Tag: Spravato

11/14/23

Voyages on the Starship Ketamine

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On October 10, 2023, the FDA issued a warning about the potential risks of compounded ketamine products for the treatment of psychiatric disorders such as depression, anxiety, OCD and PTSD. The concern seems to center on the at-home use of ketamine compounds from a multitude of online sources, dispensing oral formulations such as ketamine lozenges or tablets. Not only is ketamine not FDA approved for the treatment of any psychiatric disorder, it has known safety concerns such as abuse and misuse, increased blood pressure, slowed breathing and “psychiatric events.” The FDA said these compounds should only be used “under the care of a health care provider.”

Ketamine is a Schedule III controlled substance approved by the FDA as an intravenous or intramuscular injection to induce and maintain general anesthesia. It is not FDA-approved to treat any psychiatric disorder. It is a mixture of two-mirror-image molecules, R-ketamine and S-ketamine—arketamine and esketamine, respectively. The “S” form of ketamine (esketamine), known as Spravato, was approved by the FDA as a nasal spray for the treatment of major depression and adults with acute suicidal ideation or behavior in 2019. See “Red Flags with Spravato,” “Doublethink with Spravato?,” “Repeating Past Mistakes with Esketamine” and other articles on this website expressing concerns with esketamine/Spravato.

Spravato is also a Schedule III controlled substance and like ketamine, and has similar risks of adverse events. This led the FDA to require a Risk Evaluation and Mitigation Strategy (REMS) with esketamine, meaning that esketamine is required to be “dispensed and administered in medically supervised health care settings that are certified in the REMS and agree to monitor patients for a minimum of two hours following administration because of possible sedation and disassociation and the potential for misuse and abuse.” But ketamine and ketamine compounds can be legally prescribed off label to treat psychiatric disorders and do not have to have a FDA required REMS.

However, on February 16, 2022 the FDA published an alert describing the risks associated with the use of compounded ketamine nasal spray products. The FDA Adverse Event Reporting system (FAERS) and the medical literature identified five cases (reported between 2016 and 2021) of compounded ketamine nasal spray that resulted in psychiatric events “such as delusion, dissociation, visual hallucination, and panic attack as well as abuse and misuse.”

The reported concentrations of compounded ketamine nasal spray ranged from 125 – 200 mg/ml. Frequency of use varied from three sprays three times a day to six sprays eight times a day. The amount of medication administered to the patients with each spray is unknown. In most case reports, the patients self-administered the product at home, and it is unknown whether they were observed or monitored by a healthcare professional.

Because compounded ketamine nasal spray products are not FDA-approved, there is no FDA-approved dosing regimen for these products. There are also no data to support dosing conversion between Spravato (esketamine) nasal spray and compounded ketamine nasal spray.

The New York Times said the October 2023 alert sought to differentiate between the supervised use of ketamine as a therapy administered at clinics, and the “wellness centers” or online marketers that prescribe the drug via telemedicine so that buyers can take the drug at home. The alert included a caution that individuals receiving ketamine products from compounders and telemedicine platforms may not receive information about the potential risks associated with the product. “At-home administration of compounded ketamine presents additional risks because a health care provider is not available onsite to monitor for serious adverse outcomes resulting from sedation and dissociation.”

The pandemic-related boom in telehealth has given rise to a legion of online prescribers that dispense inexpensive ketamine lozenges, tablets or nasal sprays following a brief video interview. Some companies provide as many as 30 doses after one session, which experts say can lead to misuse.

Company executives in the compounding industry say they’d welcome government oversight. But they are concerned that a lack of flexibility in the FDA’s guidance could result in overly aggressive enforcement by state regulators. The manager of a compounding pharmacy in San Francisco said he is concerned these online sellers will ruin it for everyone. “Our fear is that regulators, if they perceive a threat to public health, will move to take this amazing medicine away and leave patients at risk.”

Psychiatric Times also expressed concerns with at-home ketamine therapy. They described a report by the All Points North Treatment Center in Edwards Colorado of 2,000 adults where 64% said they thought ketamine helped with their mental health symptoms. But 55% who tried at-home ketamine therapy also admitted accidentally or purposely using more than the recommended dose. The Editor in Chief of Psychiatric Times said, “Esketamine has to be administered in person by a trained health care provider. The use of at-home ketamine bypasses this safety net and puts individuals at risk, undermining the FDA’s REMS protocol to minimize risk and maximize safety and prevent diversion and abuse/misuse.”

There were reservations in 2019 with the approval process for esketamine, Spravato  (see “Hype and Concern with Esketamine” and “Evaluating the Risks with Esketamine”). A NPR interview BEFORE the FDA approved esketamine predicted the problem the FDA is now attempting to address in its alert for “compounded ketamine products.” A doctor who prescribed ketamine to his patients said doctors would continue to offer a generic version of ketamine for depression because it would be cheaper than the cost of Spravato with its REMS. The generic form of ketamine was cheap, and could be taken at home with the assistance of a nasal spray, he said. “Any psychiatrist or physician can prescribe [it] without the restrictions that are going to be applied to esketamine.”

A Cunning Methodology

In a new study, Stanford researchers devised a cunning workaround to disguise the dissociative properties of ketamine. A major difficulty with doing clinical trials on psychedelic drugs like ketamine is the difficulty of providing a satisfactorily double blinded methodology. Participants can usually tell whether or not they were given ketamine or a placebo. The researchers “recruited 40 participants with moderate to severe depression who were scheduled for routine surgery, then administered a dose of ketamine or placebo when the participants were in surgery and under general anesthesia.”

They were surprised to find that both groups experienced the large improvement in depressive symptoms usually seen with ketamine. The senior author of the study he was surprised to see the result. He quoted some participants as saying their life was changed; they never felt like that before. “But they were in the placebo group.” Both the ketamine and placebo groups saw their depression rating scores drop by half and stayed roughly the same throughout the two-week follow-up of the study.

