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.

07/8/15

Family Likeness in Depression Drugs?

© Brijith Vijayan  |123RF.com

© Brijith Vijayan |123RF.com

Ketamine is the new antidepressant darling, reportedly with relief in as little as 2 hours. In a previous article, “Falling Down the K-Hole,” I wrote about the use and potential problems of ketamine to treat depression. But as described below, there continues to be more to the ketamine family antidepressant story. There has also been an interest in developing ketamine-like substances, supposedly without the negative side effects. There are even ketamine treatment centers available, although insurance companies won’t pay for the treatment.

Ketamine Treatment Centers of Princeton promote ketamine to treat major depression, bipolar disorder, anxiety, PTSD and OCD. NY Ketamine Infusions offers ketamine infusion therapy to treat depression and chronic pain. One center said the potential for addiction is supposed to be minimized by administering ketamine in low doses in a medical setting, with infrequent dosing and no access of ketamine at home. Pause here for a minute and read between the lines of that last sentence before reading further.

Karl Jansen, a British psychiatrist and one of the world’s leading experts on ketamine, wrote Ketamine: Dreams and Realities. His work is a balanced pros-and-cons look at ketamine. He described multiple cases of ketamine addiction, stating: “Some users wish to return again and again, attempting to go further out and further in.” He indicated that tolerance is rapid and marked; and the ability to remember the experience fades. Yet there is little evidence of physical dependence on the drug. A few users will continue to take the drug for its cocaine-like effects, its calming effects, or its potential relief from anxiety, depression and craving. The fading of the psychedelic effects can lead to using higher doses of ketamine in order to resume its dissociation experience.

But there have been reports of ketamine psychosis. A 1994 study in the Archives of General Psychiatry (now JAMA Psychiatry) reported that ketamine produced behaviors similar to the symptoms of schizophrenia; and induced alterations in perception and symptoms similar to dissociative states. Jansen said:

Sometimes, ketamine can produce certain effects resembling psychosis. These effects can take a variety of forms. For example, the user may appear to be in a trance. Their eyes may move from side to side without seeing the external world. Limbs can move in strange ways and into bizarre postures. Despite an outward appearance of being “switched off” in some way, interviewing the person afterwards may show that the mind was staging an intense inner drama. While these people do not usually spring into action as may be seen in catatonic schizophrenia, they can suddenly sit up on the bed, speak a short phrase, and then lie down again without actually having “come ‘round.” Some people regard the odd movements and postures as a form of yoga and therapeutic bodywork. The “traveler’s tales” on their return, are often very different from the accounts typically linked with schizophrenia. Many users are absolutely convinced that their ketamine experiences were real.

Ketamine was first synthesized in 1962 by a Parke Davis pharmacist; patented in 1963; and found to be a useful anesthetic in 1965, the year it also became known as a potent psychedelic. Parke Davis patented it as an anesthetic in 1966. In the late 1960s, it was first used as a field anesthetic during the Vietnam War. It is also on the WHO list of essential medicines for a health system. It was classified as a Schedule III controlled substance in 1999.

There are reports of ketamine-related fatalities, but ketamine as the sole cause of death is rare. There have been a few reports, like this 2004 article in the Journal of Analytical Toxicology, where two men apparently died from ketamine intoxication. In 2002, an article in the International Journal of Legal Medicine reported that an EMT was found dead by his girlfriend as a result of a fatal combination of ketamine and suffocation during autoeroticism.

D.M. Turner, in The Essential Psychedelic Guide, wrote that a major concern with the safe use of ketamine was its very high potential for psychological addiction. He said that he knew several regular psychedelic drug users who never had problems controlling their use. But they would consume ketamine non-stop until their supply was exhausted. “I’ve seen very few who can use it in a balanced manner if they have access to it.” Turner’s death by drowning in 1996 was ketamine-related.

In a 2014 animal study, Gideons et al. compared the effectiveness of ketamine to another NMDA receptor antagonist, memtamine. Despite their similar potency as NMDAR antagonists, memtamine does not exert rapid antidepressant effects. Their study confirmed previous research showing this difference between ketamine and memtamine. They also discovered some differential functional effects between the two drugs that provided insight into why ketamine and not memtamine has a rapid antidepressant action.

Sanacora and Schatzberg said in their 2015 article in Neuropsychopharmacology that there was now incontrovertible evidence that single dose intravenous ketamine was associated with an improvement in depressive symptoms that could last several days. However, the actual mechanisms at work to produce the effect remained unclear. Conventional wisdom suggested that the effects of ketamine on the NMDA receptor produced the antidepressant effect. Other studies have shown several drugs that act as NMDAR antagonists with antidepressant-like effects. They also acknowledged that ketamine can produce dissociation and psychosis.

Overall, the combined data from preclinical and clinical studies using a variety of different NMDAR modulating drugs provide generally consistent evidence that antidepressant effects are associated with NMDAR antagonism, and that this is probably the primary mechanism through which ketamine is generating its antidepressant effects.

A molecular cousin to ketamine, GLYX-13 (Rapastinel), has been shown to induce antidepressant results similar to ketamine without the side effects of hallucinations, excessive sleepiness and substance abuse behavior. A study by Joseph Moskal, a molecular neurobiologist at Northwestern University, showed that GLYX-13 and ketamine produce rapid acting antidepressant-like effects in rats that lasted for 24 hours. Moskal is the Founder and Chief Scientific Officer for Naurex, the pharmaceutical company developing Rapastinel.

In February of 2014, the FDA granted fast track status to Rapastinel. Naurex, reported that Phase 2 clinical studies showed patients with major depression had a significant reduction of depressive symptoms within two hours that lasted seven days with a single dose. Repeated dosing achieved a clinically meaningful reduction in depressive symptoms that lasted ten weeks after the last drug dose. Naurex expects to begin Phase 3 clinical trials in 2015. Clinical trails are now recruiting participants to assess the effects of GLYX-13 on individuals with OCD and learning and memory in both healthy individuals and those diagnosed with Schizophrenia of Schizoaffective Disorder.

Johnson & Johnson is developing esketamine, another ketamine knock-off, and hopes to seek FDA approval in 2018. But Clinical Trails.gov, accessed in June of 2015, indicated the study for estketamine was not recruiting participants yet. Doctor Sanacara was quoted in an NPR story as saying: “I think it’s highly probable that we’ll see some version of one of these treatment being approved in the relatively near future . . . In my mind it is the most exciting development in mood disorder treatment in the last 50 years.” Sanacora has done consulting work for both Naurex and Johnson & Johnson.

The rhetoric on the clinical trials through Phase 2 for Rapastinel and esketamine sounds promising, but let’s take a wait-and-see attitude. Their molecular cousin, ketamine, has some seriously bad side effects. One question to be asked is whether or not these medications will be classified as controlled substances, as ketamine is. I think we’ll need to see whether, despite all the assurances, Rapastinel and esketamine act out just like their cousin. Like human families, bad behavior runs in pharmaceutical families.