Tag: esketamine for depression

09/3/19

Red Flags with Spravato

Darryl Brooks | 123rf.com

Spravato (esketamine) was approved as a fast-acting antidepressant for treatment-resistant depression in March 2019. There were several problems with the FDA’s approval of the drug, including the price—nearly $900 per dose, the acceptance of a withdrawal study for the needed second positive clinical trial, and the fact that it carries a boxed warning that cautions patients are at risk of “suicidal thoughts and behaviors after administration of the drug.” And like ketamine, it is a Schedule III controlled substance, putting patients at risk for abuse and misuse. It seems Spravato needs some positive spin to win a patient population.

Dr. John Miller obliged, writing an article for Psychiatric Times, “Depression’s Journey From Monoamines to Glutamate.” He traced the history of ketamine as a racemic mixture, meaning it has an equal mixture of esketamine and arketamine. Janssen developed its intranasal spray with esketamine and named this new molecular entity Spravato. The so-called “paradigm shift” of depression treatment with ketamine acting on the NMDA glutamate receptor, and appearing to reduce depressive symptoms within 72 hours, was contrasted with the older, traditional monamine hypothesis of depression that would take weeks. All other FDA-approved antidepressants before Spravato act on the monoamine system.

Dr. Miller then guided his readers through a review of the two positive clinical trials submitted to the FDA for approval of Spravato. There were actually five phase 3 clinical trials, meaning Spravato failed to demonstrate statistical significance in three of the five clinical trials. Nevertheless, he saw Spravato as crossing into “a new paradigm of TRD [treatment resistant depression].” He hoped esketamine was the first of “a long list of non-monoamine-based treatments to help improve the lives and functioning of the many individuals suffering from TRD.” By the way, Dr. Miller is on Janssen’s Advisory Board as well as the Speaker’s Bureau for Spravato.

Another study by Daly et al, “Efficacy and Safety of intranasal Esketamine Adjunctive to Oral Antidepressant Therapy in Treatment-Resistant Depression” found a “clinically meaningful treatment effect” versus placebo. The antidepressant response was rapid and dose related. It seemed to persist for more than 2 months with a lower dosing frequency. Jodi Rintelman reviewed the study for The Mental Elf, and said it gave hope for a fast-acting antidepressant. Depression scores showed statistical improvement in seven days. “That’s a huge improvement over SSRIs, which can take 4 to 8 weeks to show significant improvement in mood.”

CEP (Council for Evidence-Based Psychiatry) pointed out on Twitter how the Mental Elf article initially failed to note that eight of the study’s authors were Janssen employees. In the comments section to the blog, Andre Tomlin then cited two paragraphs quoted below that appeared in the blog article afterwards. The first was added to the Strengths and Limitations section and the second was in the Implications for Practice section.

The authors also may have a vested interest in Spravato’s commercial success. Renaissance Pharmaceuticals, LLC is manufacturing Spravato for Janssen Pharmaceuticals, Inc. Eight of the authors, including the lead author, work for Janssen Research & Development and hold stock in the company. As the U. S. Food and Drug Administration continues to provide less money for drug development, drug companies are picking up the slack. The impact of this funding trend on our patients is not yet known.

It’s important to note that while no deaths were reported in this trial, in the trials reported to the FDA for consideration, there were six deaths in the treatment arms. While none of the deaths were proven to be drug-related, three people died from suicide, one from a motorcycle accident, one had a heart attack, and the sixth person likely died as a result of complications from hypertension and obesity.

Then Bloomberg reported President Trump offered to help the Department of Veterans Affairs to negotiate the acquisition of Spravato, saying he had “really read quite a bit” about the drug and believed it could help reduce the suicide rates of veterans. He told the Veteran Affairs Secretary, Robert Wilkie, he thought Johnson & Johnson (the parent company of Janssen) would be very generous to the VA. The President said:

Give it to anybody that has the problem, because you have people calling and our folks do a great job on the phone — but it’s a telephone. . . . You have people calling for help and if those people had that, I’m hearing like instantaneously they’re in better shape.

Wilkie acknowledged the medicine was “very effective” and hoped Spravato would have the drug in all VA hospitals by the end of the year. But concern that the President’s remarks were contributing to a rushed approval by the VA, led Mark Takano, the Chairman of the House Committee on Veterans’ Affairs, to say:

I am incredibly alarmed by reporting today that suggests Spravato, a controversial new drug, is being rushed through critical reviews and may be prescribed to veterans before fully vetting the potential risks and benefits.

Already, many concerns have been raised about the drug’s safety and efficacy, its suspicious fast-track approval through FDA review, and VA’s contracting process. Today’s reporting raises additional concerns that VA’s own process for objective review is being undercut by undue influences.  Questions remain about the ultimate impact on the health and safety of veterans, who should not be made into a “test case” while the clinical community continues to gather data about this treatment.