The researchers thought it was unlikely the surgeries and general anesthesia accounted for the improvement. They theorized the positive expectations of the participants played a key role in the effectiveness reported by them. “Those who had improved more in their depression scores were more likely to think they received ketamine, even when they didn’t, implying some preexisting positive expectations for ketamine.” The senior author said this was nothing new.

Placebo is probably the single most effective, consistent intervention in medicine, full stop. It’s seen in every trial, and we should probably be paying more attention to the factors that give rise to it.

However, he said the takeaway shouldn’t be that ketamine “is just a placebo.” He thought that was a disservice to placebos. He hypothesized there may be a physiological resonance between the placebo effect and how ketamine works. “There is most definitely a physiological mechanism, something that happens between your ears, when you instill hope.” He added that the results also suggest the psychedelic experience may not be crucial to the drug’s benefits, although it likely encourages more positive expectations.

Maybe with a non-hallucinogenic psychedelic analog you can get the same benefits without having to, you know, go to outer space.

01/18/22

Safety Concerns with Esketamine

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It is approaching the three-year mark since the FDA approved Janssen’s Spravato (esketamine), in conjunction with an oral antidepressant to treat adults with treatment-resistant depression. The acting director of the Division of Psychiatry Products in the FDA’s Center for Drug Evaluation and Research said at the time, “There has been a long-standing need for additional effective treatments for treatment-resistant depression, a serious and life-threatening condition.” Esketamine was later approved to treat adults with major depressive disorder with suicidal thoughts. Despite the approval, Janssen said it is not known if esketamine is “safe and effective for use in preventing suicide or in reducing suicidal thoughts.”

Joanna Moncrieff and Mark Horowitz originally expressed concern in “Esketamine for treatment resistant depression” that history was repeating itself, that “a known drug of abuse, associated with significant harm, with scant evidence of efficacy, is being submitted for licensing, without adequate long-term safety studies.” In their 2019 article, they said they were surprised to see an article in the BMJ endorsing esketamine, as they thought it had been approved on “flimsy evidence.” Only one of three trials of acute treatment was positive and “the difference between esketamine and placebo was not large.” Particularly when compared to the large placebo effect. They acknowledged that serious adverse effects could take time to come to light, and concluded their article with the following warning:

Leaving this crucial research until after the drug is licenced, as the FDA has done in the United States … puts the public at risk and sets depressed patients up as unwitting guinea pigs in a huge and unregulated pharmaceutical experiment.

Peter Gøtzsche et al thought the safety and efficacy of esketamine was exaggerated. They thought the available evidence found that esketamine was “more likely to harm than benefit patients with resistant depression.” They thought esketamine should not be used in clinical practice. “But only as an experimental drug in randomised trials of adequate length, with long-term follow up, and with patient relevant outcomes assessing both harms and benefits.”

Horowitz and Moncrieff have updated their previous analysis in “Esketamine: uncertain safety and efficacy data in depression.” By June 2021, six 4-week efficacy trials have been published, with only one reporting a statistically significant difference between placebo nasal spray and esketamine. The one trial finding a statistically significant effect of four points, was not clinically significant given the large effect size (15.8 points) in the placebo plus antidepressant section of the study. It was also less than the 6.5-point difference used by Janssen in their sample size calculation; and had no long-term efficacy data. “The time point of four weeks in all these studies means the data are rather uninformative, since treatment-resistant depression in usually treated for months or years.”

They noted how other national health service organizations such as NICE (National Institute for Health Care Excellence) have examined the same evidence as the FDA and did not approve the drug for treatment resistant depression. However, NICE has launched a second consultation on the use of esketamine for treatment resistant depression after receiving feedback that it could benefit some patients. The results of that consultation have not been released yet. Horowitz has been critical of NICE’s delay of their decision on Twitter, saying: “Janssen’s antidepressant might not be much good, but their marketing spin is second to none. Hats off. I wonder whether NICE is in the spin room as they have been persuaded to delay their decision on esketamine for 10 months.”

Horowitz and Moncrieff compiled a table (see below) of withdrawal symptoms 4 weeks after stopping esketamine. They acknowledged the table did not establish a causal attribution between the symptoms and stopping esketamine. The large numbers in the esketamine group and longer duration of treatment also may have inflated suicides in that group.

In the safety study, one in seven patients developed ‘treatment-emergent’ suicidal ideations and six attempted suicides occurred in a group “selected for not being actively suicidal.” Using the FDA Adverse Event Reporting System (FAERS) database, Gastaldon et al found a disproportionate number of suicides could be attributed to esketamine in the first year of its use in the USA. Their conclusion was, “Esketamine may carry a clear potential for serious AEs [adverse events], which deserves urgent clarification by means of further prospective studies.”

The doses of esketamine were similar to recreational doses of ketamine, which causes tolerance, dependence and withdrawal. The FDA and Janssen said withdrawal symptoms were probably not relevant in the relapse prevention study. Yet Janssen did not report data from the Physician Withdrawal Checklist to support this conclusion.

Although it is difficult to be definitive about the nature of experiences that occur following drug discontinuation, the possibility that withdrawal effects were mistaken for relapse requires consideration, as withdrawal effects overlap with most items on the Montgomery–Åsberg Depression Rating Scale. NICE concluded that “any withdrawal effect would be difficult to distinguish from a change in depressive symptoms.”

The Janssen trial studies were also not representative of all individuals with major depression. They only included individuals who had failed two antidepressants (representing 44% of patients with depression). The studies excluded people with a recent history of suicidal intention, psychiatric comorbidity, drug and alcohol problems, vagal nerve stimulation (VNS) and deep brain stimulation (DBS).

