08/6/24

Conjuring the Antidepressant Effect of Ketamine

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.

02/22/22

Risks of Ketamine for Suicide Prevention

As 2021 drew to a close, there was another study published online that evaluated ketamine’s value in mental health therapy. As other research has shown, this metanalysis found that ketamine could quickly relieve depression and thoughts of suicide. But the rapid response was usually short-lived. While there was some evidence it helped with other disorders, the evidence base was of a small number of primarily non randomized trials with short follow-up periods, which require confirmation and extension.

The study, “Ketamine for the treatment of mental health and substance use disorders,” was published in the British Journal of Psychiatry Open. The write up of the study in Medical News Today, “What 83 studies say about ketamine and mental health,” was generally positive. However, one of the study’s co-authors thought it was best administered in a clinical environment. In such a setting, people can be provided with “preparation and psychological support during and after the ketamine infusions” which can reduce the risk of adverse events. This is a methodology that follows similar attention to the “set and setting” in psychedelic drug research.

Commenting on the study, Alan Schatzberg, a professor of psychiatry and behavioral sciences at Stanford, thought the research to date was not enough to determine whether ketamine was effective enough to be worth it. He said, “I haven’t seen enough real data to say that we [have] got a huge winner here.” One of his concerns was that he thought ketamine worked through an opioid mechanism, acting significantly with mu opioid receptors. In certain forms and situations “it’s highly addictive.” Opioid drugs had been used to treat depression until the mid-1950s, but were largely abandoned because of concern about abuse.

Schatzberg was the senior author of a 2018 study in The American Journal of Psychiatry that showed how ketamine activates the opioid system. The study was created after the authors saw research that suggested drugs that only worked on the brain’s glutamate system weren’t very effective antidepressants.

Speaking to NPR about the study, Schatzberg said: “We think ketamine is acting as an opioid. . . That is why you’re getting these rapid effects.” The researchers commented their findings challenged the current understanding of ketamine’s mechanisms of action and its antidepressant properties.

They designed their study to investigate whether ketamine activates mu opioid receptors. This meant they treated patients with depression in two ways. First, depressed patients were given an infusion of ketamine alone. Second, depressed patients were given naltrexone, which blocks the effects of opioid drugs, before they received their infusion of ketamine. This was not a blinded study for ketamine; it is essentially impossible to design a double-blinded study with drugs like ketamine that have dissociative side effects.

An analysis of a dozen patients who got both treatments showed a dramatic difference. Seven of the 12 saw their depression symptoms decrease by at least 50 percent a day after they got ketamine alone. But when they got naltrexone first, there was “virtually no effect.”

Dr. Schatzberg gave a talk on “Clinical Use of Ketamine in Suicide Prevention” for McLean Hospital and discussed the above research. In the slide below, taken from his talk, you see a clear antidepressant effect with the ketamine plus placebo group (K+P). When the same patients get naltrexone first (K+N), there is no evidence of a ketamine effect. The “B” graph shows the dissociative effect of ketamine was not blocked in the ketamine and naltrexone group, while the antidepressant effect was.

The anti-suicide effects of ketamine were also blocked by naltrexone, as shown in the graph below, taken again from Dr. Schatzberg’s McLean talk. This led the researchers to conclude, “the antidepressant effect of the ketamine is being mediated in some way through mu opioid receptors.”

Schatzberg noted how there have been five reports since 2018, three of which have been published, all of which show that mu opioid antagonists block ketamine’s behavioral effects. “We can show that ketamine works through an opioid effect.” He then asked, if this effect could be harnessed. In further research, Schatzberg and others looked at buprenorphine, which is a partial mu opioid agonist. At high doses (16-24 mg per day) it has an antagonist effect, blocking typical opioid effects. But very low doses, under 2 mg, have been used to treat refractory depression.

There was a 1995 study by Bodkin and Cole that investigated the potential for low doses (less than 2.0 mg per day) of buprenorphine to treat refractory depression. Its findings suggested a potential role for buprenorphine in treating depression. There was also a 2016 Israeli study by Yovell et al that looked at whether ultra-low doses of buprenorphine (.2 mg-.8 mg) could treat severe suicidal ideation.

At two weeks, Yovell et al had a dramatic reduction in suicidal ideation as assessed by the Beck Suicide Ideation Scale. This was true at the end of two weeks and at the end of four weeks. At the end of week 4, the buprenorphine was discontinued, reportedly without withdrawal symptoms at a one-week follow-up appointment. “It is possible that in this opioid-naïve population, the short duration and low dosages protected against dependence.” See the graph below taken from the Yovell et al study.

Notice that the dramatic reduction in suicidal ideation was not evident until after one week of ultra-low dose buprenorphine. Contrasting this to the rapid, within one day, antidepressant response noted above, raised a research question Schatzberg and other are currently investigating. Can you get a more immediate anti-suicide effect if you first pre-treat buprenorphine patients with ketamine?

Schatzberg and a team of researchers are looking at 60 patients with major depression and active suicidal behavior. They are repeating the Israeli experiment, but adding it after a ketamine infusion. All patients receive an open label, intravenous infusion of ketamine. Two days later, patients are randomized to receive ultra-low dose buprenorphine or placebo for 4 weeks. This research is ongoing; no results were discussed or presented in Schatzberg’s talk.

