A first-of-its-kind treatment for depression got a big nod on Tuesday from a group of scientists convened by the US Food and Drug Administration. Experts concluded that the drug, called esketamine and inspired by ketamine, is safe and effective and said its benefits outweighed its risks. Their input will play a key role in the FDA's final approval decision, expected in March. If given the official green light, the drug would be the first novel therapeutic for depression in 35 years. A drug inspired by ketamine, which has been called "the most important discovery in half a century," is on the cusp of becoming the first new kind of depression medication in 35 years. Called esketamine and developed by Johnson & Johnson, the drug is a nasal spray designed to treat severe forms of depression that don't respond to other medications. It's the chemical mirror image of ketamine and thought to have slightly fewer side effects than the original compound. On Tuesday, a panel of experts convened by the Food and Drug Administration voted 14-2 in favor of the drug's effectiveness and 15-2 in favor of its safety. Their recommendation will play a key role in the FDA's approval decision, expected in March. Additionally, they voted 14-2 that the drug's benefits outweighed its risks. "I think there's substantial evidence that this could be a game-changer," Steven Meisel, a system director of medication safety with Fairview Health Services who was one of the panel's 17 voting members, said on Tuesday. If the FDA approves the drug, it would be the first federally approved depression drug in nearly four decades to work differently than depression medications on the market. That's a significant milestone. Depression is the world's leading cause of poor health and disability, and as many as one in three patients don't get relief from existing antidepressants. Analysts are hopeful that Johnson & Johnson's new drug could help. "Ultimately, we think [esketamine's] risk-benefit profile favors approval, especially in a disease paradigm where little options are available," Carter Gould, the executive director of biotech equity research at UBS, wrote in a note circulated last week. The emerging science on ketamine A growing list of academic medical centers, including Columbia University, offer ketamine to patients with severe depression. Columbia Doctors Whether it's Abilify or Zoloft, almost all antidepressants work by plugging up the places where our brain takes up serotonin, a chemical messenger that plays a key role in our mood. Ketamine appears to engage a different part of the brain than traditional antidepressants, which is part of the reason it's been called "the most important discovery in half a century" for mental illness. The drug's apparent rapid-fire effects may be especially useful for staunching suicidal thinking in people who are considering taking their own lives, experts say. Ketamine also has long been used to prevent pain, which suggests to clinicians that it's relatively safe. "There is nothing approved that gets patients better this fast," Walter S. Dunn, a psychiatrist and assistant clinical professor at the University of California Los Angeles who was also one of the panel's voting members, said on Tuesday. But right now, ketamine is neither cheap nor quick to administer. Because it's given through an IV drip, the process can take 45 minutes to two hours. Each session costs $500 to $750 and is not covered by insurance, because ketamine is approved in the US only for use as an anesthetic. People given ketamine for depression are typically advised to get eight to 12 sessions, bringing the total cost to as much as $9,000. Ketamine and esketamine also have some negative side effects. The most troublesome, according to analysts and scientists, is the drugs' tendency to produce what's known as dissociative — or "out of body" — experiences. Experts worry that some patients could react negatively to the experience and then avoid the drug, or react positively and want to repeatedly use it, potentially leading to a drug-use disorder. Experts on the FDA panel said no misuse or abuse was seen in Johnson & Johnson's clinical trials, however, adding that they considered the risk of abuse among adults to be low. Read more: A 'party drug' with potential to be the next blockbuster antidepressant is edging closer to the mainstream, but it could set you back $9,000 Johnson & Johnson's nasal spray for depression Johnson & Johnson's formulation of esketamine is designed to be taken as a nasal spray alongside a traditional antidepressant, reducing the time required to administer the treatment and potentially making it less expensive. (The company has not said how much the drug could cost.) The company's clinical-trial data suggests that the drug is fairly safe and well tolerated but still has some negative side effects. More than a third of patients in two of Johnson & Johnson's last-phase clinical trials reported dissociation. To address that, researchers say, the drug should be given in the presence of a clinician who can monitor the person for at least two hours after treatment. Roughly a third of patients in the trials reported dizziness, sedation, or nausea. Also, because the studies focused on