Tag: veterans and suicide

05/18/21

Support and Defend Against Suicide

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There has been an alarming increase in the number of veterans who commit suicide each year. The latest statistics in the 2020 National Veteran Suicide Prevention Annual Report indicated that the number of veteran suicide deaths per year in 2018 was 6,435, an increase 379 per year since 2005. Age- and sex-adjusted suicide rates for the U.S. adult population was 18.3 per 100,000 in 2018. For veterans, their age- and sex-adjusted rates were 27.5 per 100,000 in 2018. “Over the period 2005-2018, age- and sex-adjusted suicide rates rose faster among Veterans than among non-Veteran U.S. adults.”

Veterans between the ages of 18 and 34 had the highest suicide rate in 2018, 45.9 per 100,000, while veterans 75 and older had the lowest suicide rate in 2018, 27.4 per 100,000. The absolute number of suicides was highest among veterans 55-74 years old, accounting for 40% of all veteran deaths by suicide in 2018. There were clear sex differences with Veterans, where the age-adjusted suicide rate among women was 15.9 per 100,000 and 39.6 per 100,000 among men. Suicide rates rose faster among men than among women both for veteran and non-veteran populations. See the following graphs from the 2020 National Veteran Suicide Prevention Annual Report.

Compared to the steep rise of suicides among U.S. adults, these increases may not seem so alarming. The suicide rate for U.S. adults has increased 47.1% since 2005. The number of American adults who died by suicide in 2018 was 46,510, and 31,610 in 2005. This compares with a 6.3% increase among veterans during the same time period. The number of suicide deaths among veterans in 2018 was 6,435; and in 2005 the number of veteran suicides was 6,056. See the following graph.

Yet an analysis of the data from the 2019 National Veteran Suicide Prevention Annual Report by Robert Whitaker suggested a somwhat disturbing factor hiding in the statistics. In “Screening + Drug Treatment = Increase in Veteran Suicides,” Whitaker noted the increase in suicide among Veterans was at least partly driven by the VA’s suicide prevention efforts. The VA’s screening protocols resulted in a greater number of veterans coming into psychiatric care, where treatment with psychiatric drugs is regularly prescribed. “Suicide rates have increased in lockstep with the increased exposure among veterans to such medications.”

Suicide prevention efforts began in the U.S. in the late 1980s, when The American Foundation for Suicide Prevention and other organizations like the American Psychiatric Association and the National Alliance on Mental Illness drew attention to suicide as an “unrecognized public health” problem. Individuals with mood disorders who were “untreated” were said to be at particularly high risk of suicide. “The Foundation pushed screening programs as a way to get more people into treatment. Its advisory board and presidents touted antidepressants as ’anti-suicide’ pills.”

The American Psychiatric Association, the National Alliance on Mental Illness, and the pharmaceutical companies that sold antidepressants all helped promote this message to the public. In 1997, their efforts prompted both houses of Congress to declare suicide a “national problem.” Two years later, U.S. Surgeon General David Satcher issued a “Call to Action to Prevent Suicide,” and the U.S. Department of Health and Human Services formed a task force, composed of individuals and organizations from the private and public sectors, to develop a “National Strategy for Suicide Prevention.” The task force published its recommendations in 2001, which doubled-down on the “public health” approach that had been promoted by the American Foundation for Suicide Prevention.

Government agencies launched suicide prevention efforts. Crisis call centers were created; depression screening programs were introduced. Checklists like the CDC Depression checklist and the Patient Health Questionnaire (PHQ-9) were developed. Medical professionals were trained to recognize the “warning signs” for suicide. “The goal was to get more people struggling with mood disorders into treatment, with antidepressants recommended as a first-line therapy.”

The prescribing rates for antidepressants have steadily increased since 2000. And the age-adjusted suicide rate has also increased from 10.4 per 100,000 in 2000 to 14.0 per 100,000 in 2017. The CDC reported past month use of antidepressants increased from 7.7% in 1999-2002, to 12.7% in 2011-2014. The age-adjusted suicide rate for Americans rose from 10.4 per 100,000 in 2000 to 14.0 per 100,000 in 2017. Whitaker’s data on suicide rates was only age-adjusted, not age- and sex-adjusted suicide rates, so his statistics will not be an exact match with those reported above in the National Veteran Suicide Prevention Annual Reports. See the following graph from the Whitaker article.

The failure of this approach to suicide prevention, which emphasizes getting people into treatment, is not a uniquely American phenomenon. In the 1990s, the World Health Organization urged countries around the world to develop national mental health policies and to improve their mental health services, which included providing their citizens with better access to psychiatric medications. The belief was that this would lead to better mental health outcomes, which would become visible in the form of reduced suicide rates.