Given the previous research, it seems likely these researchers will demonstrate a rapid antidepressive reduction in active suicidal behavior. Combining ketamine and buprenorphine as Schatzberg does in this experiment will simultaneously engage two systems that seem to mediate depression and suicidal ideation—the endogenous opioid system and the glutamatergic system. However, we need to keep in mind that both of the drugs in Schatzberg’s experiment, ketamine and buprenorphine, are classified as Schedule III Controlled Substances.

The Yovell et al study suggested that ultra-low doses of buprenorphine were successfully discontinued without withdrawal. But wasn’t that after a single treatment? Studies of ketamine’s rapid antidepressant effects indicate the changes are temporary and require repeated therapeutic interventions in order to maintain an improvement in mood. In time, could tolerance and withdrawal become evident with ultra-low dose buprenorphine as it has already been shown with ketamine?

Considering the ultimate risk of suicidal ideation leading to completed suicide, it would seem to be an acceptable risk-benefit ratio as a therapeutic intervention for suicidality. But as an ongoing, repeated cycle to treat major depression, the ketamine-buprenorphine combination does not appear to be an acceptable risk to me. In time, the patient could add physical dependency concerns with ketamine and buprenorphine to his ongoing struggle against depression.

I look forward to the completion of Schatberg’s study and hope the publication of the results will address this concern. For more information on ketamine, see this review of research by The Mental Elf and other articles on this website: “Ketamine to the Rescue?”, “In Search of a Disorder for Ketamine,” and “Is Ketamine Really Safe & Non-Toxic?”

01/5/21

In Search of a Disorder for Ketamine

Interest in getting ketamine approved to treat depression persists, even after the approval of esketamine (Spravato) in March of 2019. The rapid reversal of depression symptoms was first shown with ketamine. But as it was a generic drug, there was no financial motivation for the pharmaceutical industry to invest in its potential. There is still a mystery in knowing exactly how ketamine exerts its effects. Now there is some who theorize it may help with alcoholism.

Soon after the FDA approval of Spravato in 2019, a team of researchers at Weill Cornell Medicine revealed how ketamine induced changes in the brain circuits of mice. Carlos Zarate, who was not involved in the study, said: “It’s a remarkable engineering feat, where they were able to visualize changes in neural circuits over time, corresponding with behavioral effects of ketamine.” He thought the work would help guide what treatments should be doing before they are moved into the clinical setting. The study used cutting-edge technology to visualize and manipulate the brains of stressed mice. Mice subjected to stress display the equivalent of depressed behavior and with antidepressant treatment, they often improve.

In the new study, the researchers used light microscopes to observe tiny structures called spines located on dendrites (a neuron’s “input” wires) in the mPFC [medial prefrontal cortex] of stressed mice. Spines play a key role because they form synapses if they survive for more than a few days.

STAT News said the medial prefrontal cortex is an area of the brain that is thought to be involved in depression. Research has suggested chronic stress can affect the number of synapses in the brain. The Weill Cornell researchers wanted to see if ketamine could reverse those effects. “So they looked at what are known as dendritic spines, tiny projections that shoot off branches of neurons known as dendrites. Most dendritic spines contain functional synapses, so scientists consider them a sign of a connection between two neurons.”

After giving the mice a dose of ketamine, the effects on behavior were rapid. They were more likely to attempt to escape from an unpleasant situation, preferred sugar water over plain water and explored a maze. All three behaviors are indications the mice are not stressed. However, the effects on synapse formation were slower. New synapses did not appear until around 12 hours after a dose of ketamine. This suggested ketamine’s rapid effect was not dependent on the formation of new synapses.

The researchers then used a tool that caused the newly formed synapses to collapse. Within two days, some of the behaviors of the mice reverted back to the behaviors evident during chronic stress. This suggests the new synapses and their continuation are critical to maintaining at least some of ketamine’s effect on behavior.

Zarate noted one limitation of the study was there was only a single dose of ketamine, rather than the multiple doses that occur with human treatment. Might the spines remain after weeks of repeated treatments? “Ongoing effects with repeated administration, we don’t know.” That will be the next question asked in further research.

One caution to remember there is a big difference between stressed mice and depressed humans. Anna Beyler, a neuroscientist of the University of Bordeaux, France, also added: “There’s no real way to measure synaptic plasticity in people, so it’s going to be hard to confirm these findings in humans.” Stay tuned for more mice research.

However, ketamine research is not focused solely on depression. There was a study published in Nature Communications that investigated how maladaptive reward memories (MRMs) are associated with developing and maintaining the overconsumption of alcohol: “Ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories.” The researchers found that a single infusion of ketamine combined with motivational enhancement (MET) counseling can help heavy drinkers curb their drinking. Ninety people who drank an average of four to five pints of beer a day were recruited for the study.

These findings demonstrate MRM reconsolidation interference by ketamine and rewriting of reward structures surrounding alcohol. The subsequent, lasting clinical benefits observed suggest that this one-session intervention approach should be pursued in the future treatment of alcohol related disorders.

