When I spoke to Alex M. back in December 2007, the cheerful voice on the other end of the phone hardly met my expectations of a 46-year-old man who had spent the past 14 years in a state of suicidal depression. Alex, who wished to remain anonymous, said he had never been truly happy, and his record of taking eight to 12 antidepressant drugs through the years suggested that his doctors agreed.
Yet at the time of my interview with him, his voice showed no resemblance to the emotionless, monotonous tone of most severely depressed individuals. In fact, his voice was full of feeling, and he sounded excited.
Alex represents a psychopharmacological revolution that shows the potential to transform everything we know about clinical depression. In less than two hours, the man who had previously believed he was “predestined for sadness” emerged from an anesthetically induced stupor to what he describes as “the most profound awakening from the best sleep ever.”
“It was like, ‘OK! Let’s go! Let’s go live life now!’” Alex said.
The extraordinary anesthetic drug behind this metamorphosis is called ketamine, and it’s not new. Used as an animal tranquilizer, as well as a human sedative before major surgeries, ketamine occasionally surfaces as an illegal street drug under the alias “Special K.” Its psychedelic capabilities led to its infiltration of the infamous raves of the ’90s alongside its predecessor, Ecstasy. However, researchers have serendipitously stumbled upon its other “special” ability: its immediate, antidepressant effect on severely depressed people like Alex.
Ketamine vs. today’s antidepressants
Safe and effective antidepressant drugs have emerged relatively recently, with the most popular (e.g., Prozac, Zoloft and Paxil) hitting the market in the late ’80s and early ’90s. These selective serotonin uptake inhibitors, or SSRIs, increase the availability of serotonin in the brain, but relief from intense sadness of depression doesn’t materialize for three to eight weeks. Other forms of antidepressant medications, such as tricyclics and monoamine oxidase inhibitors (MAOIs), fail to take full effect any sooner.
“In those weeks to months, people might lose their jobs, marriages might be affected, they might even commit suicide,” said Dr. Carlos Zarate — chief of the Neurobiology and Treatment of Mood Disorders and Chief of Experimental Therapeutics and Pathophysiology Branch at the National Institute of Mental Health — in a 2007 interview. “We’re aiming higher. The next generation will be able to fix it within hours.”
At the time of the interview, Zarate was leading one of the three major research teams in the United States devoted to studying the latest breakthrough in ketamine use. His study of 20 dangerously depressed people resulted in 50% of the group feeling considerably happier within the first couple of hours of being intravenously injected with ketamine. Seventy-five percent reported a drastic lifting of their depressive symptoms by the next day.
“Most of these people thought they could never feel well again,” Zarate said.
Such was the case for Alex. A third of his life had been spent brooding about his traumatic past, dreading the future and feeling utterly hopeless. He was verbally and physically abused within his family, beaten with sticks and kicked around. Equally devastating was his history of sexual molestation, including at least one incident committed by his fifth-grade teacher. Self-medication evolved as an option for escape when Alex began experimenting with marijuana at the age of 14 and alcohol by the age of 15. Despite his suffering, he never considered the possibility he might be a victim of clinical depression.
“People can rationalize moodiness and rashness as being a teenager,” Alex said. “It’s a hormone thing. Stress. There’s always something.”
Alex lived in a state of denial and despair, spending more than a decade searching for effective treatment and trying various drugs, psychiatrists and therapy.
“You’re always hopeful. You think the medication will get you feeling productive again,” Alex said. “So you go through those three weeks waiting for the change, and then it never happens. Then you start all over again. It really just physically takes a toll on you.”
All Alex’s hopeful attempts failed — until he met Dr. Sanjay Mathew, the leader of another ketamine research group at New York’s Mount Sinai School of Medicine. Dr. Mathew was experimenting with a completely different category of drugs than the antidepressants currently on the market.
The majority of today’s popular mood pills tackle problems associated with serotonin and a group of chemical compounds known as catecholamines. The synthesis and absorption of neurotransmitters dopamine, norepinephrine and epinephrine is increased, and some patients feel relief from depressive symptoms in a matter of weeks.
Ketamine, on the other hand, blocks NMDA receptors. Blocking those receptors increases the activity of another receptor, AMPA, which researchers believe is responsible for the antidepressant effect. Both NMDA and AMPA are receptors for glutamate, a neurotransmitter only recently gaining attention for its potential association with depression.
