Tag: ketamine clinics

08/6/24

Conjuring the Antidepressant Effect of Ketamine

Image by Alfred Grupstra from Pixabay

Ketamine use and abuse has been getting several different kinds of media attention lately. The DEA and the Los Angeles police are investigating how Matthew Perry received the ketamine that killed him. Perry was undergoing ketamine infusion therapy under the care of a psychiatrist and an anesthesiologist. However, his last infusion therapy was 10 days before his death and wouldn’t explain the levels of ketamine found in his autopsy. The amount of ketamine in his blood was approximately that for general anesthesia during surgery and was listed as the primary cause of his death.

Ketamine is known as a “dissociative anesthetic hallucinogen” because it makes the person feel detached from their pain and environment. It distorts the perception of sight and sound, making the user feel disconnected and not in control. It can induce sedation (feeling calm and relaxed), immobility, pain relief, and amnesia—no memory of events while under the influence of the drug. Not surprisingly, ketamine has also been used in sexual assault. And an overdose can cause unconsciousness and dangerously slowed breathing, as it seems to have done with Matthew Perry.

Ketamine became a popular “club drug” known as Special K, Kit Kat, Super K, and others. It’s typically distributed at raves, nightclubs and private parties; and rarely sold on the street. The illegal use of ketamine in the U.S. is diverted or stolen from veterinary clinics or smuggled into the country from Mexico. It comes in a clear liquid that can be mixed into drinks, or as a white or off-white powder that is snorted or smoked, typically with marijuana or tobacco.

Ketamine produces hallucinations. It distorts perceptions of sight and sound and makes the user feel disconnected and not in control. A “Special K” trip is touted as better than that of LSD or PCP because its hallucinatory effects are relatively short in duration, lasting approximately 30 to 60 minutes as opposed to several hours.

The onset of effects is rapid and often occurs within a few minutes of taking the drug, though taking it orally results in a slightly slower onset of effects. Hallucinogen Persisting Perception Disorder (HPPD) has been reported several weeks after ketamine is used and may include experiencing the negative side effects that occurred while taking the drug initially. Ketamine may also cause agitation, depression, cognitive difficulties, unconsciousness, and amnesia.

In an interview, Elon Musk discussed his prescription use of ketamine. He said he uses a small amount once every week or so. “There are times when I have sort of a … negative chemical state in my brain, like depression I guess, or depression that’s not linked to any negative news, and ketamine is helpful for getting one out of the negative frame of mind.” He denied any misuse of ketamine, saying, “if you use too much ketamine, you can’t really get work done. I have a lot of work. I’m typically putting in 16-hour days … so I don’t really have a situation where I can be not mentally acute for an extended period of time.”

Ketamine is not an FDA-approved treatment for depression but some psychiatrists use it off-label. Ketamine infusion therapy, like that prescribed to Matthew Perry, is not covered by insurance, meaning it’s expensive. And not every psychiatrist is willing to prescribe it. A derivative of ketamine known as esketamine (Spravato) was approved in 2019 as a nasal spray. But receiving a ketamine infusion or Spravato requires close medical supervision in a clinic.

This expense and the “inconvenience” of medical supervision led to the proliferation of compounded ketamine products such as ketamine lozenges and tablets and nasal sprays from a multitude of online sources, allowing for the at-home use of ketamine, which seems to be what contributed to Matthew Perry’s accidental death. The FDA published an alert, warning of the potential danger of compounded ketamine products. “Compounded drugs are not regulated by the FDA, so there is no assurance the drugs purchased from a compounding pharmacy are what the companies claim they are.” They pose a higher risk to patients than FDA-approved drugs because they don’t undergo the FDA review for safety, effectiveness and quality.