The study’s lead researcher, Ravi Das said to Merrit Kennedy of NPR: “When people become addicted, they’re learning that kind of behavior in response to things in their environment.” He added that those memories can be long lasting and become ingrained. “Current treatments don’t target those.” Das and the other researchers thought ketamine might be able to target a heavy drinker’s memories of drinking triggered just before they received a dose of ketamine. The results were said to be a dramatic decrease in the amount of alcohol consumed. “Given the high levels of problematic drinking in the current sample, one may reasonably expect similar effects to be observed in a more severely dependent/treatment-seeking population and there is now a strong rationale to conduct such clinical trials in formally diagnosed populations.”

Peter Simons reviewed the study for Mad in America, “Ketamine for Harmful Drinking: A Look at the Data.” One of the first things he noted was while the article claimed “ketamine can reduce harmful drinking by pharmacologically rewriting drinking memories,” the results were more nuanced and not as positive as presented. “In fact, the group that did not receive ketamine had lower levels of alcohol use throughout the study.” The researchers based their experimentation on a memory-based theory of how problem drug abuse develops. According to the theory, memories of the rewards associated with drug use are triggered when a person sees the drug, which causes them to want more of it.

The theory underlying this study is that ketamine may cause short-term memory loss. But the research did not directly test this idea. Rather, the researchers looked at a broader idea—that a ketamine infusion may reduce problematic drinking.

There were three groups in the study. One group received a placebo instead of ketamine and also the alcohol memory task (RET+PBO), another ketamine and alcohol memory task (RET+KET), and the third group had no memory task and ketamine (NO RET +KET). The researchers found that the ketamine infusion and alcohol task group drank far less than their baseline levels. But they also began the study with a significantly higher baseline of drinking than the other two groups. All three groups did better over time and the group that received ketamine and the alcohol task (RET+KET), did worse than the other groups until the nine-month end point of the study, when all three groups were drinking about the same amount of alcohol. The researchers interpreted their findings as meaning that ketamine successfully reduced the amount of alcohol drank by the study’s participants. See the following chart.

However, as Peter Simon noted, “This finding is what would be predicted by chance.”

One statistical phenomenon that occurs by chance is called regression to the mean. In that phenomenon, groups that start at an abnormally high (or low) point on any scale are more likely to return to the average over time. For instance, let’s say an event occurs—like a wedding, or a holiday celebration, during which you drink much more than usual. You are most likely to return to your regular drinking amount afterward. And that’s what we see here.

The researchers do acknowledge this possibility, saying in their study, “We cannot rule out regression to the mean as a contributing factor to the observed reduction in alcohol consumption.” Yet they denied that regression to the mean was responsible for their results, calling that commonly occurring statistical phenomenon “highly unlikely.” Asserting the significance of their findings, the researchers said the lasting clinical benefits observed suggested this intervention approach should be pursued in the future treatment of alcohol use disorders.

There is another limitation to the significance of the findings in how they conceived harmful alcohol use. The researches understood problem drinking as fundamentally a learned behavior problem. “Overconsumption disorders such as harmful drinking, alcohol and substance use disorders (AUDs, SUDs), which represent leading causes of global preventable mortality and morbidity, are fundamentally acquired or learned behaviours.” Such a conception of substance use disorders is reductionistic. There is a clear element of learned behavior in the development of a drinking problem, and there is clear evidence of there being a physiological element for many individuals with alcohol use disorders (See “The Genetic Connection”).

Following the thinking of Carleton Erickson in The Science of Addiction, there is a distinction between what earlier editions of the DSM called drug abuse and drug dependence. “According to these criteria, drug abuse is intentional, ‘conscious,’ or voluntary. Drug dependence is pathological and unintended.” Alcohol dependent people have a dysregulation of the mesolimbic dopamine system and typically cannot stop drinking without intensive intervention. There is an overlap between individuals with an alcohol abuse problem and those with an alcohol dependence problem, illustrated by this chart derived from the first edition of The Science of Addiction:

Alcohol Abuse	Alcohol Dependence	Alcohol-Seeking
Mild		Little/None
Moderate		Some
Severe	Mild	A Lot
	Moderate	Even more
	Severe	All the Time

Alcohol Dependence was a continuous and compulsive pattern of use, often with tolerance and withdrawal symptoms, suggestive of a physical dysregulation. Most alcohol abusers “never become addicted in any meaningful sense.” The abuse/dependence distinction for substance use disorders was part of the DSM diagnostic system before the DSM-5. The DSM-5 collapsed the distinction between abuse and dependence, establishing a continuum of alcohol use disorder instead of two separate disorders of alcohol abuse and alcohol dependence. As a result, the above noted diagnostic distinction between abuse and dependence was lost or became unclear. The ability to discern diagnostically between learned substance problems and substance problems driven by physical dysregulation was muddled in the DSM-5.