Another confounding effect in the efficacy with esketamine is the known fact that ketamine, like other anesthetics, cause a pleasurable ‘high’ for some users. It is not clear how this drug induced euphoria and the antidepressant effects can be distinguished. Horowitz and Moncrieff concluded that:

Overall, the central points of our Analysis remain: esketamine has a clinically uncertain effect at 4 weeks, and there are no studies with longer follow-up periods more relevant for the care of people with depression. The discontinuation trial potentially conflates relapse and withdrawal and there are concerning safety signals.

Successful suicides that occurred during the clinical trials 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 the 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.” In “Nasal Spray for Depression? Not So Fast,” Kim 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 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 proposed following a 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.”

How did a drug with all of these concerns get approved by the FDA? There were exceptions made in the FDA approval process for esketamine as a “breakthrough therapy.” Witczak said the term treatment resistant depression (TRD) is the buzzword that allows drug companies to obtain FDA fast tracking:

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 is persisting in its efforts to expand the market for Spravato/esketamine. It appears to me they convinced NICE to delay announcing their decision on esketamine for 10 months in order for the company to spin some additional information. And perhaps to convince NICE to reverse its rejection of esketamine. For more on esketamine, see: “Esketamine Craze,” “Hype and Concern with Esketamine,” “Evaluating the Risks With Esketamine,” and “Doublethink with Spravato?”

06/15/21

Evaluating the Risks with Esketamine

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Esketamine, Spravato, was approved by the FDA for treatment-resistant depression in February 2019. Then on August 3, 2020, it was also approved to treat depressive symptoms in adults with major depression and symptoms other than suicidal ideation. But there have been a series of articles critical of the approvals, noting as Joanna Moncrieff and Mark Horowitz did in the BMJ, that it was licensed on flimsy evidence. They said: “The scientific community should instead be calling on the European Medicines Agency to resist the proposal to unleash another chemical on the unsuspecting public that has unproven benefits and untested harms.”

Research led by Chaira Gastaldon of the University of Verona caught the attention of Medscape Medical News in: “Serious, ‘Unexpected’ Adverse Events from Nasal Esketamine.” Gastaldon told the European Psychiatric Association 2021 Congress that esketamine “may carry a clear potential for serious and unexpected adverse events that were not reported by approval trials.” She noted that adverse events (AEs) like rapid-onset euphoria, dissociation and feeling drunk indicate there is a risk for misuse similar to ketamine. Esketamine (S-ketamine) is the left-handed isomer of ketamine.

Gastaldon and her fellow researchers collated records from the FDA Adverse Event Reporting System (FAERS) database for March 2019 to March 2020. Analysis showed that several AEs were significantly associated with esketamine when compared with other drugs. Serious treatment-related AEs were significantly more common among women; patients given higher doses of esketamine; those also taking other medications such as mood stabilizers, antipsychotics, and benzodiazepines. Gastaldon said these findings were important because esketamine was approved as an add-on medication, meaning it is to be used along with other antidepressants. Gastaldon, emphasized that these AEs were expected because they were also found in the approved trials for esketamine.

Robert McIntyre of the University of Toronto, who was not involved in the study was the lead author of an expert opinion article published in The American Journal of Psychiatry, “Synthesizing the Evidence for Ketamine and Esketamine in Treatment-Resistant Depression.” The researchers concluded that while intranasal esketamine demonstrated efficacy, safety, and tolerability for up to one year in adults with treatment-resistant depression, the evidence for its long-term safety and tolerability was insufficient. He noted there is always a calculus in medicine; what are the risks and what are the benefits of a treatment. He acknowledged there is something to be concerned about at this point. “But at this stage, by no means would I say that the risk would warrant not considering giving this to a patient with depression.”

Along with other researchers, Gastaldon critically reviewed the evidence on esketamine submitted to the FDA, aiming to draw implications for clinical practice, research and regulatory science. In “Esketamine for treatment resistant depression: a trick of smoke and mirrors?”, Gastaldon et al. questioned whether the rapid change in depression scores was due to improvement in depression or just a temporary effect of the drug on brain mechanisms. In other words, had “esketamine just modified some brain processes that impacted the depression scores, as many psychoactive substances are able to induce.”

For esketamine, understanding whether this rapid change in depression scores is due to an improvement of depression or just to a temporary effect of the drug on some brain mechanisms is of paramount relevance, as depression is a recurrent condition, and TRD is a particularly severe form of depression with symptoms persisting over long periods of time. It would be important to know if this acute effect is maintained in the long- term. For esketamine, however, long-term data are completely lacking.

Given that data on the safety of ketamine indicated the risk of abuse and associated harms, the FDA determined that a Risk Evaluation and Mitigation Strategy (REMS) was needed to see if the benefits of the drug outweigh the risks. REMS are a drug safety program required of medications with serious safety concerns. Gastaldon et al. argued that this action implied that esketamine was approved without knowledge of the potential negative consequences of esketamine prescribing. The results of the REMS could help in addressing some safety issues, “but this will require a long time and exposure of many persons with depression to this new agent.”

Reanalysis of the three efficacy trials revealed that the risk of dissociation was around 25%, almost seven times higher in the esketamine group as compared to placebo. “Again, we argue that further evidence on safety is urgently needed, given these preliminary signs suggesting that esketamine may not be safer than ketamine.”

Gastaldon also was the lead author on, “Post-Marketing Safety Concerns with Esketamine,” published in Psychotherapy and Psychosomatics. The authors concluded esketamine carries “a clear potential” for serious adverse events. “Signals for suicidal and self-injurious ideation, but not suicide attempt and completed suicide, remained when comparing esketamine to venlafaxine [Effexor].” Females and patients receiving antidepressant polypharmacy, co-medication with mood stabilizers, antipsychotics, and benzodiazepines were more likely to suffer from serious AEs.

