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're done.
At the same time, the 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 the drug within 14 weeks. After six months and several drugs, only half of the patients recovered. Thirty-three percent do not respond to any drug at all. When the pills work, they're slow — a deadly risk, given that people with mood disorders kill themselves more often than anyone else.
Also, the correspondence between brain chemicals (such as serotonin) and depression is relatively weak. A new competing theory, inspired in part by the efficacy of ketamine, posits that psychiatric illness is caused not so much by chemical imbalances as by structural changes in the brain, and that the underlying cause of these changes is psychological stress. "I really believe that stress does to mental illness what cigarettes do to heart disease," says Gerard Sanacora, 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 sea change that will allow a similar approach to mental health. New approaches can 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" in serotonin or similar signaling. One ad for Zoloft, a popular anti-depressant, featured a sad white circle cutely crawling under a gray cloud; a voiceover boasted that depression may be “related to an imbalance of natural chemicals in the brain. Zoloft works to correct this imbalance.”
But there is little evidence of this story. Prozac raises serotonin levels for a few hours, but does not alter 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 depressed people, they don't find a persistent deficit; one 2008 study even found increased levels of serotonin in the brains of depressed people. The drug tianeptine, discovered in the late 80s, lowers serotonin levels, but at the same time 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 fill parts of the brain with glutamate, the brain's signal to "act." Using 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, which release more glutamate, which in turn can trigger electrical bursts in nearby neurons. The brains of depressed people, or at least animal models of depression, show long-term glutamate excess 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 believed 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 regions are shrunken and underactive, including parts of the prefrontal cortex and the hippocampus. The brain changes that cause mood disorders, Sanakora and his colleagues believe, stem in part from chronic stress that overexcites neurons with glutamate.
Ketamine, a glutamate blocker, 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. Ketamine, on the other hand, is a well-known recreational drug that can be abused. Therefore, hallucinogenic drugs, like psychedelics such as psilocybin and ecstasy, are often viewed with suspicion by doctors, patients, and government research funding agencies, 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 had not responded to other drugs. Ketamine also works on bipolar people in their depressed phase without causing mania, as classic antidepressants sometimes do. Most of the depressed people studied responded to ketamine. For patients who are often suicidal, such a quick response can be life-saving.
Many industry leaders see the advent of ketamine and future fast-acting glutamate-based antidepressants as a major step forward for the industry. "In my opinion," Sanacora said recently, "this is the most exciting development in the treatment of mood disorders in the last 50 years."
In the US today, psychiatrists and anesthesiologists offer ketamine at prices ranging from $300 to $1,000 per dose to people who are depressed or have 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 drug application requires multi-phase clinical trials for FDA approval, usually funded by drug companies that 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 getting ketamine approved as an antidepressant, doctors could still prescribe cheap generic versions already available for anesthesia instead of more expensive proprietary 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. So despite their effectiveness, these generic pills don't attract a lot of corporate dollars.
Another exciting prospect for ketamine therapy is that if the drug prevents the symptoms 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 seizure-inducing crisis 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, rather than simply treat, mood disorders has come from 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 trauma: The frightening hallucinations associated with combat may increase soldiers' risk of mental illness.
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 PTSD. Among civilians and military personnel hospitalized with burns, 45 percent end up with post-traumatic stress disorder. But soldiers treated with ketamine on the battlefield were about twice as likely to develop PTSD, even if they suffered more severe burns that required more surgeries and longer hospital stays.
Rebecca Brahman, a neuroscientist and recent postdoctoral fellow at Columbia University, and her supervisor, Christine Denny, tried giving mice ketamine and then exposing them to stressors. The researchers tested several types of stress, including having test mice "bullied" by more aggressive mice for two weeks. After this daily hazing, the mice typically develop the equivalent of PTSD and depression: they freeze in a new location, refuse to socialize with other mice, and don't move during the forced swim test. But the mice "vaccinated" before the bullying felt much better: they did not act depressed afterwards. Brahman and Denny found that protection from a single dose lasted for weeks, even though ketamine only remained in the body for a few hours. Although they haven't tested this yet, it's possible that, like the vaccine, this protection may last much longer. Their research in rodents suggests that ketamine may work even better as a preventative than as an antidepressant.
Over time, Denny says, we could routinely use ketamine to prevent PTSD in combat veterans, rape victims, or survivors of car accidents or mass shootings. Ketamine appears to have the strongest protective effect in mice when given before stressful events, Brahman says. Since we cannot predict most traumatic life events, this would limit the drug's usefulness. But if administered post-injury before psychological damage occurs, as in the case of burned soldiers, ketamine can still be protective. Danny is currently exploring this possibility.
And in some situations, a strong shock can be predicted. "You don't know when an earthquake is going to happen," says Brahman, "but we know when we're going to send UN workers into a disaster-ravaged area." When people know they are entering an acute traumatic situation, she believes, a preventive drug given early can protect their brains from the long-term effects of the stress. Think of earthquake relief workers, firefighters or rescue workers in Syria pulling mutilated people out of the rubble.
The idea that a single injection can prevent mood disorders is a radical departure from current psychiatric thinking. But there is some precedent: 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 to protect against future breakdowns, for example.
Not everyone is convinced that ketamine is a safe option. The long-term safety of ketamine is unknown, Nestler says. No long-term side effects are seen in anesthetized patients who take much higher doses, but who do not receive the standard treatment in which it is administered as an antidepressant.
Крім того, важко похитнути репутацію кетаміну як вуличного наркотику. Але оскільки його доза як антидепресанта набагато нижча, ніж доза, яку приймають для кайфу, багато пацієнтів навіть не помічають цього. Фармацевтичні компанії також змагаються, щоб розробити менш «трипучу» альтернативу. Johnson & Johnson випустив назальний спрей з ескетаміном, версію кетаміну з меншим психоактивним впливом, яка вже схвалена FDA. Компанія Naurex завершила випробування другої фази рапастінелу, ін’єкційного препарату, який частково блокує ті самі рецептори глутамату, що й кетамін, але не є психоделічним.
Ketamine's pioneers emphasize that their prevention research is the start of a hopeful new path, not an immediate cure. Brahman and Denny stress that ketamine may not be the drug that eventually makes it widely used. Like tuberculosis drugs in the 1950s that ushered in the era of antidepressants, it pioneered this new class of psychiatric preventives. "This work shows us that we can intervene in advance and create a kind of self-reinforcing resilience to stress," says Brahman. “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.”
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