Only individuals who were never formally diagnosed with a substance use disorder were included in the study. So, this meant that individuals who were most likely to exhibit symptoms of physical dependence, such as withdrawal, cravings and an inability to limit or control their alcohol use, were excluded from the study. Was the subject pool of participants unintentionally made up of individuals most likely demonstrate the study’s results? Were the individuals in the study heavy drinkers who were not on the way to developing what was called an alcohol dependence disorder? What works with undiagnosed heavy drinkers may not work with individuals who are alcohol dependent, who have a moderate or severe form of alcohol use disorder.

For more information on DSM diagnosis and substance use, see: Misdiagnosing Substance Use. For more information on ketamine, see: Ketamine to the Rescue?, Family Likeness In Depression Drugs? or Psychedelic Depression.

06/12/18

Esketamine Craze

U.S. Department of Justice photo; in the public domain

I’ve been following the research on treating depression with ketamine and its analogue, esketamine, for over three and a half years. Since I wrote “Falling Down the K-Hole,” that research has progressed—as has the hype and unbridled enthusiasm for ketamine and esketamine as fast-acting antidepressant treatments. It seems there was also a recent media blitz extolling esketamine as “a promising new depression treatment.” Not-so-coincidentally, Janssen researchers (and others) recently published the latest results of their ongoing research with esketamine in The American Journal of Psychiatry.

The American Journal of Psychiatry study by Canuso et al. reported the results of a completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT02133001). It follows another Janssen study by Daly et al. published in JAMA Psychiatry on the efficacy and safety of intranasal esketamine. The Daly et al. study reported the results of another completed Janssen clinical trial (ClinicalTrials.gov Identifier: NCT01998958).

The Daly et al. study was published in February of 2018, while the Canuso et al. study was published on April 16, 2018. The Fix published an article on the “new study” (Canuso et al.) on April 20^th, as did The Washington Post, where it was said to be a potential “major advance in the treatment of suicidal depression.” WebMD discussed the study in an article published on April 17^th, and Medical News Today published its “announcement” on April 18^th. Additional articles include ones by Business Insider, Newsweek and BBC News—all on April 16^th—to name just a few news organizations.

Janssen Pharmaceutical Companies of Johnson & Johnson is ahead in the “race” to bring its esketamine nasal spray to market as the first of a new class of psychiatric medications known as “glutamate receptor modulators,” which are also being investigated as treatments for bipolar disorder and schizophrenia. The FDA awarded esketamine “breakthrough” status in 2016, meaning it is fast-tracking the drug through the approval process. The above two linked articles report the results of Phase 2 clinical trials, while a Phase 3 trial in underway (ClinicalTrials.gov Identifier: NCT02782104).

On May 5, 2018 Janssen and J&J announced the completion of two Phase 3 Clinical Trial studies. FierceBiotech noted J&J’s intention to present the results from the studies at the American Psychiatric Association’s annual meeting the weekend of May 5^th-6^th. The study of adults with treatment resistant depression met its primary endpoint, demonstrating a statistically significant improvement in patients’ depressive symptoms. Three secondary endpoints were not met. The study of elderly patients with treatment resistant depression “narrowly missed” its primary endpoint. FierceBiotech reported J&J said the elderly patient group often has lower response rates to antidepressants, which could explain the result.

A review of the two studies by Health News Review suggested Janssen had highlighted insignificant findings alongside modest results with its esketamine nasal spray. They noted where the press release gave a good deal of information about trial protocols and specific differences in the depression scale that was used, but didn’t address cost. “While there may be promising results to report, the findings are reported in a way that makes it difficult to understand the advances — or even to tell the advances from the things that were inconclusive.”

This release is, frankly, confusing. Hundreds of words are spent describing a trial for which there were no statistically significant findings, with the pharmaceutical manufacturer arguing that the findings should be considered anyway. The release also refers repeatedly to the “newly initiated oral antidepressant” used in both the control and placebo groups for both studies, without any information about which antidepressants were used. The release does refer to two pages on ClinicalTrials.gov, which contain relevant information on the first trial and on a second trial focused on older adults. But honestly, that’s not good enough. And the failure to address cost, even in general terms, is deeply problematic. What’s more, the primary efficacy endpoint (i.e., how they could tell whether the drug worked) is described in technical terms that are difficult to parse for many readers.

Nevertheless, as FierceBiotech noted: “J&J remains confident it is on course to file the nasal spray formulation for approval in treatment-resistant depression in the second half of the year.”

The Daly et al. study in JAMA Psychiatry reported that intranasal esketamine appeared to have a rapid antidepressant effect for more than 2 months with continued, but reduced frequency dosing. The Canuso et al. study in The American Journal of Psychiatry supported the conclusion of a rapid improvement in depressive symptoms, adding there was also evidence of improvement with some measures of suicidal ideation among patients at imminent risk for suicide.

However I’m concerned the media hype on the benefits of esketamine may sometimes be running ahead of the results. You have to carefully read the above articles in order to get through the praise for the “fast-acting benefits” of esketamine nasal spray before getting to get to the limitations of the research and the concerns with using ketamine and esketamine to treat depression. One of the first limitations to realize with both Daly et al. and Canuso et al. is that all participants in those studies were still taking their prescribed antidepressants in addition to intranasal esketamine. And as with previous ketamine studies, the beneficial effects of esketamine were temporary.