Now there has been the publication of a phase 2 clinical trial for extended-release ketamine tablets for treatment-resistant depression in the journal Nature Medicine. The lead author of the study told Medscape, “Having a tablet formulation makes it possible for patients to be safely dosed at home and would increase the number of patients who could be treated at any one time.” He added that when formulated as an extended-release tablet, taking around 10 hours to release, most of the ketamine is metabolized in the liver. “The low ketamine blood levels mean patients experience few or no side effects.” The study reported the majority of side effects were of a mild or moderate intensity. The most common adverse events included dizziness, headache, dissociation, feeling abnormal, fatigue and nausea.

The design of the study eliminated non-responders before randomization in order to reduce the risk of study failure. This meant that of the 231 enrolled in the open-label enrichment phase of the study, (where participants took a daily dose of 120 milligrams of ketamine in the slow-release pill for five days) 63 exited the study as nonresponders and 168 continued as responders. The responders were participants whose MADRS (Montgomery-Asberg Depression Rating Scale) score was greater than or equal to 12 and had reduced their scores by at least 50% during the enrichment phase. These responders were then randomized into double-blind groups of four different doses and placebo. See the figure below from the original study.

A CNN Health article on the study reported that experts thought the study was an important first step, but the trial probably biased the results, making the drug look more effective than it would be in the real world. Dr. Gerald Sanacora, who was not involved in the study, said it’s very likely participants knew they were getting ketamine rather than the placebo, and expected it to work. “It is usually easier to guess correctly once you have been exposed to the active treatment and then receive the inactive treatment.” He thought further study in a larger population was necessary. The researchers acknowledged this design likely overestimated response levels, “and future unenriched clinical trials are needed to address this issue.”

Sancora went on to say there was “significant tension” between the potential benefits of ketamine and making sure the treatment can be given safely and responsibly. “This is a step in the right direction, but we clearly need more high-quality data before we can say much more about the overall efficacy and safety of the new form of treatment and especially the safety of doing this at home.” There was also a high dropout rate of the double-blind RCT phase of the study; and one completed suicide.

Of the 168 people who initially saw benefit from the pills, 100 didn’t complete the trial. Ninety-four left because they stopped being helped by their treatment. One person left because of an adverse event. Four others left for unspecified reasons. A 65-year-old man died as a result of suicide.

An independent review committee judged the suicide was a result of the patient’s depression rather than the treatment. Experts agreed it was difficult to know whether the drug played any role in the death, and said larger studies were needed to “tease out” any serious safety issues. “One of the challenges with oral ketamine, one of the reasons that we haven’t used as much for depression as IV, is that it can be sort of unpredictable, and how much is getting into the bloodstream?”

Reflect for a minute on the above reported information. One hundred sixty-eight participants were identified as responders to ketamine treatment for treatment-resistant depression. But 100 (59.5%) didn’t complete the trial; and 94 (55.9%) left because they stopped being helped.

What seems implied, but unspoken here, is that the high dropout rate in the study was fueled by participants recognizing rather quickly that ketamine no longer had an antidepressant effect for them. This suggests two concerns with the study. First, the double-blind part of the open-label enrichment phase was broken, raising the question of the credibility of the supposedly “random” design. Second, the rapid antidepressant effect of ketamine appears to dissipate quickly, raising a concern about the wisdom of ketamine as a long-term treatment for “treatment-resistant” depression. Remember, it is a Schedule III Controlled Substance.

Additionally, there was no significant difference of relief reported between the four treatment phase groups in the study. The CNN article noted while everyone still in the study at 14 weeks reported some relief from their depression, the results when compared with the placebo group were not significant; meaning the reported relief “could have been observed due to chance alone.” So, the antidepressant effect of ketamine could merely a pharmaceutical conjuring trick—now you have it, now you don’t.

See “Evaluating the Risks with Esketamine,” Repeating Past Mistakes with Esketaine,” “Voyages on the Starship Ketamine,” and others for more information on the concerns with ketamine and esketamine to treat depression on my website.

10/6/17

Is Ketamine Really Safe & Non-Toxic?

