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First major depression treatment for decades is a nasal spray NOVA

A few hours ago, the FDA approved a drug called esketamine, the first major new depression treatment that hit the market for decades.

The drug, developed by Janssen Research & Development (a pharmaceutical company by Johnson & Johnson), is administered in the form of a nasal spray as opposed to an oral pill. Esketamine can be designed especially for people suffering from the most extreme forms of treatment-resistant depression, which can affect millions of people living in the United States who are at high risk of suicide because they cannot cope with their disease. The nasal spray will only be administered in approved and certified treatment centers, and will be limited to those who have tried at least two other antidepressants without success. Patients receiving the drug must also be monitored for at least two hours each time they use it.

"This is the first real new mechanism that has been presented in over 50 years," says Dr. Gerard Sanacora, a professor of psychiatry and head of the Yale Depression Research Program.

Unlike antidepressants such as Prozac, which occurred in place in 1

987, esketamine is a glutamatergic agent, that is, it targets glutamate, the most abundant neurotransmitter in our brain and central nervous system. "About 60-80 percent of all brain cells use glutamate as their primary chemical messenger," Sanacora says. Previous treatments have all focused on the monoamine system, which consists of another set of neurotransmitters: dopamine, noradrenaline and serotonin.

In the 1990s, researchers began to demonstrate that the glutamate system was disrupted in patients suffering from depression. They also knew that ketamine, known as "Special K" in illegal batch drug, targets the glutamate system, so the researchers decided to investigate exactly how ketamine works in the brain and whether it can relieve symptoms of depression.

In 2000, Dr. Dennis Charney along with Dr. John Krystal's first study showed that intravenous infusions of ketamine gave fast (within hours) antidepressant effects.

"I don't think anyone predicted a quick start," Sanacora says. It's a big thing, because drugs like Prozac and Zoloft often take weeks or months to get any noticeable effect.

Charney and his colleagues at the National Institutes of Health then replicated the study in more treatment-resistant patients. At the Icahn School of Medicine at Mount Sinai (ISMMS), where Charney is now dean and professor of psychiatry, neuroscience and pharmacology, he and others conducted the first study of the intranasal version of the drug, as well as the first study that demonstrated the neurobiological response could repeated. Since then, research groups around the world have begun to address the potential of the drug. Janssen's derivative product is called esketamine because it is a close cousin of ketamine, blocks a particular glutamate receptor, the NMDA receptor, from absorbing the glutamate it secretes. As a result, linkages between neurons and brain neuroplasticity are restored by the production of more synapses. (19459005) Disclosures: Charney is named as co-financier on patents submitted by ISMMS for the treatment of treatment-resistant depression. ISMMS has a license agreement with Janssen regarding these patents and it receives payments from Janssen under Charney, as an extension, is entitled to some of these payments.)

"When we undergo chronic stress, the neurons actually decrease," says Dr. Scott Russo, Professor of Neuroscience and Head of the Center for Affective Neuroscience at Icahn School of Medicine on Mount Sinai. "It is thought that they underperform. Ketamine rejuvenates these cells" especially in the prefrontal cortex, a brain region responsible for higher cognitive functions such as judgment and decision making.

But Russo notes that blocking the glutamate receptor is not indisputably responsible for the antidepressant effects. While this mechanism is indeed a catalyst, a series of "downstream effects" occur after the receptor is blocked; A single wave or ripple within this cascade of events can actually be what gives patients relief. "I would like to see animal studies to prove that [the blocking of NMDA receptors] is the only mechanism of action," he says. For example, one study showed that the brain's system of opioid receptors may be involved.

In addition, Russo says there is evidence that ketamine can reduce inflammation – a growing substance in neuropsychiatric research – but again it is probably not a primary function of the drug.

Despite these nuances, Russo is enthusiastic about the drug's approval. "I think it's a game switch," he says. "I haven't seen that kind of discovery during my lifetime – I was probably five years old when the last drug came on the market. I hope it starts a chain reaction of new drugs in psychiatric medicine."

Not everyone is growing poetically about the promise of the esketamine. Dr. Erick Turner, a psychiatrist at Oregon Health and Science University, served on the FDA Advisory Committee that evaluated the drug – but he was not present at the review panel earlier this month. He says Johnson & Johnson have violated the necessary number of adequate and well-controlled trials (two) indicating the efficacy of the drug (see second paragraph on page 9 of this FDA Information Document for confirmation of the FDA's exemption for this rule).

"As a former regulator, I worry that this has become too hyped and that it will not live up to expectations," Turner said. He also has concerns about surveillance, distribution and insurance coverage. Yet Turner acknowledges that the new mechanism is exciting. "I would like to see it explored further."

Turner notes that a combination drug called Symbyax, which was released in 2009, proved to have the same size effect. "I guess I haven't seen any evidence that this [esketamine] is better than we already have," he says, pointing to studies in elderly patients who show the effect of ketamine sometimes does not take as fast as a few hours – that it can take up to a few weeks instead.

Nevertheless, this rate due to esketamine compounds is one of its fundamental advantages.

"As a clinician, it's really hard to tell a patient," I know you feel horrible, but I would like you to start taking this drug. You may feel worse for a week or two or three before you start feeling better, but just keep taking it, Sanacora says. "When someone suffers from depression, every day feels like an eternity – and now you say they should wait weeks and possibly months before I can tell if they can even work. So this is a big progress."

Year In 2016, about 16.2 million adults in the United States had at least one major depressive episode. Of these, 37 percent did not receive treatment. A drug such as esketamine, which is at low risk of abuse (although the drug label will list any side effects and warn that there is a risk of abuse) and only has moderate side effects – may be an option for those who really need it.

"This should not be something that everyone hopes for," he says. "But there are clear situations where you need a quick start."

"The approval opens a whole new set of potential treatments," Sanacora says. He praises his colleagues – Charney, Krystal and others – to experiment with ketamine many years ago.

"Serendipity favors the prepared mind," he says. "They played in the right sandbox."

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