There were significant improvements noted in depressive symptoms at four and twenty-four hours, but at the 3-day mark, the initial dramatic improvement had flattened out, according to The Washington Post. “And by the end of the trial, at four weeks, there was no difference between the esketamine group and the control group.” Medical News Today added that there was a significant improvement in measures of suicidal thoughts after 4 hours, “but not after 24 hours” or the end point of the study at 25 days.

BBC News reported where the Royal College of Psychiatrists said the Canuso et al. study was significant, bringing esketamine “a step closer to being prescribed in the NHS.” It also pointed out how the effects had leveled out by 25 days. WebMD said psychiatrists “were cautiously optimistic” about the potential for ketamine in treating depression. Again the limited effects were noted. They added the potential for ketamine (and esketamine) to be misused. The most common side effects among participants taking esketamine included nausea, dizziness, dissociation (a sense of detachment from reality), headache and an unpleasant taste.

There was a rare editorial signed by the majority of the board of the American Journal of Psychiatry, the journal that published the Canuso et al study. They noted how the effects of intranasal esketamine were similar to those found with intravenous ketamine. If positive, longer-duration results emerged for intranasal esketamine, “it is possible that this treatment will help a significant number of patients who do not respond adequately to existing antidepressant therapies.” After reviewing the history of what “led to a national epidemic of opioid-caused deaths,” they noted how preventing abuse was seldom raised as a concern in the rise of prescription opioid use.

Ketamine drug-seeking behavior has already appeared as a clinical issue, with some patients shopping infusion clinics to obtain repeated injections for mood elevation. Some patients use the intravenous formulation intranasally repeatedly without supervision. Diversion of ketamine intended for pediatric and veterinary anesthesia, its current approved use, is occurring already.Canuso et al. observed an attenuation of ketamine-specific clinical response over time; the failure to demonstrate longer-term benefits raises questions about the risk versus the benefit of long-term use.

The authors of the editorial referred to “A Consensus Statement on the Use of Ketamine in the Treatment of Mood Disorders,” published online on March 1, 2017 by the American Psychiatric Association. The Consensus Statement only has intravenous ketamine in mind, but many of the expressed concerns also apply to intranasal esketamine. The report said its main intent was to highlight the current state of the field and the critical issues to be considered when contemplating the use of ketamine for treatment-resistant depression. The following excerpts are from the APA Consensus Statement:

Considering the known potential for abuse of ketamine and recent reports of abuse of prescribed ketamine for the treatment of depression, clinicians should be vigilant about assessing the potential for patients to develop ketamine use disorder. Close clinical follow-up with intermittent urine toxicology screening for drugs of abuse and inquiries about attempts to receive additional ketamine treatments at other treatment centers should be implemented when clinical suspicion of ketamine abuse is present. Moreover, the number and frequency of treatments should be limited to the minimum necessary to achieve clinical response. Considering the evidence suggesting that the mechanism of action requires some delayed physiological effect to the treatment and does not appear to require sustained blood concentrations of the drug to be present, there is no evidence to support the practice of frequent ketamine administration. At this point of early clinical development, we strongly advise against the prescription of at-home self-administration of ketamine; it remains prudent to have all doses administered with medical supervision until more safety information obtained under controlled situations can be collected. Discontinuation of ketamine treatment is recommended if the dosing cannot be spaced out to a minimum administration of 1 dose per week by the second month of treatment. The goal remains to eventually taper and discontinue treatment until more long-term safety data can be collected. The rapid onset of robust, transient antidepressant effects associated with ketamine infusions has generated much excitement and hope for patients with refractory mood disorders and the clinicians who treat them. However, it is necessary to recognize the major gaps that remain in our knowledge about the longer-term efficacy and safety of ketamine infusions. Future research is needed to address these unanswered questions and concerns.

Clearly, the American Psychiatric Association is concerned with longer-term efficacy and safety concerns with ketamine, particularly its potential for misuse and abuse. But that isn’t the end of concerns for ketamine and esketamine.

Janssen said esketamine belonged to a new class of drugs in psychiatry known as “glutamate receptor modulators.” They speculated that esketamine could “help restore synaptic connections in brain cells in people with major depressive disorder.” Yet two Cochrane studies questioned the efficacy of ketamine and other glutamate receptor modulators for depression and bipolar depression. Cochrane is a global independent network of researchers, professionals, and others who “work together to produce credible, accessible health information that is free from commercial sponsorship and other conflicts of interest.” Their work is recognized as an international gold standard for high quality, trusted information.

“Ketamine and other glutamate receptor modulators for depression in adults,” by Caddy et al., sought to find out if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable than placebo and other antidepressants. Only ketamine was more effective than placebo at reducing symptoms of depression. However, “These effects lasted no more than one week after treatment and clearly disappeared after two weeks.” Ketamine also caused more confusion and emotional blunting than placebo. “There was no evidence of a difference between the other nine glutamate receptor modulators included in this review and placebo or other medications.” The review concluded there was limited evidence that ketamine reduced symptoms of depression when compared to placebo.

