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Ketamine, a Darling of the Club Scene, Inspires Development of Next-Generation Antidepressants, Part 3

The views expressed are those of the author and are not necessarily those of Scientific American.

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Ketamine induces growth of tiny protuberances on a rat neuron (bottom) to allow it to better connect with neighbors.

Recent experimental research showing that the anesthetic and club drug ketamine can relieve depression quickly has intrigued a number of major pharmaceutical companies. Depression, it goes without saying, affects huge numbers and a fundamentally new and effective pharmaceutical approach to treating the disorder hasn’t emerged in decades.

The enthusiasm for ketamine is such that physicians, often working out of small clinics, have already started prescribing low doses of the generic anesthetic off-label for fast relief of le cafard—and drug companies are contemplating whether to get into the act by creating new drugs based on ketamine’s biochemistry  (Read part 1 and part 2).

A Johnson & Johnson subsidiary in Europe has gone as far as midstage clinical trials for a ketamine nasal spray. The trial there uses a slightly altered version of ketamine (esketamine, the “s isomer for techies), which omits part of the molecule and leaves the most pharmacologically active portion in place, enabling less of the compound to be administered. “You can get away with a 30 to 40 percent lower dose,” says Husseini Manji who leads neuroscience research at Johnson & Johnson.

The U.S. Food and Drug Administration has put Johnson & Johnson’s version of esketamine on a fast track for approval, although, even if all goes well, patients may still have to wait a years to get a script. Esketamine, already used as an anesthetic in Europe, is not the only idea on the table. Ketamine appears to work (details still coming in from labs) by blocking a docking site, or receptor, on a neuron—in this case a spot where the essential signaling molecule glutamate attaches. The blockade triggers a complex chemical cascade that ends up restoring an impaired neuron’s ability to communicate with other brain cells.

If that process is multiplied over millions of neurons in two critical brain regions—the hippocampus and the prefrontal cortex—drugmakers hope the blues will lift like a cloud. Johnson & Johnson is working on other projects that tap into ketamine research—one of which is  looking at a wholly new drug that targets selected portions of this glutamate receptor in the hope of fine-tuning the antidepressant effects further. Other large pharmas, including AstraZeneca  and Roche, are pursuing similar strategies.

If a formal FDA imprimatur is forthcoming, the issue of off-label prescribing may persist. One issue, which must be resolved through clinical trials rather than trial and error at ketamine clinics, is whether a spray works as well as intravenous infusions. The generic non-isomer form of ketamine is already used off-label as a nasal spray and not all reviews are positive. “It helped but not as much as the infusion,” says Dennis Hartman, a patient with depression who sought help from ketamine-prescribing physicians, one of whom provided a spray.

A ketamine-like drug, if approved, will inevitably be more expensive than the generic anesthetic deployed in upstart depression clinics. Esketamine or one of its FDA-sanctioned cousins will probably be covered via a health insurance plan, but insurers’ love of low-cost generics may mean that consideration could still be given to covering plain-vanilla ketamine, even if it hasn’t run the clinical-trial gantlet. In fact, Carlos Zarate, a leading ketamine researcher who works at the National Institute of Mental Health, has even fielded calls from insurers wanting to know more about the generic drug to determine whether to put it on their formularies.

It is also still unclear whether the medical establishment, with a helping hand from law enforcement, may have to come to terms with what might be described as off–off-label prescribing—the depressed patient without insurance who learns about the possibility of a mood-altering quick fix and engages in the unsupervised self administration of Special K purchased in a club or on the street.

Hartman knows someone who went this route. “This personal friend received a ketamine infusion [from a physician],” Hartman says. “He achieved very strong relief, very similar to mine. After he relapsed, he went and sought this illegal form and he did not get the same effect.” If Johnson & Johnson’s esketamine trials result in a salable drug, the company has  plans to safeguard it from those who want to divert it for recreational use.

What to do about ketamine is a question being posed everywhere, not just stateside. A New Zealand government official issued a report in July that instructed health boards throughout the country to scrutinize off-label prescribing more closely after a complaint lodged against a ketamine-supplying physician.

Inevitably, the grassroots appeal of an old drug with a new use that might provide hope for the deeply depressed is starting to generate its own social networks. As many as 20 physicians involved in prescribing ketamine interact on the Linked-In group called Ketamine for Psychiatry. Hartman is involved with setting up a new Web site, The Ketamine Advocacy Network, to foster activism among patients—another echo of medical marijuana’s legacy.