Researchers from the UK, Denmark and Australia have now conducted three studies of whether such efforts have affected suicide rates, and all came to the same conclusion: improved access to psychiatric services and psychiatric drugs was associated with an increase in national suicide rates.

Soon after Prozac came to market in the late 1980s a significant number of patients taking Prozac began having suicidal thought (See “Antidepressant Fall from Grace, Part 1”). There were numerous case reports of people taking the drug who committed suicide. At this point, there is clear evidence that SSRI and SNRI antidepressants can prompt suicidal impulses and acts in some users. In 2003, David Healy and a team of researchers conducted a metanalysis of all random controlled trials (RCTs) of SSRIs and found that suicide attempts were 2.28 times more likely with an SSRI than a placebo.

Like the federal government, the VA sees suicide as a “public health” issue. In 2006 it appointed a National Suicide Prevention Coordinator. The next year it established a toll-free Veterans Crisis line. It has steadily increased resources devoted to this issue, even spending almost $20 million for Make the Connection to market the VHA’s services to veterans. The VA introduced mandatory screening for all veterans. This screening is a regular feature of VHA care, with screening of some sort as part of every patient appointment.

The VA’s clinical guidelines for treating depression and PTSD, the two most commonly diagnosed psychiatric disorders, recommend SSRI and SNRI antidepressants as first-line therapies. A 2015 report by the General Accounting Office (GAO) said 94% of all VHA patients diagnosed with depression from 2009 to 2013 were prescribed an antidepressant. “Studies of VHA patients with PTSD have reported that about 80% are prescribed a psychiatric medication, with antidepressants the drug class of choice.” Polypharmacy, taking multiple medications, is common with 35% of those diagnosed with depression taking two classes of psychiatric drugs and 15% taking three classes of drugs. Those diagnosed with PTSD had an even more pronounced polypharmacy, with 36% taking two classes of psychiatric drugs and 25% taking three or more classes.

In the 2016 report, Suicide Among Veterans and Other Americans, the VA divided patients into four subgroups: 1) undiagnosed and untreated (for a mental health or substance use disorder); 2) undiagnosed and treated (with either a psychiatric drug or non-pharmacologic treatment); 3) diagnosed and untreated; and 4) diagnosed and treated. Given the regular screening for mental health disorders, undiagnosed patients apparently did not show symptoms of depression, PTSD or any other psychiatric disorder that would have generated a diagnosis during the screening process. These patients should be at low risk of suicide and theoretically, any treatment should further reduce this risk.

The “diagnosed” patients should be at a higher risk of suicide. Suicide prevention efforts focus on getting these patients into treatment, with antidepressants seen as a first-line therapy than can lower the risk of suicide. Thus, if suicide prevention efforts are helpful, the suicide rate for the diagnosed patients who are treated should be lower than for diagnosed patients who, for whatever reason, shun treatment. The 2019 GAO report found that 18% of diagnosed patients did not get treatment.

The results were as follows. Those without a diagnosis who received MH treatment were more likely to die by suicide than those without a diagnosis who did not receive treatment. “In 2014, those who got treatment died at twice the rate of the ‘untreated’ group.”

Those with a mental health or substance use diagnosis who received mental health treatment were also about twice as likely to die by suicide than those who were diagnosed but did not receive mental health treatment. “The difference in suicide rates for the treated and untreated groups is consistent over time, year after year.” The suicide rates for those diagnosed with a mental health or substance use diagnosis have remained stable since 2005. They have hovered around 70 per 100,000 population. “The reason that the suicide rates for VHA patients have been rising is that the VA’s suicide prevention efforts—the outreach campaigns and the mandatory screening—have led to a steady increase in the number of veterans diagnosed and treated for those disorders.”

The data for the four subgroups suggested an increased the risk of suicide with the diagnosed and treated group having the greatest risk:

  • Undiagnosed/untreated: 24.8 per 100,000
  • Diagnosed/untreated:  34.4 per 100,000
  • Undiagnosed/treated: 47.6 per 100,000
  • Diagnosed/treated: 68.2 per 100,000

This finding runs directly counter to the variable suicide rates that would be expected if the “treatment” were effective. Yet it is consistent with RCT data showing antidepressants double the risk of suicide compared to placebo. Since the VA launched its suicide prevention efforts in 2006, there have been more than 70,000 suicides. “That is a number greater than the total of all combat deaths since 9/11.”

When you join the military, you take an oath to “support and defend” the Constitution against all enemies, foreign or domestic. Fulfilling that oath means you risk being killed in combat. But it doesn’t mean you have to be willing to risk committing suicide from taking psychiatric medications.

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.”