Esketamine: Miracle Cure or New Epidemic in the Making?

Esketamine: Miracle Cure or New Epidemic in the Making?

written by: Dr. Jodie Skillicorn
by: Dr. Jodie Skillicorn
Jama psychiatry twitter photo esketamine Jama psychiatry twitter photo esketamine

This month the media announced with great fanfare the first "new" antidepressant drug in 60 years, which promises alleviation of depression in as little as two hours. Good-bye Prozac, Hello esketamine. Sound too good to be true? You may be right. Exactly what is this miraculous, novel treatment for depression? Well, first, it's not really so new or novel. It's actually an old drug—redesigned and repurposed. Ketamine was originally developed in 1962 to be used as a surgical anesthetic, created to replace PCP (phencyclidine), also known on the street as Angel Dust, Wack, PeaCePill, and Rocket Fuel. PCP—initially embraced by the medical establishment—was later discontinued due to the risks of postoperative psychosis, anxiety, depression, and later, an escalating epidemic of abuse. Ketamine, a structurally similar compound, was designed to be less potent, and with a shorter duration of action to make it safer for surgical use. Like PCP, ketamine is an addictive dissociative hallucinogen that is no longer used routinely in humans because it, too, was found to have adverse effects. Ketamine, however, continues to be routinely used as a surgical anesthetic for animals. In the 1990s, ketamine, like PCP, became a popular club drug known by catchy names like Special K, Cat Valium, Super Acid, Jet, or simply "K." It was known for its hallucinogenic out-of-body experiences called "K-Holes." It was also used by sexual predators, as its odorless and colorless properties allow it to be easily mixed into drinks, leaving victims unable to move, speak, or clearly recall what happened. Esketamine, like PCP, cocaine, nicotine, alcohol, heroin, and other drugs, acts on the brain by activating glutamate, an excitatory neurotransmitter, which plays a pivotal role in addiction. It also acts like an opioid. In fact, a recent study published in the American Journal of Psychiatry found that when opioid receptors were blocked, the antidepressant effects were eliminated, suggesting that activation of the opioid system is required for the temporary depression-alleviating effects. Sounds like the perfect storm, no? Offer depressed, desperate patients an addictive drug that will temporarily numb pain and emotions while providing temporary euphoria. What could possibly go wrong? Given that we are in the midst of an opioid epidemic, we don't have to search through history books to find the answer to that question. Marketing of oxycodone followed the same game plan. Inform physicians and the public the medication is safe and effective at reducing pain (or depression). Educate the public that no amount of pain (or sadness) should be acceptable, when a medication can "eliminate" it. Ignore and bury all data suggesting possible short- and long-term harm and addiction potential, even when data clearly shows otherwise from the very beginning. When millions of Americans are trapped in the cycle of addiction created by the drug, adamantly blame the problem on the patients (and continue to bask in the billions of dollars in sales). Meanwhile, manufacture a new drug to counteract the effects of the old one. It's hard to deny this is a brilliant marketing plan. But are we really going to fall into that trap again for the hope of another magical pill promising to make all our problems disappear? Surely, the FDA would be on high alert for potentially addictive medications in hopes of protecting the public from another epidemic. One would hope the FDA would insist upon stringent research exploring short- and long-term effects on the body and brain, and the potential for abuse and addiction. In fact, just the opposite has occurred. Most drugs require a minimum of two well-controlled, positive trials to get FDA approval, but this drug—with an established scary history of abuse and addiction—was rushed through with only one controlled trial establishing effectiveness. The fact that two other trials funded by the pharmaceutical company failed to show any greater effectiveness than placebo, did not slow the fast track to approval. Getting positive results in one out of three trials might plausibly be acceptable if the drug has an established history of safety and tolerability, but that's certainly not the case with esketamine. In fact, just last year a small trial testing the use of repeated doses of intranasal esketamine was suspended after five of the ten participants developed severe side effects including high blood pressure, psychosis, and severe motor incoordination that made it impossible to use the inhaler without assistance. In another clinical trial including 230 participants, 41 "serious" adverse events were reported amongst 34 patients, including two deaths, which the investigators determined were "unrelated." Maybe that's true, but it probably warrants further investigation. Some of the most common side effects found in esketamine trials include dissociation, out of body experiences, confusion, anxiety, dizziness, blurred vision, motor incoordination, issues with attention and judgment, dry mouth, nausea and vomiting, increased blood pressure, and potentially increased suicidal ideation. With such "benign" side effects, why require more research? Ironically, although suicidal ideation is a potential side effect, the medication is being researched as a potential treatment for suicidal ideation. One study found decreased suicidal ideation after 4 hours (basically, while the patient is still on a euphoric high), but not at 24 hours, or 25 days after treatment. In fact, even the "successful" trials of esketamine show that it is only effective at alleviating symptoms of depression for a week or two at most. Many people turn to drugs for the temporary high that makes one forget one's pain, yet once the drug's effects dissipate one only feels worse upon returning to one's unchanged life, pain, and problems. It's the same reason a large percent of the population has a glass of wine or a beer after a rough day at work. It offers a temporary reprieve and escape, but we all know it is just that—temporary. We also know that for those who turn to alcohol or drugs repeatedly to escape reality, a tolerance develops, requiring higher doses to offer the same momentary benefit. That's the pattern of addiction, whether it's with legal or illegal, prescribed or non-prescribed drugs. The results are predictable. We've seen it with opioid addiction. We've seen it with benzodiazepines, stimulants, PCP, and Special K in the past. We keep delusionally repeating the same patterns and expecting different outcomes. The FDA, to its credit, did place a Black Box warning on esketamine as a requirement for approval, acknowledging up front the potential for sedation, issues with attention and judgment, suicidal ideation, and risk for abuse and addiction. I guess the public has been warned. Pharmaceutical companies and some psychiatrists will work to convince the public that the warnings are unwarranted, that the medication is safe. For a mere $590 to $885 per treatment, or around $6000 a month for twice-weekly intranasal administration of the drug in a provider's office, you can ask your doctor if esketamine is "right for you," as the commercials like to tell us. Unfortunately, your doctor will not truely be able to answer any questions regarding the risks versus benefits of esketamine, as there are few short-term and virtually no long-term studies on the consequences of the drug's repeated use. Crucial to know is that long-term data from animal studies and those addicted to ketamine, suggest the possibility of irreversible brain, liver, and kidney damage. 'Time is money,' goes the old adage. When there's money to be made, why wait around to find answers to questions we'd rather ignore?