We demand that VA provide documents and information about its review and contracting process to adequately address critical questions—including whether VA officials were pressured by the White House or the Mar-a-Lago “three” to prescribe this drug to veterans. Spravato should not be added to VA’s formulary until we have more answers about what this means for our nation’s veterans.

The VA announced that it would offer Spravato for treatment-resistant depression, but would not include it on the VA’s formulary, meaning doctors need prior approval before prescribing and buying the medication for patients. A VA spokesperson said VA psychiatrists could offer Spravato “when clinically indicated,” but would have to keep “with the FDA-approved indications for esketamine use and safety requirements.” Susan Carter, the VA’s director of media relations said the VA will closely monitor the drug’s use and effectiveness and compare it with other treatments. Mark Takano said he asked the VA to provide documents and information to ensure the VA was not “pressured by the White House” to prescribe Spravato to veterans. Takano said: “Spravato should not be added to VA’s formulary until we have more answers about what this means for our nation’s veterans.”

Three psychiatrists, including one who is a therapist for the MAPS Clinical Study of MDMA-Assisted Psychotherapy for PTSD, wrote an opinion article for Vice, “The New Ketamine-Based Antidepressant Is a Rip-Off.” They pointed out where esketamine was no better than placebo in two of the three short-term Phase III trials submitted to the FDA for approval. Yet they thought the problems with the drug weren’t the biggest concern. Spravato (esketamine) is just a way for “Johnson & Johnson to make a significant profit off gullible insurance companies and vulnerable patients.”

Ordinary ketamine is a racemic medication, meaning it is made up of two molecules that are mirror images of each other. Because ordinary ketamine is generic, Johnson & Johnson simply isolated one of the two molecules in regular ketamine so that it qualified as “new.” The reality is that we don’t know whether esketamine is more or less effective than regular ketamine because there have been no head-to-head trials between the two. Johnson & Johnson only tested esketamine against a placebo, likely because they feared esketamine might actually perform worse than the generic version.

Kaiser Health News described a series of red flags overlooked by the FDA with Spravato. There was only modest evidence of its effectiveness and then only in limited trials. Janssen provided no information on the safety of Spravato for long-term use beyond 60 weeks. And as noted above, there were three patients who died by suicide during clinical trials. Facing political pressure to rapidly bring drugs treating life-threatening conditions to market, the FDA endorsed it anyway.

Some deep misgivings were expressed by members of the FDA advisory board in its day-long review meeting. Dr. Jess Fiedorowicz, a member of the advisory committee and the director of the Mood Disorders Center at the University of Iowa, said Spravato’s benefit was “almost certainly exaggerated.” He was surprised by the vote, which was strongly in favor of the drug. The approval process for esketamine (Spravato) shows how drug makers take advantage of several steps in the FDA approval process to bring a potentially lucrative drug to market.

The first Step was taken in 2013 when Janssen was able to get the FDA to approve esketamine as a “breakthrough therapy” for it potential to rapidly reverse depression. This is a holy grail for suicidal patients, especially those found in emergency rooms. That potential was based upon a two-day study with 30 patients being given esketamine intravenously. This “breakthrough therapy’ status placed esketamine in a fast track for approval, with more frequent input from the FDA.

The second Step in the process occurred during discussions between FDA regulators and Janssen regarding the amount and quality of evidence required by the agency. With regard to Spravato, questions were raised about how many drugs must fail before a patient’s depression in considered “treatment-resistant”? And how many successful clinical trials are necessary for FDA approval of a potentially life-saving drug?

The third Step left the FDA’s expert advisory committee hamstrung in reaching a verdict before they met. With Spravato, the FDA had pre-approved Janssen’s study design. This caused Fiedorowicz to abstain from voting because he considered the study design to be flawed.

The expert panel cleared the drug according to the evidence that the agency and Janssen had determined was sufficient. Dr. Matthew Rudorfer, an associate director at the National Institute of Mental Health, concluded that the “benefits outweighed the risks.” Explaining his “yes” vote, he said: “I think we’re all agreeing on the very important, and sometimes life-or-death, risk of inadequately treated depression that factored into my equation.”

But others who also voted “yes” were more explicit in their qualms. “I don’t think that we really understand what happens when you take this week after week for weeks and months and years,” said Steven Meisel, the system director of medication safety for Fairview Health Services based in Minneapolis.

Although the drug received breakthrough status for its potential for results in 24 hours, the trials were not strong enough for the FDA to say it was “rapid-acting.” Janssen only provided one successful short-term trial when the FDA typically requires at least two. In order to reach the two-trial threshold, the FDA permitted the company to count a trial conducted for a different purpose: relapse and remission trends. And the single positive efficacy trial showed a mere 4-point improvement in depression symptoms compared to the placebo treatment on a 60-point scale used by some clinicians to measure depression severity. Some committee members pointed out how the study wasn’t really blind since participants could recognize they were getting the drug from side effects like a temporary out-of-body experience.