The desperation to find new antidepressants means that ketamine will remain an object of fascination for mental health professionals and their patients. In the next five years, regulators and physicians are going to have to figure out how, if at all, the drug fits into the psychiatrist’s pharmacopoeia. In the meantime, doctors and patients are increasingly adopting their own home-grown solutions.

Image Source: Ronald Duman, Yale University

Gary Stix About the Author: Gary Stix, a senior editor, commissions, writes, and edits features, news articles and Web blogs for SCIENTIFIC AMERICAN. His area of coverage is neuroscience. He also has frequently been the issue or section editor for special issues or reports on topics ranging from nanotechnology to obesity. He has worked for more than 20 years at SCIENTIFIC AMERICAN, following three years as a science journalist at IEEE Spectrum, the flagship publication for the Institute of Electrical and Electronics Engineers. He has an undergraduate degree in journalism from New York University. With his wife, Miriam Lacob, he wrote a general primer on technology called Who Gives a Gigabyte? Follow on Twitter @@gstix1.

The views expressed are those of the author and are not necessarily those of Scientific American.

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  1. 1. farmingfool 6:51 pm 09/14/2013

    Ketamine comas have been used in the successful treatment of CRPS, a chronic pain condition, also known as RSD. Because of the sad state of health care in America, where insurance companies can overrule medical advise, those of us suffering with excruciating pain are left to only read about successful case studies because the insurance companies won’t pay for in patient treatment. Denial is based on, “no long term longitudinal research proving effectiveness ” and until big pharma discovers a way to patent this age old drug no one will pony up the money for the research. Millions of us are left out here with medical offices promoting electrically stimulating nerve centers by running wires up my spinal column because this is the “gold standard” of CRPS treatment. Only works on 1/2 the patients and only half of the pain but insurance companies will pay for it because big pharma has ponied up the funds. Wonder how long it will ate o get depressed enough suffering with intractable pain to see no other way to end the suffering except to oft myself. All I wanted was someone to scope my knee to fix some problems from an accident, insurance would only pay for a TKA. What I am left with is intractable pain, unable to do what I love and denied what might cure it by the industry that caused it. Go figure!

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  2. 2. kebil 7:36 pm 09/14/2013

    Ketamine could also be taken orally, and it used that way in the treatment of chronic pain, as well as by people abusing the substance. A higher dose of ketamine may be required when taken this way as a substantial amount is broken by first pass metabolism, but this can easily be overcome by using a higher dose. Of course, for initial clinical studies, using intravenous infusion avoids the substantial interpatient variability in absorption, thus produces more reliable and reproducible results.

    Alternatively, we already have other NMDA blockers (which is how ketamine works) that are available without a prescription. Dextromethorphan works via the same mechanism as ketamine. It is the active ingredient in most cough syrups, and may also be effective in relieving depression. I can’t see any drug company being excited about studying the use of dextromethorphan as it is an old drug, long off patent, and therefore would not generate sufficient revenue. Pharma would rather go looking for a new (and patentable) NMDA blocking compound in order to cover the cost of the approval process.

    It is not all good, when it comes to these types of drug, however. At higher doses they act as dissociative anaesthetics. They are abused for their psychedelic like effects, and they are not the sort of drug that you can take in the morning (at the doses being described) and go to work. They are more like a substitute for ECT than a replacement for Prozac, which may be part of their appeal.

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  3. 3. PhramNerd 5:23 pm 02/28/2014

    Ketamine protocol involves controlled infusion at a clinic which avoids abuse potential. Not to mention the dosage is below the recreational use.

    Ketamine has a history, in both veterinary medicine and human. Safety shouldn’t be a big deal. Long-term use studies will continue to provide data on that. To argue a wait for that is silly, since we have ongoing “long-term” studies for various already “approved” drugs. Many are prescribed antidepressants.

    Speaking about antidepressants, and the risks invovled with Ketamine. Is there really a good argument here?

    From studies now coming out indicating publication bias to the risks (especially the metabolic effects of antidepressant and antipsychotics which are heavily used psychiatric medicine ) of most the commonly prescribed antidepressants. Many have horrible profiles. There is no “big secret”(the data can back that up), yet we play this double standard game with FDA and their “approval process” when it comes to the safety and effectiveness of Ketamine which only impedes progress. I’m not saying the FDA shouldn’t evaluate the effectiveness and safety of drugs including Ketamine, only that it is hard to argue grounds “risks” of Ketamine given the FDA’s approval record in what it has already approved for treatment in depression.

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