“Ketamine and other glutamate receptor modulators for bipolar depression” sought to answer the same questions, namely if ketamine and other glutamate receptor modulators were more effective than placebo or other antidepressants and whether they were more acceptable. It was possible that ketamine could be an effective add-on medication to mood stabilizers for people with acute bipolar depression, “but due to the small amount of data usable for analysis we are unable to draw any firm or reliable conclusions.

Reliable conclusions from this review are severely limited by the small amount of data usable for analysis. The body of evidence about glutamate receptor modulators in bipolar disorder is even smaller than that which is available for unipolar depression. Overall, we found limited evidence in favour of a single intravenous dose of ketamine (as add-on therapy to mood stabilisers) over placebo in terms of response rate up to 24 hours; ketamine did not show any better efficacy in terms of remission in bipolar depression. Even though ketamine has the potential to have a rapid and transient antidepressant effect, the efficacy of a single intravenous dose may be limited. Ketamine’s psychotomimetic effects could compromise study blinding; this is a particular issue for this review as no included study used an active comparator, and so we cannot rule out the potential bias introduced by inadequate blinding procedures.

A very small pilot study done by the Black Dog Institute in Sydney Australia was published March 15, 2018 in the Journal of Psychopharmacology. The study sought to investigate how repeated use of intranasal ketamine might work for patients with severe and treatment-resistant depression. All participants were trained to self-administer the ketamine nasal spray; the process was similar to other commonly used nasal spray medications. But the study participants could not get through the needed ten sprays to get the full dose.

As soon as the ketamine hit their bloodstreams, the subjects started losing motor coordination, which got so bad that none of them managed to do all the sprays without the help of research staff monitoring the treatment. When the researchers tried to space out the nasal sprays with a five-minute interval, things only got worse – the subjects’ blood pressure shot up, and they started experiencing psychotic-like effects as well.

The study had to be cut short because of the adverse side effects. The researchers pointed to an earlier ketamine nasal spray trial where the drug was well tolerated. They speculated the 2014 trial had better tolerance because of a lower dose (50mg instead of 100mg) and their study’s participants being trained to use the nasal spray, resulting in their subjects ending up with higher levels of the drug in their blood streams. “Our results suggest that absorption via the intranasal mucosa may be too rapid when careful attention is paid to the administration technique, resulting in the development of rapid and intense side effects.”

So despite the hype and unbridled enthusiasm for the potential of ketamine and its analogue esketamine as fast-acting antidepressant treatments, the existing evidence is not conclusive. And the safety and efficacy concerns, particularly with regard to long-term use and addiction, are not known. Existing evidence with intravenous ketamine suggests the real potential for abuse. And it doesn’t look like it will be a good idea for subjects to self-administer intranasal ketamine or esketamine in the privacy of their homes.

10/6/17

Is Ketamine Really Safe & Non-Toxic?

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

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

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 26^th 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.

04/19/16

Ketamine to the Rescue?

Enthusiasm for using ketamine to treat depression has been growing. The interest in the fast action effects of ketamine for treatment-resistant depression began with the publication of a study by Zarate et al. in 2006 that found “Subjects receiving ketamine showed significant improvement in depression compared with subjects receiving placebo within 110 minutes after injection.” Since then, dozens of studies have been done and thousands of people have been treated for depression off label with ketamine. Now the American Psychiatric Association has a ketamine task force and is seriously considering an endorsement of ketamine for treatment-resistant depression.

An NPR story featured psychiatrist David Feifel’s work in treating depression with ketamine. Feifel began treating people with low dose ketamine in 2010. After reading the papers on ketamine, he said he was electrified. People were getting better in hours. “It became clear to me that the future of psychiatry was going to include ketamine, or derivatives of ketamine, or the mechanism of action in some way.”

He said it was hard for him to take the “wait and see” approach suggested by other psychiatrists when people are desperate for help. It didn’t make sense to him. Sara Solovitch, writing for The Washington Post, said some experts are calling it the most significant advance in mental health treatment in fifty years.

Ketamine has been around since the 1960s. It is regularly used as an ER anesthetic because it can rapidly stop pain without affecting vital functions like breathing. It’s often the go-to painkiller for children who come to the ER, say with a broken bone. It’s used in veterinary medicine and is an important tool in burn centers. It’s also been used as date-rape drug, because of some of the self-same properties that make it an attractive ER anesthetic. It will quickly numb and render someone immobile.

A single dose of ketamine costs under $2. The drug is easily available in any pharmacy; and doctors are free to prescribe it for off-label use. But ketamine treatment for depression is expensive. Dr. Feifel charges $500 for an injection and $1,000 for an intravenous infusion. The high cost is attributed by practioners to the medical monitoring and IV equipment required during an infusion.

It isn’t an approved depression treatment, so the costs are out-of-pocket, placing it out-of-reach for many people. But clinics are going up everywhere. A directory found 19 different centers in the US as of the beginning of February, in 2016. Dr. Feifel is afraid something will happen to a depressed patient at one of these unregulated clinics that could set back efforts to make the drug more widely available.