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An article in The Morning Call, a newspaper for Allentown and the Lehigh Valley area of Pennsylvania, announced that a local company, the Lehigh Center for Clinical Research, would be conducting clinical trials for two pharmaceutical companies to gain FDA approval for modified versions of ketamine as a treatment for depression. The psychiatrist running the trials said the drugs could hit the market in the next few years. He said: “It’s exciting and promising but I think we have to wait to see it used in the widespread population to know whether it’ll be safe and non-toxic.” I thought the safety and toxicity of a new drug was supposed to be assessed BEFORE the FDA approved its release into the wider population.

There have been waves of excitement and concern over the past few years about the development and use of ketamine and ketamine-like drugs to treat depression. Ketamine has been an FDA approved medication since 1970, where it was used as an anesthetic in the Vietnam War. It is classified as a Schedule III Controlled Substance by the DEA, meaning it has a potential for moderate to low dependence or high psychological dependence. Ketamine is also a recreational drug known as Special K because of its dissociative properties. “Due to the detached, dreamlike state it creates, where the user finds it difficult to move, ketamine has been used as a ‘date-rape’ drug.” See: “Falling Down the K-Hole” and “Family Likeness in Depression Drugs?”

The excitement over ketamine, as a treatment for depression, centers on its rapid relief of depressive symptoms; sometimes within hours of it being administered. But the effects fade rapidly and require frequent, repeated treatments. Currently ketamine is administered intravenously, similar to its use as an anesthetic. There is an intranasal spray version (Esketamine) in the works. See: “Psychedelic Depression,” Ketamine to the Rescue?,” and Ketamine Desperation.”

The clinical trails being done by the Lehigh Center for Clinical Research would appear to be for Esketamine, by Janssen Research and Development, and Rapastinel, by Allergan. While Esketamine is a nasal spray, Rapastinel is administered by weekly IV injections. Both are currently in Phase 3 clinical trials. This involves randomized, double blind testing in several hundred to several thousand patients. Upon successful completion of their Phase 3 trials, a pharmaceutical company can request FDA approval for marketing their drug. Somewhere around 70 to 80 percent of drugs that make it to Phase 3 are eventually approved.

Although Esketamine and Rapastinel are similar to ketamine in several ways, they are still distinct NMEs (new molecular entities), patented by their respective pharmaceutical companies. Ketamine was first developed in the 1960s and has been off patent for decades, meaning there is no profit in Pharma companies pursuing ketamine-based treatment for depression. But since ketamine is an FDA approved drug, it can be used off label to treat depression. And there are a growing number of ketamine treatment facilities around the U.S. and Canada that do just that.

Earlier in 2017 All Things Considered on NPR featured a story on the off-label use of ketamine to treat depression, “Ketamine for Severe Depression.” Psychiatrist Gerard Sanacora said over 3,000 patients have treated at dozens of clinics with ketamine for depression. He has personally treated hundreds of people with low dose ketamine. Sanacora said when he is asked how he can offer it to people on the limited amount of available information and without knowing the potential long-term risk, he responds “How do you not offer this treatment” to individuals likely to injure or kill themselves, who have unsuccessfully tried the standard treatments?

Sanacora and others authored “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders” that was published in JAMA Psychiatry in April of 2017. They noted how several smaller studies have demonstrated the ability for ketamine “to produce rapid and robust antidepressants effects in patients with mood and anxiety disorders that were previously resistant to treatment.” It also cautioned that while ketamine may be beneficial to some patients, “it is important to consider the limitations of the available data and the potential risk associated with the drug when considering the treatment option.”

Zorumski and Conway published “Use of Ketamine in Clinical Practice” in the May 2017 issue of JAMA Psychiatry. They also noted the increasing evidence from small studies that ketamine has rapid antidepressant effects in patients with treatment-resistant depression. They commented how ketamine is having a major effect on psychiatry. “If clinical studies continue to support the antidepressant efficacy of ketamine, psychiatry could enter an era in which drug infusions and deliveries with more rapid responses become common.” They indicated the cautions of Sanacora et al. were noteworthy and should be emphasized.