Only the abstract of “Post-Marketing Safety Concerns with Esketamine” was available to me without paying $39 to Psychotherapy and Psychosomatics. However, Mad in America looked at Gastaldon et al.’s analysis of the FDA adverse event reports in, “New Research Questions Safety of Esketamine for Depression.” Rare AEs, not reported in regulatory trials of esketamine, such as self-injurious ideation, depressive symptoms, panic attack, paranoia and mania were detected. The most frequently reported adverse events (AEs) 5% or above were: Dissociation (9%), Sedation (7%) and Drug ineffectiveness (5%). The researchers concluded:

This study showed that the esketamine safety profile in the real-world population might be slightly different from that described in regulatory trials, and therefore further data from clinical practice would be required to better understand the safety profile of esketamine and provide an evidence-based framework for rational prescription. More real-world research is urgently needed, including pragmatic clinical trials, observational studies, and individual-participant meta-analyses on rare and unexpected AEs.

Concerns with esketamine are nothing new. There were problems noted with the FDA approval of Spravato, including only modest evidence of its effectiveness in limited trials; and no information provided on the safety of Spravato beyond 60 weeks, despite its potential for abuse. One member of the FDA advisory committee that ultimately approved Spravato thought its benefit was almost certainly exaggerated; another thought true treatment-resistant patients were weeded out of the trials. The FDA lowered the criteria bar for determining “treatment resistant depression.” Now patients had to fail to respond to two different antidepressant pills, not two different classes of antidepressants. This change meant that 49 of the 227 participants included in Janssen’s only successful efficacy trial failed just one class of oral antidepressants, not two.

Erick Turner, a member of that advisory committee, wrote about concerns he had about the efficacy of esketamine and its FDA approval for The Lancet. He noted seven concerns, including a lax definition of treatment-resistant depression, an 81% of response to esketamine with placebo, and a failure to formally demonstrate rapid onset. “In any case, only about 10% of patients who received esketamine achieved a rapid clinical response.” He wondered whether the novel mechanism of action encouraged leniency with the concerns he listed.

See “Hype and Concern with Esketamine,” “Doublethink with Spravato?” and “Red Flags with Spravato” for more on these concerns.

Not to be deterred by these findings, a group of employees of Janssen, the company that brought Spravato (esketamine) to market, responded to Gastaldon et al. in “Comments to Drs. Gastaldon, Raschi, Kane, Barbui and Schoretsantis.” Their reply was also published in Psychotherapy and Psychosomatics. They acknowledged the work of Gastaldon et al. in identifying potential safety signals related to esketamine. But they thought Gastaldon et al.’s interpretation of their findings was overstated.

In summary, our comprehensive surveillance has not revealed any new safety signal and confirms that Spravato® [esketamine] product labeling adequately addresses esketamine’s risks. Additionally, data are being collected in a prospective long-term safety study (NCT02782104). Janssen remains committed to ongoing esketamine safety monitoring via robust risk management and pharmaco-vigilance surveillance programs, including REMS, to ensure that up-to-date safety information is available to prescribers and patients.

It seems to me that this is the heart of the problem. Supporters of esketamine see its safety monitoring and REMS as providing “up-to-date safety information” to prescribers and patients. Critics see the need for a REMS as pointing out that esketamine was rushed to market without first gathering information on its potential long-term negative consequences. The drug companies themselves are responsible for managing and reporting the results of a REMS to the FDA. Can Janssen be trusted to not strategically massage the data found by NCT02782104 in order to present a favorable outcome with esketamine?

12/1/20

Doublethink with Spravato?

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In case you missed it, Janssen announced the FDA’s approval of a new indication for Spravato “to treat depressive symptoms in adults with major depressive disorder with suicidal ideation of behavior.” Spravato (esketamine) was originally approved by the FDA as a fast-acting antidepressant for treatment-resistant depression in March of 2019. Janssen and the FDA seem to be forging ahead despite misgivings expressed with the approval of esketamine from a number of sources, including members of the advisory board that approved Spravato. But perhaps the most damning and confusing endorsement of Spravato can be found in Janssen’s announcement of this new indication.

The announcement was released on August 3, 2020 and stated its approval was based on Phase 3 data showing that Spravato reduced depressive symptoms in as little as four hours in some patients, with symptom improvement maintained through the four-week treatment period. “Spravato is the first and only approved medicine that has been shown to reduce depressive symptoms within 24 hours.” First Spravato was approved as a fast-acting antidepressant for treatment resistant depression, and then it was approved to treat depressive symptoms with a new population: adults with major depression and suicidal ideation behavior. But you would be wrong to conclude the new approval was because it was shown to treat suicidal ideation in the new population. Here is what the August 3rd Janssen announcement said:

The effectiveness of Spravato in preventing suicide or in reducing suicidal ideation or behavior has not been demonstrated. Use of Spravato does not preclude the need for hospitalization if clinically warranted, even if patients experience improvement after an initial dose of Spravato. Spravato carries a Boxed Warning regarding a Risk Evaluation and Mitigation Strategy (REMS) and the risk of suicidal thoughts and behaviors.

So Janssen was proud to announce Spravato was approved by the FDA to treat depressive symptoms other than suicidal ideation in adults with major depression and suicidal ideation! The doublespeak does not end there. The paragraph from which the above quote was taken referred its readers to “Important Safety Information” below in the press release. In the section on “Important Safety Information,” the press release repeated the two conditions for which the FDA approved Spravato: adults with treatment-resistant depression and depressive symptoms in adults with major depressive disorder with suicidal thoughts or actions. It also warned that antidepressant medicines “may increase suicidal thoughts and actions in some people 24 years of age and younger.” And then you see a similar disclaimer to the one above:

It is not known if Spravato is safe and effective for use in preventing suicide or in reducing suicidal thoughts or actions. Spravato is not for use in place of hospitalization if your healthcare provider determines that hospitalization is needed, even if improvement is experienced after the first dose of Spravato.

