that along with taking the edge off the rush, the antidepressive effects might be prolonged.

Until relatively recently, most depression research focused on the neurotransmitters serotonin and noradrenaline. Selective serotonin reuptake inhibitors (SSRIs) like Prozac boost serotonin within hours, but, curiously, significant antidepressant effects are not seen for up to four weeks.

Why the delay in the response? Could serotonin and the so-called “chemical imbalance theory” of depression be a red herring? It turns out ketamine, specifically the neurological pathway it follows, may provide some answers.

You may have heard a bit about neuroplasticity lately. Hailed as one of the most exciting developments in neuroscience, it revolves around the rather thrilling idea that your brain, rather than being a static mass once you reach adulthood, is actually a flickering circuit board, growing new neurons and sprouting fresh synapses throughout your life. “It’s not like you grow up and that’s it,” confirms Loo. “Your brain is very plastic. It’s changing and adapting all the time.”

The flipside of neuroplasticity is that as well as the potential for growth, your brain cells can also shrink and die, something researchers believe occurs in response to the release of corticosteroids triggered by chronic stress and psychological trauma.

A review published in the Archives of 
General Psychiatry found the brain’s hippocampal volume is reduced by approximately 10 to 15% in people with serious depression. The result is a sharp deterioration in mood and cognitive performance as cells wither like 
heat-struck grapes on a vine. “That’s why 
people get stuck in depression,” says Loo. “They say, ‘I can’t think clearly, I can’t focus, my brain doesn’t work.’”

The primary reason for the shrinkage is a decrease in a substance called brain-derived neurotrophic factor. Often referred to as brain fertiliser, BDNF is a 
protein that promotes regrowth and repair of neurons, says Professor Peter Schofield, executive director of Neuroscience Research Australia. “It can even cause neurogenesis, the birth of new neurons,” he says.

The exciting thing about ketamine is that 
by acting directly on nerve cells’ glutamate 
system, rather than serotonin, it blocks the action of the N-methyl-D-aspartate (NMDA) receptor, in turn leading to a rapid increase in levels of BDNF. This allows your brain cells to regrow into the normal range, reckons Loo. “We think that’s why the effects seen on ketamine are so dramatically different,” she says. “It’s utilising the brain’s plasticity.”

SSRIs also boost BDNF, but, significantly, peak levels aren’t reached until around the four-week mark. The final end point, the 
regrowth of neurons, is the same, says Loo, 
but ketamine gets there quicker.

The findings give rise to the hope that ketamine can provide a blueprint for pharmaceutical companies to formulate drugs that use the glutamate pathway to directly target BDNF. “If this is shown to be effective, it will promote a billion-dollar industry in new antidepressants,” predicts Leyden.

Another option is that ketamine itself could be used to elevate mood in depressed patients in that critical period before traditional antidepressants take effect. “From a public health perspective, that’s really useful in terms of morbidity, suicide risk and treatment costs,” says Loo. “The applications are tremendous.” But we are about 10 years away from that, says Cape Town-based psychologist Rafiq Lockhat. And, adds Lockhat, even if it were to be 
approved, it wouldn’t be in its current form because of the hallucinations it causes.

There is something else that boosts BDNF
that anyone can access, any time. You probably don’t need a neuroscientist to tell you what it is. Numerous rodent studies have found increased production of the protein in the brain after exercise, as have plasma studies in humans. A study on male track cyclists at the University of Lille Nord de France, for example, found a significant increase in their peripheral BDNF levels after track sessions.

“Exercise has the same effect of increasing your BDNF levels as ketamine, but it’s milder,” says Loo.

That’s good news, because a healthy brain is a very finely balanced super-computer. Simply flooding it with BDNF could easily upset that balance, warns Schofield. But the incremental top-up provided by daily exercise is like refilling your tank at the petrol station. It’s 
practically a necessity.

“If you exercised 20 hours a day, maybe it would be bad for you, but in one or two hours it would be hard to overdrive the brain,” says Loo.

Exercise as a treatment for mild depression is nothing new. But the BDNF pathway could go some way to explaining why, in some cases, it’s a legitimate alternative to medication.

Just how effective it can be was illustrated by a study at Duke University that followed three groups of depressed patients. The first group exercised, another took antidepressants and a third did both. After four months, between 60 and 70% of patients in all three groups were no longer depressed. Significantly, although those taking medication responded quicker, the effects of exercise lasted longer.

Loo says she’s had patients who’ve eased mild forms of depression with exercise – for them it’s like a mild antidepressant.

You can’t go into a clinical trial expecting miracles. As exciting as ketamine’s potential is, it’s fanciful to think that an illness as elusive, mysterious and multifaceted as depression will ever be cured by any one treatment. In every trial conducted so far, a proportion of the participants haven’t shown an improvement. And that’s what it is, a clinical trial. Psychiatrist Dr Bavanisha Vythilingum warns that people who use ketamine without medical supervision risk serious side effects, psychosis or even death.

Additionally, last year, a study at Yale showed genetic variability in the expression of the BDNF gene could affect patient response. In a separate study at the US National Institutes of Mental Health, ketamine’s antidepressant effects were found to be strongest in those born with two copies of a protective version of the gene – around 60% of the population.

It appears John may have been one for whom ketamine isn’t effective, as he fails to complete the six treatments. For Nathan, though, the results have been positive.

“There’s been a massive improvement,” he says after his final treatment. “I felt like I could breathe again. Things seemed to slip over me. 
I didn’t get hooked into my mind so much.”

In Nathan’s case, the antidepressant effects lasted for around four or five days after each dose. “It’s not perfect, but it’s the best result I’ve had,” he says. He’s now awaiting approval for a maintenance phase of the trial.

In the longer term, he now knows there’s something out there that can assist him. That’s significant for a few reasons. It means his 
mental demons can be beaten, that a broken mind can be mended. But most importantly, the drug has given him something none of us would ever want taken away: hope.

For more information on the ketamine trial, visit blackdoginstitute.org.au.

By Ben Jhoty