people with severe forms of depression that don't respond to other medications, suicide was a known risk among the participants. In Johnson & Johnson's trials, at least three patients died by suicide. On Tuesday, experts said these deaths were not likely a direct result of esketamine — if anything, they could have occurred because it didn't work well enough, said Qi Chen, an FDA safety reviewer on the panel. Julie Zito, a pharmacy professor at the University of Maryland who was one of two people who voted against esketamine's effectiveness, said she didn't see enough evidence of substantial improvement in mood among the clinical-trial participants. Other researchers on the FDA panel said the drug still appeared to be more convenient than available antidepressants and the IV version of esketamine because the nasal spray doesn't require an IV and could be given as frequently as once a week. Esketamine also appeared to work better than a placebo in people with severe forms of depression over a month. However, the latest clinical trial — one of five studies presented to the FDA — was not able to show that the drug was statistically superior to a placebo. That's a key finding that other trials appeared to support. For a study published last May, Johnson & Johnson's neuroscience partner, Janssen Research, had nearly 240 adults with severe depression take a traditional antidepressant plus a nasal spray for a month. Half got a spray with Johnson & Johnson's drug, while the other half got a placebo spray. Those results were promising: The people who got the esketamine spray saw significantly better improvements in their depressive symptoms than those who got the placebo. The month before, researchers did a small, daylong version of the study and came away with similar results. But the latest study, of nearly 350 adults, did not show numbers statistically significant enough to bolster the other findings. Nevertheless, most of the experts on the FDA-assembled committee said they considered the drug an effective treatment for severe depression. Some said the latest study still suggested positive results even though the findings didn't reach statistical significance. "I was persuaded not only by the two positive trials but even by the partial evidence in the third trial that was at least pointing in the same direction," Wilson Compton, the deputy director of the National Institute on Drug Abuse with the National Institutes of Health, said on Tuesday.<doc-sep>In a move that may clear the way for the first new treatment in years for depression, an expert panel recommended on Tuesday that federal regulators approve a nasal spray that delivers the active ingredients of ketamine, a popular club drug in the 1980s and 1990s. The new drug, called Esketamine and developed by Johnson & Johnson, is aimed at people with severe depression, particularly those with suicidal thinking. The panel, with 17 voting members, including psychiatrists and consumer representatives, was nearly unanimous in deciding that the drug’s benefits outweighed its risks. The Food and Drug Administration typically follows the recommendations of its expert panels. In recent years, scores of clinics have opened around the country, offering to administer intravenous ketamine for depression, on a schedule similar to that of electroshock therapy: as a series of treatments, over a period of days or weeks, and sometimes including follow-up or “booster” visits months later. These treatments, at an average cost of $3,000, are officially “off-label,” and usually are not covered by insurance. Their effectiveness is not well studied, although people who have received the course of treatment have reported rapid, if not always lasting, relief. If approved, Esketamine would be covered by most insurers. [Like the Science Times page on Facebook. | Sign up for the Science Times newsletter.]<doc-sep>An experimental nasal spray, which has a compound similar to the "club drug" ketamine, has been recommended as a new depression treatment by an advisory panel to the Food and Drug Administration Tuesday. The influential panel voted 14-2 in favor of Johnson & Johnson's drug esketamine, a treatment developed to treat major depression in patients who have not benefited from at least two different therapies. The panel said the benefits of the nasal spray outweighed the risks. Side effects include dizziness, nausea and an unpleasant feeling of dissociation, according to the company. One member in the panel abstained from voting. Esketamine is a variation of the anesthetic ketamine, which is also abused as a recreational party drug with the street name Special K. Intravenous infusions of ketamine have been shown to help people with severe depression who experience suicidal thoughts, but the researchers expect that the nasal spray will take effect more quickly and be easier to use. "I think esketamine has the potential to be a game-changer in the treatment of depression ... I use the term potential because the issues of cost and patient accessibility need to be addressed," said Walter Dunn, a panel member who voted in favor of the approval. The nasal spray acts quickly, showing benefits after four hours. The hope is that the spray can help the 30 percent to 40 percent of patients with major depression who don't respond to antidepressants, most of which take at least four weeks to take effect. Currently, Eli Lilly's Symbyax is the only FDA-approved drug for treatment-resistant depression. Major depressive disorder affects over 300 million people globally, and the rate of attempted suicides in people with this condition is about 20-fold higher than that of the general population, according to the company. However, depression is a tricky area of development. Patients in clinical trials often show a big placebo response, masking the efficacy of the drug being tested. The FDA, although not mandated to follow the panel's recommendation, is expected to announce its decision on esketamine by March 4.<doc-sep>
