Scientists seek fast-acting antidepressant, from ketamine to laughing gas

Promising new research from Johns Hopkins University this month pinpoints a compound that could treat symptoms of depression within hours — and targets the condition in a whole new way, offering hope to patients who haven’t benefited from traditional drugs.

It’s just the latest in a flood of research into fast-acting antidepressants, as scientists explore everything from laughing gas to magnetic stimulation to the hallucinogenic street drug ketamine. The goal: to give quick relief to patients who now have to wait weeks or months for conventional drugs to kick in — if they even end up working at all.

“Having a more rapid-acting option is a critical need,” said Lisa Monteggia, a neuroscientist at University of Texas Southwestern who does research in the field.

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The research has attracted big-name pharmaceutical companies, including Allergan and Johnson & Johnson, which is conducting Phase III clinical trials on a ketamine drug. More experimental work is going on in labs across the country.

“It’s a reinvigorated field,” Monteggia said.

The new therapies could have a huge market. Antidepressants are the prescription drug most frequently used by people between ages 18 and 44, according to the Centers for Disease Control and Prevention. About 1 in every 10 people in the United States has taken antidepressant medications, and of those individuals, 14 percent have taken them for more than a decade.

“The population of people who need better, more effective treatment is enormous,” said psychiatrist and Yale University neuroscientist Dr. John Krystal.

For decades, depression has been treated with drugs like SSRIs — selective serotonin reuptake inhibitors — which work by changing the balance of the neurotransmitter serotonin in the brain to help brain cells communicate better, boosting a patient’s mood. But it can be a long and expensive process to find the right drug and the right dose for each individual.

The hottest, most hyped prospect for faster treatment involves ketamine. As a prescription drug, ketamine is an anesthetic, often used in veterinary medicine. As an illegal street drug known as “Special K,” it can cause hallucinations and a dream-like trance.

Back in 2006, researchers at the National Institute of Mental Health reported that depressed patients treated with ketamine “showed significant improvement in depression” and that the effects lasted through the following week. But the study was small — just 18 patients.

Since then, research and experimentation has continued, with some psychiatrists administering ketamine off-label to patients who have not responded to other treatments.

“Our experience with ketamine over the years is that it’s well-tolerated,” said psychiatrist and neuroscientist Dr. Dennis Charney, dean of the medical school at Mount Sinai. But not enough is known about how to maintain the drug’s antidepressant effects, perhaps through booster doses. “It’s still a work in progress,” Charney said.

Ketamine also currently has a significant accessibility issue, as it’s most typically delivered through an IV infusion. “That makes it very difficult for the average psychiatrist to administer it in their office,” said Krystal, who is financially invested in the development of the Johnson & Johnson ketamine drug.

Ketamine works by inhibiting the action of NMDA receptors, which allow for messages to pass between the brain and the spinal column. Specifically, it affects glutamate, a chemical that normally regulates the flow of information in that communication channel.

That’s opened a whole new avenue of research.

Another promising class of compounds, known as ampakines, also affect glutamate in the brain. Ampakines affect attention span and alertness, but researchers are currently investigating whether they can also be used for treatment-resistant depression.

In the research from Johns Hopkins, published in Molecular Psychiatry, scientists pinpointed a compound — called CGP3466B — which targets a different network of proteins.

Researchers ran two common behavioral tests on mice to test the drug’s effectiveness. First, they observed how quickly mice gave up trying to escape from a pool of water. Mice treated with the drug spent an extra 30 seconds trying to get out. Scientists also measured how quickly mice braved a new environment to get a piece of food — and those treated with the compound acted twice as fast as those without. The researchers will continue to investigate the mechanisms at play causing that reaction, and from there, hope to test its effects in larger animals and potentially humans.

Other researchers are experimenting with nitrous oxide (commonly called laughing gas), xenon gas, magnets, infrared waves, and deep-brain stimulation as instant treatments for mood disorders like depression and anxiety. Last spring, a panel of experts named fast-acting psychiatric treatments one of the developments most likely to transform patient care in the next decades.

But veterans of the field caution that many of the proposed therapies will likely fizzle.

“The history of development of novel antidepressants,” Krystal said, “is filled with drugs that appeared to be promising in animal models [but] turned out to not be effective.”

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