Depression is the most common mental illness in the United States, affecting 30 percent of Americans at some point in their lives. But despite half a century of research, ubiquitous advertising, and blockbuster sales, antidepressants just aren't very effective. They treat depression as if it were caused by a chemical imbalance: add more of one key ingredient or deepen another, and you'll solve the problem.
At the same time, treatment can be extremely ineffective. According to the 2006 STAR*D study, the largest clinical trial of antidepressants, less than a third of depressed patients respond to a drug within 14 weeks. After six months and several medications, only half of the patients had recovered. Thirty-three percent do not respond to any drug at all. When the pills do work, they are slow - a deadly risk given that people with mood disorders kill themselves more often than anyone else.
Also, the correlation between brain chemicals (e.g., serotonin) and depression is relatively weak. The new competition theory, partly inspired by the efficacy of ketamine, argues that psychiatric illness is caused not so much by chemical imbalances as by structural changes in the brain, and that psychological stress is the main cause of these changes. "I really believe that stress has the effect on mental illness that cigarettes have on heart disease," says Gerard Sanakora, a professor of psychiatry who is leading the ketamine trial at Yale University.
If Sanakora and like-minded researchers are right, we may be on the verge of a dramatic change that will allow a similar approach to mental health. New approaches could prevent mental illness before it occurs by providing a vaccination for the mind.
Pharmaceutical companies often say that a mood disorder is caused by a "chemical imbalance" of serotonin or a similar signal. One advertisement for Zoloft, a popular antidepressant, depicted a sad white circle crawling cute under a gray cloud; the voiceover boasted that depression can be "linked to an imbalance of natural chemicals in the brain. Zoloft works to correct this imbalance."
But there is little evidence for this story. Prozac raises serotonin levels for a few hours, but doesn't change mood for weeks. When scientists deplete serotonin in healthy people, it doesn't upset them. And when doctors measure serotonin levels in the cerebrospinal fluid of people with depression, they don't find a permanent deficit; one 2008 study even found increased levels of serotonin in the brains of depressed people. The drug tianeptine, discovered in the late 80s, reduces serotonin levels but also relieves depression. Studies have shown that people in love have lower serotonin levels, not higher.
Meanwhile, since serotonin cannot explain depression, a more likely candidate emerges.
The most important effect of stress hormones is to flood parts of the brain with glutamate, the brain's signal to "act." Used by 80% of the neurons in the cerebral cortex, this key neurotransmitter controls mental processes from memory to mood. Glutamate causes neurons to generate sudden bursts of electricity that release more glutamate, which in turn can cause electrical spikes in nearby neurons. The brains of depressed people, or at least animal models of depression, show a long-term excess of glutamate in key parts of the brain.
This excess glutamate causes the neuron to fire faster than it should and triggers a cascade of signals inside the cell, damaging its structure. This harmful process, called excitotoxicity, is thought to be associated with bipolar disorder, depression, epilepsy, and neurodegenerative diseases such as Alzheimer's, Huntington's, and Parkinson's. In the depressed brain, many areas are shriveled and underactive, including part of the prefrontal cortex and hippocampus. The brain changes that cause mood disorders, Sanakora and his colleagues believe, come in part from chronic stress that overstimulates neurons with glutamate.
Ketamine, which blocks the action of glutamate, works faster than any other drug and helps up to 65% of patients who do not respond to existing treatment.
Ketamine has an amazing history. Since 1962, it has been the primary anesthetic for adults and children in emergency departments because it relieves pain, dulls consciousness, and rarely causes breathing or heart problems. On the other hand, ketamine is a well-known recreational drug that can be abused. Therefore, doctors, patients, and government agencies that fund research are often suspicious of drugs that cause hallucinations, as well as psychedelics such as psilocybin and ecstasy, despite their potential to treat depression or anxiety.
But, since 1999, many studies have replicated the positive results of ketamine therapy, often in patients who did not respond to other drugs. Ketamine also works on bipolar people in the depression phase without causing mania, as classical antidepressants sometimes do. Most of the people with depression studied responded to ketamine. For patients who are often suicidal, this quick response can save lives.
Many leaders in the industry see the advent of ketamine and future fast-acting glutamate-based antidepressants as a big step forward for the industry. "In my opinion," Sanakora recently said, "this is the most exciting development in mood disorder treatment in the last 50 years.
Today in the United States, psychiatrists and anesthesiologists offer ketamine at a cost of $300 to $1,000 per dose to people who are depressed or in chronic pain. Insurance usually does not cover the cost of the infusion because, although ketamine is FDA-approved as an anesthetic, it has not been approved as an antidepressant. Each new use of the drug requires multi-phase clinical trials for FDA approval, which are usually funded by pharmaceutical companies, which have little incentive to invest in drugs they cannot monetize. Ketamine received its original patent in 1966, and it has long since expired. So, even if pharmaceutical companies went through the expensive process of approving ketamine as an antidepressant, doctors could still prescribe the cheap generic versions already available for anesthesia instead of the more expensive patented versions designed to treat depression. This is an old story. Lithium carbonate, which also acts on glutamate receptors, is still one of the most reliable drugs for treating bipolar disorder. But lithium, which is an element, cannot be patented. Thus, despite their effectiveness, these generic pills don't attract many corporate dollars.