Sara Solovich reported there a growing number of academic medical centers that are offering ketamine treatments off-label for severe depression. These medical centers include: Yale University, the University of California at San Diego, the Mayo Clinic and the Cleveland Clinic. A San Francisco psychiatrist, Alison McInnes, thinks this is the next big thing in psychiatry. Psychiatry has “run out of gas” in trying to help depressed patients. “There is a significant number of people who don’t respond to antidepressants, and we’ve had nothing to offer them other than cognitive behavior therapy, electroshock therapy and transcranial stimulation.”

Dr. McInnes reported a 60% success rate for people with treatment-resistant depression who try ketamine. Dr. McInnes is also a member of the APA’s ketamine task force. She expects the APA to support ketamine treatment in 2016.

Ryan, Marta and Koek did a literature review on ketamine as a treatment for depression in a 2014 issue of the International Journal of Transpersonal Studies, “Ketamine and Depression: A Review.” They acknowledged that the largest challenge with ketamine was extending its benefit for the longer term. Repeated infusions of ketamine showed some promise, but it is far from clear what the optimum dose, frequency and number of infusions should be. “It also worth noting that some patients do not benefit from ketamine, despite multiple treatments.”

Ready for the drawbacks? “Even low-dose ketamine infusion can cause intense hallucinations.” Patients experience a kind of lucid dreaming or dissociative state where they lose track of time and have out-of-body experiences. Many people enjoy it; but others don’t. The treatment effects are often temporary. Dr. Feifel reported one patient whose depression remission would begin to fade within twenty-four hours. With others, the remission can be longer; even weeks. The fleeting remission effect means that many patients return for booster infusions. A business executive from Seattle flies back-and-forth to New York for bimonthly infusions. Sometimes his remission periods will last six months.

Gerald Sanacora, the director of the Yale Depression Research Program, said ketamine infusion is an extremely important treatment. His concern is that people may begin using it as a first-line treatment—before CBT (cognitive behavioral therapy) or antidepressants like Prozac. “Maybe someday it will be a first-line treatment. But we’re not there yet.”

It’s a medication that can have big changes in heart rate and blood pressure. There are so many unknowns, I’m not sure it should be used more widely till we understand its long-term benefits and risks.

There isn’t a registry yet for tracking ketamine patients treated for depression. So the number of people treated, the frequency of those treatments, the dosage levels, follow up care—and importantly—adverse effects from ketamine treatment aren’t known. Carlos Zarate, the NIMH’s chief of neurobiology and treatment of mood disorders, said: “We clearly need more standardization in its use.” In his opinion, it should still be used in a research setting or a highly specialized clinic.

There also seems to be a turf war or sorts brewing. Ketamine was once almost exclusively a drug known to anesthesiologists. Psychiatrists are now saying that with the use of ketamine for depression growing, it should be left for psychiatrists to prescribe. David Feifel said:

The bottom line is you’re treating depression. . . . And this isn’t garden-variety depression. The people coming in for ketamine are people who have the toughest, potentially most dangerous depressions. I think it’s a disaster if anesthesiologists feel competent to monitor these patients. Many of them have bipolar disorder and are in danger of becoming manic. My question [to anesthesiologists] is: “Do you feel comfortable that you can pick up mania?”

Six of the providers in the above-linked directory are specialists in anesthesiology. Six are psychiatric specialists. The rest are a mixture of specialists in emergency medicine, neurology, internal medicine and even family medicine. Enrique Abreu, A Portland Oregon anesthesiologist who began treating depressed patients with ketamine in 2012, said: “Most anesthesiologists don’t do mental health, and there’s no way a psychiatrist feels comfortable putting an IV in someone’s arm.”

Ketamine in larger doses than are being used in the above discussed depression research is a club drug known as “Special K,” “K,” or Ket.” It is a Schedule III Controlled Substance, meaning it is classified as having an addictive potential. Current depression research has not indicated dependence as an adverse effect, likely because of the low doses currently being used. When used with other sedating drugs like alcohol, the potential of slowing or shutting down the central nervous system are increased. And it is possible to overdose on ketamine. While some clinicians like Drs. Feifel and McInnes would like to see ketamine treatment revolutionize the psychiatric treatment of depression, caution in waiting for the results of further research seems advisable.

Unfortunately, I don’t think that will happen. Psychiatric treatment of depression is in crisis. Even the articles and researchers cited here seemed to acknowledge this. Dr. McInnes said psychiatry has “run out of gas” in trying to help depressed patients. Dr. Fiefel said he found it hard to “wait and see” what further research found regarding ketamine, when so many people were desperate for help.

Pharmaceutical companies stopped doing research into new antidepressants. The chemical imbalance theory of depression is now referred to as more of an urban myth than a true description. Pharma and psychiatry need an antidepressant savior and it seems they hope it will be ketamine.

07/8/15

Family Likeness in Depression Drugs?

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.

10/8/14

Falling Down the K-Hole

Over the past few years, there has been an increased interest in using ketamine to treat depression and other psychiatric disorders, such as PTSD. It is fast acting relief for symptoms of both depression and PTSD. For depression, it is effective within two hours and was reported to help a greater proportion of individuals than traditional antidepressants. Sounds like there is tremendous potential here, right? Maybe.