Because of the limited data to guide clinical practice, these limitations extend to almost every recommendation in the consensus statement, including, perhaps most importantly, patient selection. The bulk of the literature describes the effects of ketamine in patients with treatment-refractory major depression. The definition of treatment-refractory major depression and where treatments such as ketamine fall in the algorithm for managing treatment-refractory depression remain poorly understood. . . . It is unclear whether patients with depression that is not treatment-refractory or patients with other psychiatric illnesses are appropriate candidates for ketamine treatment, and extreme caution must be exercised in patients with psychotic or substance use disorders.

So then comes the Short et al. study in the journal Lancet Psychiatry in July 2017, “Side Effects Associated with Ketamine Use in Depression.” It was the first systematic review of the safety of ketamine in the treatment of depression. After searching MEDLINE, PubMed, PsycINFO, and Cochrane Databases, they identified 60 out of 288 articles that met their inclusion criteria. “Our findings suggest a selective reporting bias with limited assessment of long-term use and safety and after repeated dosing, despite these being reported in other patient groups exposed to ketamine (eg, those with chronic pain) and in recreational users.”

Science Daily reported that the lead author for the study said there were major gaps in the research literature that should be addressed before ketamine was widely used as a clinical treatment for depression. “Despite growing interest in ketamine as an antidepressant, and some preliminary findings suggesting its rapid-acting efficacy, to date this has not been effectively explored over the long term and after repeated dosing.” Given that ketamine will likely involve multiple, repeated doses over an extended time period, “it is crucial to determine whether the potential side effects outweigh the benefits to ensure it is safe for this purpose.”

Commenting on the Short et el. Study for Mad in America, Peter Simons also noted the expressed concern with the selective reporting bias and a limited assessment of long-tem use and safety after repeated dosing. Researchers are generally careful to report safety and side effect data on studies of ketamine used recreationally or for chronic pain. However, depression research tended to ignore the safety and side effect concerns with ketamine, often not reporting such issues at all.  “Most people receiving ketamine had acute side effects.” Studies that did report adverse events said that after acute dosing, patients in ketamine treatment reported more frequent side effects.

Common side effects led a number of patients to withdraw from the study. Suicidal thoughts were common and there was one suicide attempt reported. Previously reported potential long-term adverse effects from ketamine include: urinary tract problems, liver toxicity, ulcerative cystitis, neurocognitive deficits and memory problems, and dependence or addiction. Some of the many additional side effects that were reported included:

 

  • Worsening mood
  • Anxiety
  • Emotional blunting
  • Psychosis
  • Thought disorders
  • Dissociation
  • Depersonalization
  • Hallucinations
  • Increased blood pressure
  • Increased heart rate
  • Decreased blood pressure
  • Decreased heart rate
  • Heart palpitations/arrhythmia
  • Chest pain
  • Headaches
  • Dizziness
  • Unsteadiness
  • Confusion
  • Memory loss
  • Cognitive impairment
  • Blurred vision
  • Insomnia
  • Nausea
  • Fatigue
  • Crying/tearfulness

Because of the extensive list of potential adverse effects, as well as the unknown possibility for harm from long-term use, the authors of Short et al. recommended large-scale clinical trials with multiple doses of ketamine. Long-term follow up to assess the safety of long-term regular use was also recommended. “As it stands, the safety of ketamine treatment for depression is unknown—and that is largely due to inadequate and biased reporting of safety issues.”