And finally, the FDA lowered the criteria bar for “treatment-resistant depression.” Initially, that meant trial participants had to have failed two classes of oral antidepressants. Less than two years later, the FDA loosened that definition to say a patient needed to have only failed with two different pills, no matter what the class. Forty-nine of the 227 participants in Janssen’s only successful efficacy trial had failed just one class of oral antidepressants. Dr. Erick Turner, a former FDA reviewer who serves on the committee but did not attend the meeting said “They weeded out the true treatment-resistant patients.”

Red flags were waving all around the approval of Spravato, but they seemed to be disregarded by the FDA. Is the pipeline of developing new antidepressants so bankrupt that the FDA has to turn the clinical trial process into a game of limbo by continually lowering the bar for approval of a new medication?

For more on the worries with ketamine and Spravato, see “Hype and Concern with Esketamine.”

03/12/19

Hype and Concern with Esketamine

© lightwise | 123rf.com

Just before Valentine’s Day in 2019 an FDA advisory panel voted in favor (14 yes, 2 no, 1 abstain) of approving esketamine for the treatment of adult patients with treatment resistant depression (TRD). Psychiatry Advisor reported the decision was based on 5 Phase 3 studies. Patients in the studies had a diagnosis of Major Depression and a history of inadequate response to at least two previous antidepressants, the FDA criteria for TRD. Two of the five studies “showed that esketamine nasal spray plus a newly initiated oral antidepressant was associated with a statistically significant, clinically meaningful, rapid, and sustained improvement of depression symptoms.” So why are some experts concerned and hesitant?

In a STAT News article, Dr. Wendy Marsh said overall, esketamine is definitely of value. Dr. Eric Turner, a psychiatrist who serves on the FDA advisory committee, but couldn’t attend the recent meeting, said: “There’s sort of a split in academia. Some are cheering for something new and others are more skeptical.” Part of the concern is what the label “Treatment Resistant Depression” allows. Writing for Mad in America in “Nasal Spray for Depression? Not So Fast,” Kim Witczak said TRD is the new buzzword that allows drug companies to obtain FDA fast tracking or designation as a “breakthrough therapy.”

Such designation gives the pharmaceutical company the ability to present smaller, fewer clinical trials in order to get their drug to market quicker. While most approved antidepressants currently on the market had to show effectiveness data from at least two positive short-term trials, Janssen only presented one positive short-term trial and the second is an incomplete picture as it is from a withdrawal trial. Janssen’s other trials failed to meet their primary endpoints for efficacy.

Janssen, a subsidiary of Johnson & Johnson, submitted five Phase 3 studies: three short-term, one maintenance and one long-term safety study. One of the positive studies was a randomized trial in adults under the age of 65 with TRD who were started on an oral antidepressant and esketamine. After one month, around 70% of patients taking esketamine responded, where just over 50% in the placebo group had. The second positive study was a maintenance-of-effect study, where participants who responded to esketamine in one of the short-term studies are randomly assigned to either continue with the drug or be switched to a placebo. The FDA typically wants two successful studies, “but historically, withdrawal studies haven’t counted towards the total.”

Eric Turner said: “The threshold has been two adequate and well-controlled trials. In this case, they only got one.” Based on that, he would have voted no had he been at the meeting. Julie Zito was at the meeting and was one of the two advisory committee members who did vote “no,” thinking the risks if esketamine outweighed the benefits. If the drug was approved, she would like to see providers, patients and the families of patients keep tabs on possible side effects and how well the drug is working.

Dr. Gerard Sanacora, a psychiatrist who has been involved in several esketamine trials and has also served as a consultant to Janssen, said: “This is gonna be the big question: How do we use this in the clinic?” Current treatment protocol calls for esketamine to be given twice a week for the first month, then reduced to once a week or once every two weeks during the maintenance phase. But there are still questions about long-term treatment with esketamine, including how long to keep a patient on the medication and what the risks of long-term use might be.

Kim Witzcak also noted there were successful suicides that occurred during the clinical trials that were glossed over or presented as unrelated to esketamine. The FDA “Briefing Document” for the committee indicated there were three successful suicides; all were esketamine-treated subjects. After parsing the differences between all three cases, the Briefing Document said: “Given the small number of cases, the severity of the patients’ underlying illness, and the lack of a consistent pattern among these cases, it is difficult to consider these deaths as drug-related.” Witzcak said: “In my opinion, we need more information on the potential link to suicide before an assumption can be made that it’s safe.”