Spravato was approved “to treat depressive symptoms in adults with major depressive disorder with suicidal ideation of behavior,” but not to treat the symptom of “recurrent suicidal ideation”! See Medscape for “What are the DSM-5 criteria for diagnosis of major depressive disorder?” The same doublespeak is included in advertisements for Spravato. Erick Turner, a former reviewer of psych meds for the FDA, posted the following advertisement on Twitter:

Note his highlights of the same information discussed above. In an earlier post, dated August 6, he said: “The FDA has *not* approved esketamine for suicidal ideation. But the indication for which it was approved was worded [in a way that] will mislead many people into thinking that it was. How could the FDA allow Janssen to get away with this slick marketing?” In case you are skeptical about the above advertisement being photoshopped, here is a link to a similar ad for Spravato, that uses the same language highlighted above.

This seems to be some marketing spin placed on the results of phase 3 clinical trials for esketamine. ASPIRE I and ASPIRE II were said to suggest that esketamine nasal spray may address the unmet need for a rapid acting antidepressant in patients with MDD at imminent risk of suicide. Depressive symptoms were significantly decreased in both trials. However, while there was improvement in the severity of measured suicidality, there were no statistically significant differences in the severity of suicidality. ASPIRE I, which was published in the Journal of Clinical Psychiatry, also said the study site investigator did not think any suicide-related adverse events were related to esketamine. The trials were with patients with major depressive disorder (MDD) who were at high risk of suicide, but let’s not simply accept the site investigator’s assessment and dismiss the significance of the suicide-related adverse events.

There were 4 attempted suicides and 1 completed suicide among patients with esketamine treatment. In ASPIRE II, there were 3 attempted suicides among patients with esketamine treatment. Both ASPIRE I and ASPIRE II pointed out that standard antidepressants effectively treat depressive symptoms, including suicidal ideation, but they require 4-6 weeks to have a full effect. Although there were significantly decreased symptoms of depression, there were still suicide attempts and one completed suicide in ASPIRE I and II, despite the rapid treatment effect with esketamine. So esketamine can’t claim that it provides rapid relief for suicidal ideation within the population its was just approved to treat—adults with major depressive disorder with suicidal ideation of behavior.

Joanna Moncrieff and Mark Horowitz published the following comments on esketamine in the British Journal of Medicine on October 8, 2019. There had been a BMJ editorial endorsing esketamine, “Esketamine for treatment resistant depression.” They said they were surprised to see the endorsement, as esketamine has been licensed on flimsy evidence for treatment resistant depression. “The very existence of Treatment Resistant Depression is a testimony to the ineffectiveness of the pharmacological approach to depression.”

Moncrieff and Horowitz pointed out the esketamine trials were only for 28 days, and noted there is almost no data on the adverse effects from long-term treatment. Serious adverse effects from long-term treatment will take time to come to light. “Yet we know from the recreational drug scene that ketamine use is associated with severe bladder problems and that prolonged use of euphoriant drugs like ecstasy can cause depression in itself.” This means that crucial research data was left to be gathered after the drug was licensed in the US. Doing so “puts the public at risk and sets depressed patients up as unwitting guinea pigs in a huge and unregulated pharmaceutical experiment.”

A report of post-marketing adverse events with esketamine was published in the journal Psychotherapy and Psychosomatics in August 2020. In “Post-Marketing Safety Concerns with Esketamine,” Gastaldon et al reported their analysis of data found in the FDA Adverse Event Reporting System (FAERS). The researchers looked at esketamine-related adverse events between its original approval by the FDA in March of 2019 and March of 2020. The FAERS database contained 962 cases of esketamine-related adverse events such as: dissociation (212), sedation (173), feeling drunk (20), anxiety (63), suicidal ideation (64), depression (65), depressed mood (12) and completed suicide (11). Note again where suicidal ideation and completed suicide still occurred. The link here is to the abstract of the article, but you can access “Free Supplementary Material” that contains the number of cases I’ve included here in parentheses.

There have been concerns expressed about Spravato/esketamine from the time it was initially approved by the FDA. The independent advisory committee voted 14-2 that the benefits of esketamine outweighed the risks. But STAT wrote some experts weren’t convinced there was enough data at the time to show that esketamine was effective. They wanted data on how the drug should be used in the long run.

Johnson & Johnson, the parent company to Janssen, submitted five Phase 3 studies: three short-term studies, one maintenance study, and a long-term safety study. Two of those were positive. One of the studies was of adults under 65 with treatment-resistant depression. The second was a maintenance-of-effect study, where participants who responded to esketamine in one of the short-term studies were then randomly assigned to either taking esketamine or a placebo. Historically, such withdrawal studies have not been counted toward the needed two studies.

At the time, Erick Turner was a member of the FDA advisory committee that evaluated esketamine. When the panel met to vote on recommending approval to the FDA, Turner couldn’t participate because of travel reasons. He said: “The threshold has been two adequate and well-controlled trials. In this case, they only got one … Based on that, I would have voted no.” Julie Zito was one of the two advisory committee members who did vote “no” on whether the benefits of esketamine outweighed its risks. She said if Spravato was approved, she hoped providers, patients and the families of patients would work together to keep tabs on possible side effects and how the drug was working.

Remember that Gastaldon et al reported esketamine gathered together 962 adverse event cases on FAERS in its first year on the market. FAERS reported that data as of June 30, 2020, reported 1,305 adverse events; 619 serious cases that included 39 deaths, 18 of which were completed suicides. The case count for dissociation had risen to 266; to 221 for sedation; to 83 for suicidal ideation; and to 84 for depression. There were another 343 adverse events from esketamine reported to FAERS in three months; and 7 more completed suicides.

Even though it has been given a Risk Evaluation Mitigation Strategy (REMS), long-term adverse events will likely include concerns with substance misuse. Like ketamine, esketamine ‘s chemical cousin, it is a controlled substance (Schedule III). Ketamine is known recreationally as the popular club drug “Special K.”