Sleep deprivation and electroconvulsive therapy (ECT) are the only fast-acting antidepressant therapies used today, and ECT is typically considered a last-resort treatment because of its myriad of cognitive side effects.
“Imagine people coming to the [emergency room] needing to be hospitalized because of their depression,” said Dr. John Krystal, who headed another ketamine research team at the Yale University School of Medicine. “They could be treated without having to be hospitalized. Mothers who can’t take care of their children can be cured quickly. It can change people whose lives are jeopardized from depression.”
Behind the scenes: One subject’s experience
Alex M.’s suicidal symptoms qualified him for Dr. Mathew’s ketamine experiment, and he found himself beginning a difficult treatment in October 2007. Before the ketamine injection, Alex was required to fill out an endless number of questionnaires that forced him to report his emotional history and face any repressed memories he may have had. Self-reports, brain scans and intensive interviews were performed in order to assess Alex’s mood before the infusion. By the time researchers sat Alex down for the moment of truth, his emotions were threatening to overcome him. A minor dosage of ketamine was injected in Alex’s veins, and the questioning from surrounding researchers maximized. As the drug’s sedative side effects kicked in, he dropped to his knees, sobbing on the floor. Alex described it as a breakthrough, a moment of clarity.
“I experienced how profoundly sad these [traumatic events of my past] were, and then I moved past it. It became less of an impediment,” he said. “I realized the source of some long-term mental pain. It was an awareness that allowed me to move forward.”
Researchers followed up with Alex for the next two weeks as the antidepressant effects became more pronounced. Most patients experienced a similar psychological liberation, but Alex exceeded the average duration of antidepressant effects by about a week. His two weeks revealed a hopeful reality: the possibility of happiness.
“When you’re depressed over a long period of time, you truly forget what it feels like to feel good and bright, mood-wise,” he explained. “The ketamine gave me that goal back. It really helped to redefine what I was capable of. Feeling. Living.”
The world was perceived in a whole new way. Alex vividly remembers a moment of eating salad, amazed at how wonderful it tasted. (“And it was just salad!”) His diet switched to healthier foods, and he finally found enough motivation to exercise. The research team continued their intense interrogation sessions, but Alex no longer minded. In fact, he looked forward to them. Instead of feeling forced to dwell on painful memories, his mood proved optimistic, and his pencil would excitedly circle multiple “10’s” on measurements of his mood.
Abuse potential and side effects: The obstacles facing ketamine
Though the study of about 163 patients has generated extremely positive results, ketamine cannot yet be declared a miracle drug. Adverse side effects currently stand in the way of the drug’s use as a first-line antidepressant, and the drug remains somewhat controversial among those who associate it with its abuse, which largely exists because of its psychedelic effects.
“Hallucinations are rare, but they are a possibility,” said Dr. Gerard Sanacora, who worked alongside Krystal at Yale. He added that ketamine includes other possible temporary side effects, such as cognitive and perceptual impairment (imagine having one too many cocktails), a feeling of dissociation and memory impairments.
Alex experienced strong cognitive and perceptual impairment within the first hour, but it was a small price to pay for his subsequent state of hope and increased happiness. Still, these side effects remain possible among other patients, and researchers are currently studying its mechanism of action in the hopes of developing a safer agent that works similarly.
An April 2012 study published online in the journal Biological Psychiatry detailed a recent discovery, by Zarate and colleagues, of biological markers that could help identify which depressed patients will respond to ketamine as an antidepressant. The markers — which involved electrical brain activity and factors detectable through blood, genetic markers and a sleep-specific brain wave — also offer insight into the neurological effects of ketamine that lead to the antidepressant outcome.
“The more precisely we understand how this mechanism works, the more narrowly treatment can be targeted to achieve rapid antidepressant effects and avoid undesirable effects,” Zarate said in an NIH press release.
Hope was enough for Alex. When we talked in 2007, he was married with two children and said his experience with ketamine research produced an obvious change in his family life. The entire household was affected and became noticeably happier with his enhanced mood. Alex said he couldn’t receive ketamine treatments again until they appear on the market, so he was being treated with a similar medication. The experience of the study keeps him satisfied more than anything.
“It sustains me every single day. A cruddy day is not the end of the world. It’s just a cruddy day,” Alex said. “Today is important. Today is my life. Ketamine was a reality check.”