The adverse events identified in the Briefing Document as of the greatest concern were sedation, dissociation, and increased blood pressure; most of which occurred within the first two hours of administration. In order to minimize the risk of misuse and abuse of esketamine, the committee has proposed the following Risk Evaluation Mitigation Strategies (REMS). The FDA can require REMS for certain medications with serious safety concerns to help ensure the benefits of the medication outweigh its risks. “REMS are not designed to mitigate adverse events of a medication, rather, it focuses on preventing, monitoring and/or managing a specific serious risk by informing, educating and/or reinforcing actions to reduce the frequency and/or severity of the event.”

First, they would ensure esketamine is only dispensed to hospitals, certified outpatient pharmacies, and certified outpatient sites of care. A healthcare professional would monitor patients when they self-administer esketamine and then watch for transient dissociative and blood pressure changes until the patient is stable to leave the healthcare setting.

Second, pharmacies, practitioners and healthcare settings that dispense the drug would be specially certified to be sure esketamine is not dispensed directly to patients. They would be educated about the risks of esketamine and the importance of monitoring patients after the dose is self-administered.

Third, prescribers would register patients in the REMS program. “As part of the enrollment process, patients would be informed of the risks and the need for patients to report adverse events to their provider between patient visits.”

But Witzcak said she thinks most of the FDA Advisory Committee members vote for these controversial drugs and assume the REMS program will address any of their potential safety concerns. “What they fail to realize is that the REMS program is not enforceable and the drug companies are responsible for managing and reporting to the FDA.” She does not trust the drug companies and the FDA to do what they said they would do.

Eric Turner was also concerned with the hype around esketamine. He’s worried that although there is evidence that esketamine works, it will be seen and hyped as superior to other drugs for treatment-resistant depression or as a therapy that can produce rapid results—”two points he says studies don’t yet support.” Gerard Sanacora said patients will often wonder why they can’t just try the drug before seeing whether they respond to standard oral antidepressants. He is concerned the excitement over esketamine will lead patients to want it as a first-line treatment; or even a cure. “The danger is having it so positively portrayed. . . . I’ve been around enough to know this is not necessarily a condition [depression] that responds to miracle drugs.”

The drug is a chemical mirror of ketamine, used as an anesthetic and abused recreationally as “Special K.” For several decades ketamine has been known to be a drug of abuse. And in 1999 it was designated as a Schedule III controlled substance. Ketamine is abused for its dissociative and hallucinogenic effects. It also exists as a popular “club drug” used at nightclubs and raves. Like ketamine, esketamine would be a Schedule III controlled substance. Hopefully the hype over esketamine will not overshadow the potential dangers and adverse events.

On March 4, 2019 the NPR show, All Things Considered, said the FDA was expected to approve esketamine. Courtney Billington, the president of Janessen Neuroscience said if approved, it would be marketed under the brand name Spravato. While he confirmed it will only be available in approved and certified treatment centers and limited to patients who have unsuccessfully tried at least two other antidepressants, it was predicted that doctors already comfortable prescribing ketamine will continue to do so. A psychiatrist or physician can prescribe ketamine without the restrictions that will be applied to esketamine. “The generic form is cheap and can be taken at home in a nasal spray once patients know the right dose.”

Then on March 5, 2019 the FDA approved esketamine (Spravato). Johnson & Johnson, the parent company for Janessen, said the wholesale cost of each esketamine treatment will be in the $590 to $885 range, depending on the dose. As an aside, there will likely be a tolerance built with Spravato over time, requiring increased doses for the same antidepressant effect. The projected J&J price means that the recommended twice-weekly treatments during the first month will cost at least $4,720 to $6,785. Treatments afterwards will cost about half as much. A ketamine infusion directory stated the costs for ketamine infusion range from $400 to $2,000.

Spravato contains a boxed warning that cautions “patients are at risk for sedation and difficulty with attention and thinking (dissociation), abuse and misuse, and suicidal thoughts and behaviors after administration of the drug.” Stop a minute and think about this. Spravato has been approved for treatment-resistant depression, and the noted side effects include misuse/abuse of the drug itself and suicidal thoughts and behaviors! And the work around coming at some point will be the development of a nasal spray device that can be used with ketamine without the restrictions applied to Spravato.  In pursuit of the newest possible “treatment” for depression, FDA has crossed a boundary into territory that apparently sets aside the maxim to “First do no harm” when approving drugs. Are the risks of Spravato really worth it?

I’ve written several articles here addressing concerns with ketamine or esketamine. This is the twelfth one. See: “Falling Down the K-Hole,” “Esketamine Craze” and “Is Ketamine Really Safe & Non-Toxic?” for more information; or just search for ketamine or esketamine. You can read “Bait and Switch: the Great Ketamine ‘Breakthrough’” for a personal story about someone who almost enrolled in one of the failed clinical trials.

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 20th, 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 17th, and Medical News Today published its “announcement” on April 18th.  Additional articles include ones by Business Insider, Newsweek and BBC News—all on April 16th—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 5th-6th. 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.