The data used to approve Spravato for treatment resistant depression was flimsy to begin with. Now the FDA has approved it to treat adults with major depressive disorder who struggle with suicidal ideation. This widens the population approved to use Spravato and increases the market to whom Janssen can legally market Spravato. Nothing good will come of this. The “good news” in Janssen advertising is now Spravato can be marketed to adults with major depressive disorder and suicidal ideation. But ironically, Spravato has not been demonstrated to be effective in preventing suicide or in reducing suicidal ideation.

This kind of rhetoric reminds me of George Orwell’s classic book 1984, in which he wrote: “Doublethink means the power of holding two contradictory beliefs in one’s mind simultaneously, and accepting both of them.” Does it seem that Janssen is attempting to get some people to doublethink with Spravato? For more on Spravato/esketamine, see “Hype And Concern With Esketamine” and “Red Flags With Spravato.”

09/10/19

Better Living Through Spravato?

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The Military Times reported on Wednesday August 21, 2019 that President Trump said he had instructed Veteran Affairs officials to make a massive purchase of Spravato from Johnson & Johnson in an effort to stem the problem of suicide among veterans. VA research indicates there are about 20 veterans daily who are successful suicides. The President believes Spravato can “really do something” for suicide prevention. He said, “It’s pretty well known, it just came out. We have calls in to Johnson & Johnson now, we’ve been talking to them for two months on buying a lot of it. . . . Hopefully we’re getting it at a really good cost.”

This seems to be the latest step in efforts to find a solution to the problem of suicide among veterans. In 2015 Congress passed the Clay Hunt Suicide Prevention Act, named for a Marine Corps veteran activist who took his own life in March 2011. The legislation required VA officials to provide annual reviews of mental health care and suicide prevention. While the 2018 annual report gave high marks to the department for their mental health support, that did not translate into fewer suicides. Rege Riley, the National Commander for AMVETS, said “More than 24,000 veterans have died by suicide since the passage of the Clay Hunt Act. . . . God willing, we won’t be stuck with the same system we have now in 2023, with a new report that highlights only that what (they) keep doing continues not to work.”

In response, there has been legislation proposed, while the White House announced on March 5, 2019 the formation of a new task force on preventing veterans suicide, PREVENTS—the Presidents Roadmap to Empower Veterans and End a National tragedy of Suicide. The new order gives agency officials a year to develop plans for a more aggressive approach to suicide prevention. VA officials estimate that around 70% of veterans who take their lives have little or no contact with the federal veteran system. The task force will look to develop a new grant system similar to the Housing and Urban Development-VA Supportive Housing (HUD-VASH) program that is widely credited with decreasing the number of homeless veterans by half.

The very same day the FDA announced the approval of Spravato. Over the next 24 to 48 hours the Department of Veterans Affairs was flooded with requests and orders for the drug, largely because the President thought the drug would be good for the VA and he wanted to buy “truckloads” of it. By the end of the week, more than 20 people at the Veterans Health Administration (VHA) were actively trying to get Spravato to patients. “Within two weeks, likely a record for the usually lumbering approval process, the VHA was announcing that the drug would be made available to vets. By the end of March, scores of physicians would be involved.”

How the president learned of the drug and how exactly his enthusiasm was communicated to the VA remains a mystery. The White House declined to answer questions on that subject, as did the VA. Johnson & Johnson, and its subsidiary Janssen Pharmaceuticals which makes the drug, had been partnering with the VA on anti-suicide programs as Spravato was being developed. J&J was also working with a trio of Trump associates from his Mar-a-Lago club who have influenced VA policies. The three associates did not return phone calls and messages from the Center.

There was a report by the Guardian saying sources inside the VA said staffers were essentially told by a senior official to drop everything and accelerate the availability of Spravato because the president had expressed enthusiasm for it. Additionally, while the drug trials for Spravato were being done, “J&J was also involved with a trio of men Trump knew through his Florida social club Mar-a-Lago who became advisers on VA issues.” The VA downplayed the claim, saying the three men were just individuals giving advice. The three said they “offered our counsel, and the advice of these healthcare experts, to assist the president, secretary and VA leadership in their making essential decisions.” Records from the Center for Responsive Politics indicated Johnson & Johnson spent a total of $6.6 million that year lobbying the federal government about pharmaceuticals and health products. In 2018 and 2019 it lobbied the VA on matters including “partnership with the VA on suicide prevention.” The company also gave $14,165 to Trump’s 2016 campaign.

Not everyone—even at the VA—is convinced of Spravato’s potential. In June of 2019, a team of VA clinicians voted against putting Spravato in the VA’s formulary for approved drugs. Instead, the VA will require prior authorization for patient’s treatment with the medication. A VA spokesperson said, “These evidence-based processes will ensure the medication is prioritized for use in veterans who have not previously responded to adequate trials of other available treatments for major depression.” A Johnson & Johnson representative said the company was committed to working with the VA to ensure access to Spravato for patients who need it. “We firmly believe that people suffering from treatment-resistant depression, including our nation’s veterans, deserve the opportunity to benefit from this breakthrough medicine.”

There are serious reservations with the FDA’s approval of Spravato that include questions about how it was approved, how well it works, whether it is safe and its cost. “Data from the drug’s trials shows it to be only marginally better than placebos in its performance, several researchers and psychiatrists said after looking at the data.” There were also three successful suicides during the clinical trials of Spravato. Janssen, the subsidiary of J&J that brought the drug to market, said the deaths were not considered to be related to Spravato and the FDA concurred. The FDA Briefing Document for the advisory committee that voted 14 to 2 to approve Spravato 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.” Kim Witczak, a national drug safety advocate, said “In my opinion, we need more information on the potential link to suicide before an assumption can be made that it’s safe.” See “Hype and Concern with Esketamine” and “Red Flags with Spravato” for more on the concerns with Spravato/esketamine.

