01/18/22

Safety Concerns with Esketamine

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

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?

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 3^rd 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.”

04/19/16

Ketamine to the Rescue?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

07/22/15

No Laughing Matter

In his famous work, The Varieties of Religious Experience, William James discussed what he said was the ability of nitrous oxide (laughing gas) to produce “mystical consciousness” to an extraordinary degree. “Depth beyond depth of truth seems to be reveled to the inhaler.” But the revelation fades as the gas wears off. What is left seems like nonsense to the awakened mind. But the sense of “a profound meaning” persists. James said he knew more than one person who was persuaded that a genuine metaphysical revelation could come in a nitrous oxide trance. Now, laughing gas is being researched as a treat for depression.

James said he had personally tried nitrous oxide, and even wrote of his experience in print. He said one impression from these experiments stayed with him—that our waking consciousness was but one of several other potential form of consciousness. “No account of the universe in its totality can be final which leave these other forms of consciousness quite disregarded.” Looking back on his own experiences, he saw them converge towards a kind of insight that he felt had metaphysical significance.

His essay was “Subjective Effects of Nitrous Oxide,” and it appeared in the 1882 volume 7 issue of Mind. It can be found in a few places online. I’ve linked it on the website Erowid, which will also have other references we’ll examine. In his essay, James said that the keynote of nitrous-oxide intoxication was an intense sense of metaphysical illumination that occurred as the altered state of consciousness was wearing off.

The mind sees all logical relations of being with an apparant subtlety and instantaniety to which its normal consciousness offers no parallel; only as sobriety returns, the feeling of insight fades, and one is left staring vacantly at a few disjointed words and phrases, as one stares at a cadaverous-looking snow peak from which sunset glow has just fled, or at a black cinder left by an extinguished brand.

What James saw as the most coherent and articulate of his bursts of insight was this: “There are no differences but differences of degree between different degrees of difference and no difference.” James said there was an initial rapture of emotion in “beholding a process that was infinite” that turned to horror as the individual realized they were caught in an inevitable fate, “with whose magnitude every finite effort is incommensurable and in the light of which whatever happens is indifferent.”

As James himself said in the essay, just as every person’s encounter will vary, the individual’s personal experience with nitrous oxide will vary from time to time. However, he still thought that there still was a common thread running through all those who were intoxicated with nitrous oxide, namely an “intense metaphysical experience.”

A group of researchers, Nagel et al., reported on a pilot study done to assess the potential of nitrous oxide as a rapidly acting treatment for treatment resistant depression (TRD). The theory was based upon the influence of nitrous oxide on the NMDA receptor, which has been “implicated” in the neurobiology of depression. Other NMDA receptor antagonists, such as ketamine, have been shown “to provide a rapid and sustained antidepressant effect” when used at low doses. Given the similar mechanisms of action, the researchers hypothesized that nitrous oxide may also have rapid antidepressant effects on treatment resistant depression. So they designed a study to assess the immediate (2 hours) and sustained (24 hours) antidepressant effects of nitrous oxide in TRD patients.

Patients received either an admixture of up to a maximum of 50% nitrous oxide and 50% oxygen (as the active ingredient) or 50% nitrogen/50% oxygen (as the placebo) for one hour. Outcomes were assessed for each participant at baseline, 2 hours after treatment and 24 hours after treatment. The results indicated a significant improvement in depressive symptoms at 2 and 24 hours. There was also a sustained improvement with some participants for 1 week. Yet there were several limitations noted by the researchers of this study.

The full 60-minute nitrous oxide treatment was only completed by 15 of the 20 patients. The placebo treatment was completed by 20 individuals. The side effects for the treatment group were noted to be mild or moderate (nausea, anxiety, vomiting) and immediately reversible. This suggested an acceptable risk/benefit ratio of nitrous oxide for TRD to the researchers.

Their discussion suggested several limitations of the study. The small sample size meant that the results should be interpreted with caution until the results were replicated in larger populations. They also noted that the euphoric effects of nitrous oxide are hard to mask, so the blinding attempted in the study may not have been adequate. Despite knowing this, the researchers did not try to assess whether or not the participants were aware of their group assignment, “and this limits our conclusions.”

They also pointed out that there could have been a masking effect of depressive symptoms, meaning that: “the depressive symptoms were not really altered, but rather ‘covered up’ by other effects.” They noted where symptom masking has been evident with rapidly acting psychostimulants like cocaine and methylphenidate, “which promote a transient alteration in mood but not a true antidepressant effect.” Their preliminary study concluded there was evidence that nitrous oxide may have rapid and marked antidepressant effects in patients with TRD. They called for further studies that would attempt to determine optimal antidepressant dosing strategies and the risk/benefit of nitrous oxide in a larger and more diverse population of individuals with TRD.

Psychiatrist Sandra Steingard expressed reservations with the promotion of nitrous oxide as a rapid acting treatment for depression. She commented that while she never personally tried nitrous oxide herself, she knew others who did and expected that her mood would undoubtedly have been elevated as theirs was. Her suggestion was the observed “treatment’ effects of nitrous oxide were actually drug effects that would occur with any individual who used it. She proceeded to voice several questions on the use of nitrous oxide, ketamine or stimulants to treat depression. She thought there was a huge potential for harm; possibly greater than the drugs psychiatrist currently prescribed for depression.

What are the long term side effects? How hard is it to stop them? How do we deal with the corrupting influence of the profit driven forces so powerful in medicine? Most of these drugs are still studied over weeks and then prescribed for years. With drugs like stimulants, ketamine and nitrous oxide, I have a particular worry because these drugs are known to cause psychosis. Colleagues of mine have told me that they do not see people who become psychotic on stimulants. If they don’t, they are not looking. I am not comfortable assuming when an 18 year old develops psychotic symptoms after several years of treatment with an antidepressant that these two things are not related or that the psychosis was inevitable because the person had a diathesis to Bipolar Disorder. Stimulants are used to create animal models of psychosis because we have known for decades that stimulants can cause a person to become psychotic.

Erowid is the website for an organization that seeks to “provide accurate, specific, and responsible information about how psychoactives are used in the United States and around the world.” So you will find pro and con information on the use and effects of psychoactive substances there. Here are a few of the catalogued articles on problems from nitrous oxide use and abuse: “Asphyxia deaths from the recreational use of nitrous oxide;” “Suicide by nitrous oxide poisoning;” B 12-related medical problems from nitrous oxide: “Nitrous oxide myleopathy in an abuser of whipped cream bulbs [whippets] (nitrous oxide is used in whipped cream cans), “Myleneuropathy after prolonged exposure to nitrous oxide,” and this case report from outside of Erowid of a woman who developed myleopathy.

Below is a quote from a 1991 article on “Health hazards and nitrous oxide” in medical settings. Here is a link to a case report of an individual who suffered paranoid delusions after abusing whippets.

Although N2O was for many years believed to have no toxicity other than that associated with its anesthetic action, bone marrow depression in patients administered N2O for extended periods of time and neurological abnormalities in health care workers who inhaled N2O recreationally have disproved this notion.

Simply put, regardless of the short-term reversals of a depressed mood state, it does not seem that there will be any long-term benefits from the therapeutic use of nitrous oxide (N2O). And there seems to be plenty of concerns with its use. Treating depression with laughing gas is no laughing matter.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: treatment resistant depression

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Evaluating the Risks with Esketamine

Doublethink with Spravato?

Ketamine to the Rescue?

No Laughing Matter