I hope that these concerns are seriously considered and factored into the FDA’s assessment process for approving Esketamine and Rapastinel. Otherwise, the real safety and toxicity assessment of these drugs will be done on the first wave of depression sufferers prescribed the new drugs for treatment-resistant depression. Given the short length of clinical trials, the long-term effectiveness and impact on a patient’s quality of life, including potential misuse of the drugs, will not be clear  for either Esketamine or Repastinel until Phase 4 Post Marketing Surveillance Trials are completed … after the drugs are on the market. Will they live up to their therapeutic promise or become another example of the Pharma patent medicine show?

02/14/17

Psychedelic Depression

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You are lying in a comfortable reclining chair in a private room with low lights. You are dressed in your street clothes, but you are also connected to monitors for blood pressure, pulse and oxygen saturation. A medical practitioner locates a vein on your arm and uses a tiny needle to insert a thin, flexible tube into your vein. You barely feel the needle inserted because it doesn’t hit any muscle. The tube is connected to a bag of fluid raised a couple of feet above your head and it delivers a carefully measured dose of ketamine directly into your bloodstream to treat your depression.

The above description is for a procedure called ketamine infusion, as it was described on the Ketamine Advocacy Network website. Further reading suggests you will have an almost ethereal experience. It could include a dissociative effect, an out-of-body sensation. You will appear to be asleep, but in reality your mind is very active. “In a state of deep relaxation, you may find that you’re able to reflect on past traumas or current anxieties in a very calm, matter-of-fact way – with zero emotional pain.” Many patients prefer to let their thoughts wander. They suggest doing whatever maximizes your sense of calm and relaxation, as long as your doctor agrees.

Although most patients find the experience relaxing and pleasant, some can have brief moments of fright. Patients who begin the infusion in a state of high anxiety seem most susceptible to this. Many are desperately pinning all their hopes on ketamine to relieve their suffering, which is totally understandable but can amp up their anxiety. Some patients get very tense at the thought of not being in total control of their thoughts or body. Try your best to relax before the infusion begins.

What’s not to like about the above-described treatment for depression? First, remember that it is not an FDA-approved treatment. Second, ketamine used in higher doses than in an infusion is the club drug favorite, Special K. Third, the antidepressant effect from ketamine is limited and of an unknown origin.

Ketamine is a Schedule III controlled substance, approved as a general anesthetic. As Peter Simons reported, it is not approved by the FDA as a treatment for depression and other mental health concerns because of a lack of clear benefit and limited knowledge of its risks. There is some truth to the fact that as a generic drug, it is not attractive for pharmaceutical companies to develop it as a therapeutic agent; they won’t make billions of dollars with it. But the research for its efficacy in treating depression is mixed. Simons referred to a new study by Voort et al. in the Journal of Affective Disorders that extended the duration of depressive symptom remission, but did not fully remit the depression.  He said:

Only one of the twelve patients experienced remission of depression. The pattern shown by previous studies is similar. Within hours after treatment, patients experience a euphoric release of depression, but depressive symptoms return within a day or two. For some patients, they return worse than before. Additional treatments every day or every week have the same effect, but the effect is not cumulative. Once weaned off the continual weekly ketamine treatments, around 90% of patients relapse. As evidenced by this current study, even with continuous treatment, only a small number of patients experience any benefit.

Adverse effects can include increased symptoms of depression, anxiety, and suicidality. Only seven of twelve participants reported any therapeutic effect, and only one patient experienced remission by the end of the trial. One person died by suicide and another was hospitalized for suicidality. “These results confirm suspicions that ketamine is a dangerous experimental treatment with limited benefits and serious risks.” These seem to be further reasons why the FDA has yet to approve ketamine as a treatment for depression.

The addictive potential with ketamine is a real concern. The fast-action and rapid fading effect of the drug seems to potentiate its psychological dependency. Ketamine is also widely misused in East and South-East Asia. In Ketamine: Dreams and Realities, Karl Jensen, a British psychiatrist and a leading authority on ketamine said it was far more likely to create periods of dependence than other psychedelic drugs. “The risk is certainly very high in comparison with drugs such as LSD, DMT, and psilocybian mushrooms, but it is not more than half of those who like it.”