Photo : Teresa Crawford ( AP ) One of the largest hurdles to ketamine becoming a mainstream depression treatment may have just been cleared. On Tuesday, an independent expert panel convened by the Food and Drug Administration discussed whether a nasal spray version of the drug developed by Johnson & Johnson should be approved by the FDA. In a majority vote, they agreed that the drug’s benefits outweighed its risks in treating cases of depression that haven’t responded to other treatments, though not without some conditions. The vote all but signals the drug’s eventual approval, since the FDA rarely strays from these decisions. Ketamine has had a complicated history. Originally and still used as a sedative for people and animals, it’s also a common party drug, since it can cause a euphoric if disorienting high. For years now, though, doctors have been experimenting with using small doses of ketamine as a treatment for depression. What’s made ketamine so enticing as an antidepressant is that its effects in boosting mood seem to happen within hours or even minutes, while other antidepressants can take weeks to work. That rapid action is especially important for people in middle of an immediate crisis who are struggling with suicidal ideation. Currently, though, depression is an off-label use for ketamine. It’s also usually administered via an IV in specialized clinics. Thus, it has been difficult for people to gain access to the drug. The small-scale nature of ketamine treatment has also made it hard to prove that the drug really can be effective for depression. Johnson & Johnson’s version of the drug, if it wins FDA approval, would seemingly address these issues. Aside from being more convenient as a nasal spray, J&J’s version is based on the chemically similar esketamine. Esketamine, Johnson & Johnson hoped, would cause fewer side-effects like sedation or dissociation while still providing a similar antidepressant effect. The FDA also had its hopes pinned on the drug, granting it a Breakthrough Therapy designation, a process that speeds up the review of a potential treatment for a serious or life-threatening condition. It wasn’t necessarily a given that J&J’s drug would be recommended for approval, though. Out of the five Phase III clinical trials (the gold standard of evidence) submitted, only two trials showed that esketamine performed better than a placebo. One of these trials involved adults younger than 65 who were given flexible doses of the drug; the other was a randomized withdrawal trial, where volunteers are randomly selected to go off the drug or continue treatment (in all the trials, the patients were taking at least one other antidepressant). Most antidepressants approved by the FDA, the panel noted, had evidence from at least two or more Phase III trials, not including a randomized withdrawal trial. Ultimately, however, the 17-member panel overwhelmingly voted for approval, with 14 voting yes, two no, and one abstaining. In explaining his rationale, panel member Walter Dunn, a professor of psychiatry at the University of California, Los Angeles and psychiatrist at the VA, went as far to call the drug a “game-changer” for depression treatment. One major factor that influenced many of the “yes” votes was the FDA’s proposal for how it would approve the drug, if it did so . In the trials, patients were more likely to experience side-effects within two hours of a dose. So the FDA proposed that it would likely approve the drug to be taken only in certain health care settings, where patients could be supervised for two hours. The supervised doses would be part of a larger “Risk Evaluation and Mitigation Strategy,” or REMS, program for the drug. The dosage of ketamine given for depression is typically much lower than what people use to get high recreationally. But doctors have still worried about the risk of abuse, pointing to reports of patients becoming dependent on the drug. The restrictions on how esketamine will be taken, the FDA said, would help prevent misuse. As currently proposed, esketamine would be given twice a week at a clinic for the first four weeks alongside another new oral antidepressant, then weekly for the next four. Afterward, patients can stay on a weekly schedule, or switch to every other week, for as long as needed—but they would always receive their doses under supervision. Panel members who voted yes and no stressed the need for more research on the drug’s effects, though, even if it wins approval.