Spravato as the solution for the military calamity of suicide very likely will take us to a worse place. Psychiatrist Peter Breggin noted that activation side effects from antidepressants mimicked symptoms of PTSD, “and are likely to worsen this common disorder in soldiers, increasing the hazard when they are prescribed to military personnel.” He concluded there is a strong probability that the increasing suicide rates among active-duty soldiers was “in part caused or exacerbated by the widespread prescription of antidepressant medication.” He said the symptoms of activation can combine adversely with similar PTSD symptoms found commonly in soldiers during and after combat. He suggested the military study the relationship between psychiatric drug treatment and suicide.

David Joslin was a medic for roughly 20 years He served as a combat medic throughout his military career. He jumped on every opportunity to excel in his field, attending advanced trainings whenever possible. He had deployments in Iraq and Afghanistan totaling 28 months of combat in Infantry and Cavalry units. The end of his military career came as the result of a break with reality during a simulated scenario at the Medical Skills Simulation Training Center (MSTC) in Fort Wainwright, Alaska. He was not, as he had thought, back in Iraq or Afghanistan. “There was no threat, I was not in danger, and I could not differentiate between the false reality that had been in my head and where I actually was.”

Towards the end of his military career he was prescribed a series of psychiatric medications. Effexor was the fifth different antidepressant they tried. He was prescribed Restoril to sleep, but it didn’t work. Prasosin made his nightmares go away, but made him catatonic. Adderall was prescribed to help him focus better, but it took away his appetite and made him “twitch like a meth addict.” Lowpressor treated the mild high blood pressure he developed after the heavy medication regimen. “At the height of my ‘better living through chemistry’ I was prescribed roughly 12 various drugs for the different symptoms that I was working through and the side effects the other drugs were creating. I literally lived one dose to the next.”

He slept on average two hours each day, and spent the rest of the time spiraling through depression and anxiety. He spent months of on-and-off contemplation of dying, but came to the conclusion suicide was not an option for him. He also came to realize the heavy volume of medications he was on was a significant part of the problem. He felt like “a helpless bundle of chemically controlled emotions, and not a man really in control of himself.” He doesn’t recommend the risk he then took when he flushed all his medications, putting himself into an acute psychiatric drug withdrawal. Nevertheless, “Regaining control of my life enabled my recovery, and it was only made possible through recognizing that the drugs I had been prescribed were causing irreparable harm, and would have killed me if I had stayed on them.”

Spravato has questionable efficacy with depressive symptoms and the data from the drug’s trials suggest it was only marginally better than placebos. More information on its potential link to suicide is needed before assuming it can be safely distributed to anyone, especially military veterans suffering from depression and PTSD. Better living through Spravato is not likely to happen and has the potential to worsen the veteran’s mental health problems.

09/3/19

Red Flags with Spravato

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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.”

05/7/19

Psychedelic Renaissance?

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Spravato (esketamine), a chemical cousin of ketamine (Special K), was recently approved by the FDA as a fast-acting antidepressant. MDMA is now in a Phase 3 clinical trial for PTSD. Psilocybin has received a breakthrough therapy designation for treatment-resistant depression by the FDA. Clinical research into the therapeutic effects of psychedelics has resumed for a variety of conditions, including depression, substance abuse and individuals living with serious medical conditions like cancer. This has led to calls for increasing the availability of psychedelics by loosening the regulatory restrictions that currently limit the drugs’ use for research.

In his book, How to Change Your Mind, Michael Pollan said beginning in the 1990s, a small group of scientists, psychotherapists and so-called “psychonauts,” have sought to resurrect what they saw as a wrongful termination of research into the therapeutic value of psychedelics. “A new generation of scientists, many of them inspired by their own personal experience of the compounds, are testing their potential to heal mental illnesses such as depression, anxiety, trauma and addiction.” Others are using psychedelics in conjunction with brain-imaging technology to explore the links between brain and mind. “The hoary 1960s platitude that psychedelics offered a key to understanding—and ‘expanding’—consciousness no longer looks quite so preposterous.”

Psychedelics are currently classified as Schedule I controlled substances, meaning they have a high abuse potential; no accepted medical use; and have safety concerns, even under medical supervision. Some advocates are calling the DEA to place them into Schedule III, along with ketamine, anabolic steroids and buprenorphine. Writing for Scientific American, Rick Strassman described his own research with DMT in the 1990s. One of the most difficult impediments he faced was DMT being Schedule I.

After nearly two years of close work with FDA and DEA, an effective system developed allowing our studies to proceed. My subsequent applications to use psilocybin and LSD were much more quickly and easily approved. The New Mexico project’s success established the current American regulatory framework that has allowed for the current burgeoning of human studies with psychedelics.

Psychedelics have unique characteristics that make it difficult to fit them into the criteria used to define schedule placement. “Their safety and efficacy exist only within highly structured specialized treatment settings.” Outside of that structure, psychedelics retain their ability for abuse and are capable of debilitating, psychological damage. “How one understands the psychedelic drug state determines the assessment of risks and benefits, and thus drives recommendations for rescheduling.” William Richards, the clinical director for the John Hopkins University psychedelics research program, publicly advocates for the increased availability of the drugs, referring to their ‘inherent spirituality’ in lectures and talks.

Glorifying psychedelics’ benefits and rendering innocuous their adverse effects therefore may explain the Hopkins group’s recent publication of a paper suggesting rescheduling psychedelics into Schedule IV—the most liberal recommendation yet to appear.

Strassman suggested a new category—IA—that would acknowledge psychedelics’ abuse potential, while allowing for their use. “The security requirements established by the DEA for possession of psychedelics for clinical research—background checks of those handling the drugs, secure storage, regular inventory, etc.—would be the same as for Schedule I substances.” Significantly, only those with specialized training would be permitted to administer psychedelics to humans. With such a regulatory structure in place, He thought the clinical promise of psychedelic drugs could be realized without exposing patients to unnecessary risk. “It would also ensure that we maintain scientific rigor, intellectual honesty and high ethical standards as we continue investigating how these drugs produce their fascinating effects.”