Tolerance is rapid and marked; and the ability to remember the experience fades. Some users, he said, will continue to take ketamine for its cocaine-like effects, its calming effects or its potential to relieve anxiety or depression. However, the fading effect can lead to using higher doses in order to resume its dissociation experience. Jensen then gave an extended quote from The Essential Psychedelic Guide, by D.M. Turner, who died from a ketamine-related incident. The Erowid report on Turner said that in 1996 Turner drew a hot bath, injected an unknown amount of ketamine “and settled in for the last trip of his life.” He lost consciousness at some point and drowned. Turner wrote:

A major concern regarding safe use of Ketamine is its very high potential for psychological addiction. A fairly large percentage of those who try Ketamine will consume it non-stop until their supply is exhausted. I’ve seen this in friends I’ve known for many years who are regular psychedelic users and have never before had problems controlling their drug consumption. And I’ve seen the lives of several people who developed an addiction to Ketamine take downward turns. After about two years of once-per-week Ketamine use I even found that I had developed an addiction…Amongst those I know who use Ketamine, I’ve seen very few who can use it in a balanced manner if they have access to it…One of the most remarkable things I experienced in becoming aware of and breaking my Ketamine addiction was the intervention of…[psilocybian mushrooms and DMT]. The DMT provided insights into the negative effects Ketamine was having on my life: a reduction in ambition; a reduction in healthy mortal fears, such as the fear of death; as well as a reluctance to confront fears or difficult tasks and situations directly. Frequent use of Ketamine can lure one as an escape since a blissful and fantastic state of fearless, disembodied consciousness is so easily available.

For more discussion of ketamine and its use as a treatment for depression, see: “Ketamine Desperation,” “Family Likeness in Depression Drugs?”, “Ketamine to the Rescue?”, “Falling Down the K-Hole.”

Although ketamine is a generic drug, esketamine (C13H18CINO) is a patented knock-off of ketamine (C13H16CINO) by Janssen Pharmaceuticals, a division of Johnson & Johnson. In August of 2016 esketamine was granted its second designation by the FDA as a Breakthrough Therapy for treating major depression with an imminent risk of suicide. A Breakthrough Therapy Designation expedites the development process of a drug when it demonstrates the potential for substantial improvement over existing therapies of if it for life-threatening conditions.

Esketamine is an intranasal product, not administered by infusion. Like ketamine, it is a general anaesthetic and a dissociative. It acts primarily as an antagonist with the NMDA receptor, but is also a dopamine reuptake inhibitor. It is more potent and is eliminated more quickly from the body than ketamine. There is also some evidence that it has a more dissociative (hallucinogenic) effect than ketamine.

A study published in Biological Psychiatry by Singh et al. reported the efficacy and safety data from one of the completed FDA trials for esketamine. Science Daily quoted Murray Stein, a deputy editor for Biological Psychiatry, as saying the study showed benefits of the drug over placebo and suggested that the lower of the two doses could be equally effective and also safer. “Though the mechanism of ketamine (and esketamine) antidepressant effects remains unclear, this study clearly demonstrates a benefit, at least in the short term, of this drug for treatment-resistant depression.” Additional clinical trials are testing a wide range of doses to determine the optimal dosing, assessing other possible side effects, and seeking to establish the safety of esketamine in the longer term. Unfortunately, clinical trials don’t last long enough for most drugs to clearly establish an adverse effect like addiction.

There are now two separate drugs in development as fast-acting antidepressants, esketamine and ALKS-5461, whose active ingredients can be reasonably inferred to lead to addiction. As was already mentioned, ketamine is currently classified as a Schedule III controlled substance by the DEA, as is buprenorphine, the active ingredient in ALKS-5461. I hope the FDA will acknowledge the very real risk of addiction with these new molecular entities. The seductive allure of a fast-acting antidepressant could override this concern and lead to their approval as antidepressants without this needed warning. If they are approved, they should at least be classified as Schedule III Controlled Substances.