A 2006 study by lead author Carlos Zarate and other researchers found that subjects receiving a single dose of ketamine “showed significant improvement in depression” within 110 minutes after injection. “Robust and rapid antidepressant effects resulted from a single intravenous dose of [ketamine]; onset occurred within 2 hours postinfusion and continued to remain significant for 1 week.” However, it was reported by Franz Vallenweider and Michael Kometer that: “all but 2 of the patients relapsed within 2 weeks after a single dose of ketamine.”

A 2011 study (and here) confirmed the alleviation of major depressive symptoms within two hours from a single, low-dose of ketamine. Its effects lasted up to two weeks. The researchers suggested that ketamine appeared to work so quickly by increasing the synthesis of BDNF, or brain-derived neurotropic factor. The increase in BDNF is caused by ketamine deactivating a chemical that normally suppresses BDNF production. “BDNF is a nerve factor that helps brain cells grow and develop new neurons.”

A 2012 study by lead author Matthew Sanjay and others reviewed the emerging literature on the potential rapid-onset antidepressant properties of ketamine. They cited data from a 2009 study that ketamine was associated with “rapid reductions in explicit and implicit suicidal cognitions within the first 24 hours.” They also noted a report from the NIMH where patients previously non-responsive to ECT (electro convulsive therapy) “showed significant improvement in depressive symptoms.”

There were acute impairment of working, episodic and semantic memory, but it did not effect the retrieval of previously learned information. The acute impairments were also temporary. There were no residual deficits found 3 days after drug administration. The Sanjay study concluded that enthusiasm for the early ketamine studies should be tempered by concerns for the validity of these studies; that the antidepressant action is short lived; and uncertainty regarding its safety with a depressed population. “Accordingly, ketamine therapy remains a highly experimental treatment approach for MDD and adoption in psychiatric practice settings at this time is premature.”

Another 2012 article, “Ketamine for Depression: Where Do We Go from Here?” said that while adverse effects had generally been mild, some patients experienced brief changes in blood pressure, heart rate, or respiration. They supported further research of ketamine to treat mood disorders. “However, given the paucity of randomized controlled trials, lack of an active placebo, limited data on long-term outcomes, and potential risks, ketamine administration is not recommended outside of the hospital setting.”

A 2013 study reported in the American Journal of Psychiatry was a randomized controlled study. Ketamine again demonstrated rapid antidepressant effects. It added further support to studies showing that NMDA receptor modulation as a potential mechanism for “accelerated improvement in severe and chronic forms of depression.” Reservations on its use in clinical practice were again expressed because of its short action and safety concerns.

Ketamine is not a new drug. It was developed in 1962 by Parke-Davis and is used as an anesthetic in human and veterinary medicine, usually in combination with another sedative drug. It has been used for several decades as a recreational drug under nicknames such as “Special K,” “K” or “Ket.” It makes users feel disassociated or disconnected from their body and can cause hallucinations. The user can feel sleepy, sluggish, confused or clumsy. They may babble, appear drunk, or have trouble remembering who they are.

It comes as a clear liquid and a white or off-white powder. It can be injected, mixed in a drink as a date-rape drug or sprinkled on tobacco or marijuana and smoked. It is virtually tasteless and causes a person to become disoriented, confused, suggestible, easily manipulated and compliant.

The victim is usually compliant, suggestible, and shows no overt resistance. As a result they can be easily led into a private setting and usually do not resist whatever is done to them. When given in a sufficient dose the victim has no memory of what happened. On the street this period of dissociated amnesia is called ‘being stuck in the K hole.’

The K-hole state can mimic catatonic schizophrenia, out-of-body experiences or near-death experiences. Since it is an anesthetic drug, ketamine could cause vomiting with its use. And “eating or drinking before taking the drug increases the risk of choking on one’s own vomit.” It is addictive, classified as a Schedule III drug by the DEA. Taken with other sedating drugs like alcohol, the effects of slowing or shutting down the central nervous system are increased. It is possible to overdose on it.

The 2014 Global Synthetic Drugs Assessment reported that ketamine is widely misused in East and South-East Asia; more than in the Americas and Europe. “Extensive ketamine use has also been reported in Brunei Darussalam, India, Myanmar and Singapore.” Between 2008 and 2011, 60% of global ketamine seizures occurred in mainland China and Hong Kong.

In “A Word to the Wise About Ketamine,” Alan Schatzberg noted that the data on ketamine as an antidepressant is still relatively limited. He said that without more data on what ketamine can do clinically, and knowing it can be a drug of abuse, “it is difficult to argue that patients should receive an acute trial of ketamine for refractory depression.” Waiting until there was greater understanding about its effects and risks was his recommendation. Although the recent studies are exciting and open up new avenues for depression research, “until we know more, clinicians should be wary about embarking on a slippery ketamine slope.”

The almost unbridled enthusiasm over the potential of ketamine to treat depression needs to be reined in. We don’t want to find ourselves “falling down the k-hole” instead of exploring ketamine’s potential to treat depression.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: ketamine for depression