Another exciting prospect of ketamine therapy is that if the drug prevents the manifestations of a mood disorder, it may prevent harmful anatomical changes. Just as a vaccine causes the body to arm itself against a particular virus, a drug like ketamine administered before a crisis that causes a breakdown can protect the brain from the effects of stress. Like a vaccine, the drug may only need to be administered once for long-term resistance.
The first evidence that ketamine can prevent mood disorders, not just treat them, came on the battlefield. American soldiers wounded in Iraq were treated with various anesthetics, including ketamine. Because ketamine can cause hallucinations, surgeons are concerned that it could worsen the injury: the frightening hallucinations associated with combat can increase the risk of mental illness in soldiers.
But they found the opposite. Of the 25,000 service members wounded in Iraq between 2002 and 2007, the data showed that veterans treated with ketamine for burns had lower rates of post-traumatic stress disorder. Among civilians and soldiers hospitalized for burns, 45 percent end up with post-traumatic stress disorder. But soldiers who were treated with ketamine on the battlefield were about half as likely to develop PTSD, even if they had more serious burns that required more surgeries and longer hospital stays.
Rebecca Brachman, a neuroscientist and recent doctoral student at Columbia University, and her advisor Christine Denny tried giving ketamine to mice and then subjecting them to stressors. The researchers tested several types of stress, including when the experimental mice were "hazed" by more aggressive mice for two weeks. After this daily hazing, the mice usually develop the equivalent of post-traumatic stress disorder and depression: they freeze in the new location, refuse to socialize with other mice, and do not move during a forced swim test. But the mice "vaccinated" before the abuse felt much better: they did not act depressed afterwards. Brahman and Denney found that the protection from a single dose lasted for weeks, even though the ketamine remained in the body for only a few hours. Although they have not yet tested this, it is possible that, like a vaccine, this protection could last much longer. Their rodent studies suggest that ketamine may work even better as a preventative than as an antidepressant.
Denney says that over time, we may be able to use ketamine regularly to prevent post-traumatic stress disorder in combat veterans, rape victims, or survivors of car accidents or mass shootings. Ketamine seems to have the strongest protective effect in mice when given before stressful events, says Brahman. Since we cannot predict most traumatic life events, this would limit the drug's usefulness. But if it is administered after the trauma before psychological damage occurs, as in the case of burned soldiers, ketamine may still be protective. Danny is currently exploring this possibility.
And in some situations, a severe shock can be predicted. "You don't know when an earthquake is going to hit," says Brahman, "but we know when we're going to send UN workers into a disaster area. When people know they're going into an acute traumatic situation, she says, a preventative drug administered in advance can protect their brains from the long-term effects of stress. Think of earthquake relief workers, firefighters, or rescuers in Syria pulling injured people from the rubble.
The idea that a single injection can prevent mood disorders is a radical departure from current psychiatric thinking. But there are some precedents: talk therapy and mindfulness meditation have long focused on building resilience to stress. Patients with bipolar disorder take "neuroprotective" drugs such as lithium not to treat current symptoms, but as protection against future breakdowns, for example.
Not everyone is convinced that ketamine is a safe option. The long-term safety of ketamine is unknown, says Nestler. No long-term side effects have been observed in anesthetized patients who take much higher doses, but they have not received the standard treatment with which it is administered as an antidepressant.
In addition, it is difficult to shake ketamine's reputation as a street drug. But since its dose as an antidepressant is much lower than the dose taken to get high, many patients don't even notice it. Pharmaceutical companies are also competing to develop a less "trippy" alternative. Johnson & Johnson has released esketamine nasal spray, a version of ketamine with less psychoactive effects that is already approved by the FDA. Naurex has completed Phase II trials of rapastinel, an injectable drug that partially blocks the same glutamate receptors as ketamine but is not psychedelic.
The ketamine pioneers emphasize that their prevention research is the beginning of a new path that offers hope rather than an immediate cure. Brahman and Denney emphasize that ketamine may not be the drug that will eventually make it into widespread use. Much like the anti-tuberculosis drugs in the 1950s that ushered in the era of antidepressants, it is the first to pave the way for this new class of psychiatric preventative medications. "This work shows us that we can intervene in advance and create some kind of self-reinforcing resilience to stress," says Brachman. "We didn't know that before; that's what's important. Everything else - whether we should use it, how we should use it - that all comes later."
Based on the materials of Nautil.us