11/1/16

Ketamine Desperation

© Novic | stockfresh.com
© Novic | stockfresh.com

Jeff wants to smile again and know what happiness is like again. He wants to not feel the urge to kill himself again. He has been hospitalized in psychiatric facilities and has taken a variety of antidepressants and mood stabilizers for his bipolar disorder, but nothing worked. He remained employed as a football analyst until the sky fell in on him and he lost his job. “He was suicidal; so overwhelmed with despair, that he couldn’t even leave his house.” He finally found a treatment option at the Ketamine Clinics of Los Angeles. And so goes one of many testimonies of ketamine’s potential as a rapid treatment for depression.

Steven Mandel MD, the President and founder of the Ketamine Clinics of Los Angeles, is an anesthesiologist who uses ketamine to treat patients who are depressed and suicidal. The standard protocol is to give low dose IV infusions of ketamine. It worked for Jeff. He said, “It’s been remarkable.” His wife looked at him and saw the smile on his face and had the biggest smile herself in response. Jeff thought it was immoral to withhold ketamine from the general public. You can watch a four-minute video on Jeff and Dr. Mandel’s treatment here.

Over the last ten to fifteen years, ketamine has been getting a significant amount of research and media attention as a fast-acting treatment for depression. Reporting for The Washington Post, Sara Solovitch quoted Dennis Hartman as saying: “My life will always be divided into the time before that first infusion and the time after.” But the relief is temporary. “Clinical trials at NIMH have found that relapse usually occurs about a week after a single infusion.”  And it can cause intense hallucinations or a kind of lucid dreaming or dissociative state where some patients lose track of time.

NIMH studies suggest the psychedelic experience with ketamine may play a small but significant role in the drug’s efficacy. Steven Levine, a psychiatrist who has treated 500 patients with ketamine said:

With depression, people often feel very isolated and disconnected. Ketamine seems to leave something indelible behind. People use remarkably similar language to describe their experience: “a sense of connection to other people,” “a greater sense of connection to the universe.”

Hartman travels back-and-forth to an anesthesiologist in New York City for his bimonthly infusions of ketamine. He doesn’t consider himself permanently cured, “but now it’s something I can manage.” In 2012 he helped to found an organization called the Ketamine Advocacy Network, a group that screens ketamine clinics, advocates for insurance coverage and spreads the word on the effectiveness of ketamine to treat depression. The problem is the treatment is not FDA approved. And in higher doses, ketamine is known as the club drug, “Special K.” See previous articles, “Ketamine to the Rescue?” and “Falling Down the K-Hole.”

The promise of ketamine as a fast-acting alternative to other antidepressant medications had led to a growth industry for ketamine clinics around the U.S. and multiple pharmaceutical companies doing their own research into developing ketamine derivatives without the side effects. Ketamine is known to interact with the NMDA receptor involved in learning and memory. So scientists assumed the same receptor was responsible for the anti-depressive action of ketamine. STAT News reported this led to more than a dozen companies trying to develop drugs that target the NMDA receptor. “But these drugs haven’t worked as well as ketamine.” AstraZeneca pulled out of developing its own highly touted ketamine derivative, lanicemine in 2013 when it failed to show long-term benefits.

Iadarola et al. published a 2015 article in the journal Therapeutic Advances in Chronic Diseases that reviewed the growing literature on ketamine efficacy as an antidepressant treatment. They confirmed the temporary effects from ketamine; the effects waned after several days in most patients. The authors suggested that after achieving the antidepressant response from ketamine, the effects could be maintained with intermittent doses of ketamine as described above with Dennis Hartman. Pharmaceutical companies aren’t really interested in moving forward with ketamine infusion since the drug has been long off patent and they can’t make a billion dollar profit on a drug that is off patent. So they seek to develop biosimilars to ketamine.