One study published in the Journal of Psychopharmacology did produce some interesting effects with psilocybin. Two randomized controlled trials with late-stage cancer patients suggested that a single, high dose of psilocybin had “clinically significant and long-lasting effects on mood and anxiety.” There were no serious adverse events; no participants abused psilocybin; no cases of prolonged psychosis or hallucination. “No participants required hospitalization.”

Single moderate-dose psilocybin, in conjunction with psychotherapy, produced rapid, robust, and sustained clinical benefits in terms of reduction of anxiety and depression in patients with life-threatening cancer. This pharmacological finding is novel in psychiatry in terms of a single dose of a medication leading to immediate anti-depressant and anxiolytic effects with enduring (e.g. weeks to months) clinical benefits. Even though it is not possible to attribute causality of the experimental drug (in terms of sustained clinical benefit) after the crossover, the post-crossover data analyses of the two dosing sequences suggest that the clinical benefits, in terms of reduction of cancer-related anxiety and depression, of single-dose psilocybin (in conjunction with psychotherapy) may be sustained for longer than 7 weeks post-dosing, and that they may endure for as long as 8 months post-psilocybin dosing. The acute and sustained anti-depressant effects of psilocybin in this trial are consistent with a recently published open-label study of oral psilocybin treatment in patients with treatment-resistant depression (TRD) in which psilocybin (25 mg) was associated with 1 week and 3 months post-psilocybin anti-depressant effects.

Reflecting on the results of the study, Stephen Ross, MD, the director of Substance Abuse Services at the Langone Medical Center, said it possibly provides a new model in psychiatry. “This is potentially earth shattering and a big paradigm shift within psychiatry.” David Nutt, MD, PhD, of the Imperial College London said the studies were the “most rigorous controlled studies to date” using psilocybin. Others urged caution applying and interpreting the results. Jeffrey Lieberman, MD, from Columbia University said:

[W]e cannot tell if the anxiolytic and antidepressant effects of the drugs are direct results of their serotonergic effects or secondary to the mystical altered state of consciousness that they produce. Since other serotonergic agonists (eg, lisuride) do not produce this psychedelic experience it has been suggested that psychedelic drugs must bind to the 5-HT2A receptors in a special way or exhibit functional selectivity or receptor bias.”

A study of the abuse potential for psilocybin confirmed low abuse and no physical dependence potential. The study used all 8 factors required to guide the FDA and DEA recommendations for the Controlled Substance Act (CSA). They suggested placement as a Schedule IV Controlled substance. There was “no clear evidence of physical dependence and withdrawal in preclinical or clinical studies, or among those who chronically used illicit products.” The authors said the lack of therapeutic and mechanistic studies of psilocybin and other psychedelics stems from the lack of federal funding for the research and the barriers imposed by a Schedule I classification, not a lack of interest among researchers.

While some psychedelics like psilocybin may be viable therapeutic options, there simply isn’t enough modern controlled trials. James Rucker, MD, MRCPsych, PhD, of the King’s College London Institute of Psychiatry, said: “Psychedelics deserve to be investigated in modern, controlled trials if we are to know whether they are useful treatments in psychiatry, or not . . .  At the moment there isn’t enough high-quality evidence to make that judgment.”

The biggest barrier to their wider use likely stems from the lack of research. Buy there are additional obstacles in doing the research. Most pharmaceutical companies aren’t interested because of the legal obstacles with Schedule I substances and because it’s not profitable to develop treatments with these drugs. The FDA approval of esketamine as a new molecular entity (NME) is the exception. Another problem is the impossibility of using a placebo control or blinding because of the identifiable effects from psychedelics. Finally, there is the challenge of obtaining sources of psilocybin that meet the standards required for the clinical trials. Rucker said:

I think everyone in this field is interested in one thing — that psychedelics get a fair hearing by Western medicine by undergoing well-funded, well-designed controlled trials . . . Then we will know whether they have any benefit, and we can judge whether this benefit is suitably balanced against any harm they might do. Until then we won’t know, and that is a worse state of affairs than knowing.

Benjamin Bell, from John Hopkins University, wrote “The psychedelic renaissance is here.” He is a proponent of psychedelic medicine, and gave a clearly biased history of how research into psychedelics was “turned off,” after Timothy Leary made the phrase “turn on, tune in, drop out” famous. “Researchers in the field are posed at the precipice of progressing forward with revolutionary studies and may conscientiously move our culture forward with them. But moving the culture will require awareness and action from scientists and citizens.” Researchers believing that psychedelics are important and useful need to recognize how that faith is a double-edged sword “and we must remain truly willing to reconsider beliefs in light of new evidence, or it will be impossible to convince the broader public to do the same.”

Researchers have the opportunity and responsibility to properly communicate their findings and recommendations to the public. He thought this was vital if psychedelics were to be integrated into medical use within the wider culture. Meaningfully, he then said: “It is important to remember psychedelics are not the ultimate panacea for treating mental health concerns.” With time and reams of further research, they may become invaluable components of the medical and mental health toolkit. If the research is carefully and systematically done, I’d cautiously agree.

Let’s not repeat the mistake made with marijuana—failing to reschedule it so research into its risks and benefits is easier to do. The science—not the rhetoric—should be the deciding factor in the medicalization and the legalization of psychedelic substances. Rescheduling psychedelics as suggested by Rick Strassman seems reasonable and would permit the researchers holding back from doing psychedelic research to forge ahead. Some psychedelics, like psilocybin, appear to have potential while ketamine and the ketamine knockoff Spravato increasingly ring alarm bells for me because of their abuse potential and the quickness with which their effects seem to fade. For more information on ketamine and esketamine, see: “Hype and Concern with Esketamine” and “Is Ketamine Really Safe & Non-Toxic?”

03/12/19

Hype and Concern with Esketamine

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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.