The latest pharma compound to target the NMDA receptor is esketamine, which Janssen Pharmaceuticals, a division of Johnson & Johnson, is developing as an intranasal spray. Johnson & Johnson announced on August 16, 2016 that the FDA granted esketamine a Breakthrough Therapy Designation. This is the second time esketamine has received a Breakthrough Therapy Designation. The first was in November of 2013. The Breakthrough Therapy Designation is to expedite drug development when a drug demonstrates the potential to be a substantial improvement over available therapies for serious or life-threatening conditions.

But the real excitement may still be ahead. The STAT article cited above reported on a new research study published in the May 26th 2016 issue of the journal Nature that demonstrated a derivative of ketamine could achieve the same benefit, but without the side effects. The study was done on mice, so it has a ways to go in drug development before it can compete with esketamine. Dr. Todd Gould, who led the Nature study, suggested the ineffectiveness of previous studies that targeted the NMDA receptor were because they were looking in the wrong place. His research team showed that the effectiveness of ketamine as an antidepressant doesn’t come from the NMDA receptors—at least not in mice.

In the body, ketamine turns into a molecule called hydroxynorketamine — or HNK — and that molecule is actually what treats the depression. Gould’s team also found that HNK does not interact with the NMDA receptor, and it doesn’t have some of the side effects that ketamine does.

Gould said they have a game plan to move forward with the clinical development of HNK. He and his coauthors have filed a patent application for certain uses of HNK. Outside researchers thought the study was well-done science, but they aren’t convinced it’s time to give up on the NMDA receptor. Their drugs targeting the NMDA receptor are further along in drug development. And they are not convinced they are beating a dead horse just yet. STAT reported that Dr. John Krystal, a psychiatrist and neuroscientist who consults for companies developing NMDA-target drugs said: “In my view, it is quite premature to move away from the hypothesis that NMDA receptor antagonists have antidepressant activity based on this single study.” True, but to you rush to bring your ketamine-like drug to market first?

There will still be the same adverse effects as with ketamine, won’t there? And the temporary nature of the mood elevation is still there, isn’t it? The lack of long-term effects led to the AstraZeneca decision to stop development with lanicemine. And esketamine is “an investigational antidepressant medication, for the indication of major depressive disorder with imminent risk for suicide.” That sounds like a short-term use designation.

Uli Hacksell, chief executive of Cerecor, a Baltimore company that has a Phase 2 drug candidate directed at the NMDA pathway, also took issue with the claim that such drugs might be going after the wrong target, and he said that the paper will have no implications for his company’s development plans. “We think that the clinical data we get with our molecule will speak for themselves,” he said.

One outside researcher, Dr. Francis Collins, the director of the National Institutes of Health (NIH), was quite supportive of Gould’s research. In his NIH Director’s blog, Collins described the background work leading up to the Gould study. He then said:

 HNK appears to come without the side effects of ketamine. After receiving HNK, mice didn’t show changes in their physical activity, coordination, or sensory perception, as is normally seen after a dose of ketamine. HNK also doesn’t appear to have the same potential for abuse either. When given the option, mice will choose to self-administer ketamine, but not HNK.

The new evidence confirms that HNK doesn’t block NMDA receptors like ketamine does. While there’s more to discover about how HNK works, the evidence reveals an important role for AMPA receptors, another type of glutamate receptor in the brain.

Long-term ketamine users can have irreversible urinary tract and bladder problems. Erowid, a pro-drug website, conducted an online survey that indicated there was a clear correlation between total lifetime use of ketamine and the likelihood of reporting bladder/urinary problems. Now these are health problems that occur with higher doses of ketamine than those used to treat depression. Lower doses over the long-term may not have the same adverse effects. However, these known health concerns should not be overlooked in the rush to bring a new fast-acting antidepressant to market. Ketamine (and its derivatives) to the rescue of depression may not turn out to be the super cure some think it is.