06/22/21

Drugs Do Not Fix Chemical Imbalances

Researchers at Harvard’s McLean Hospital observed that the public perception of mental illness was increasingly understood in neurobiological and genetic terms. There is some evidence that these explanations had an unintended consequence of reducing optimism for recovery among individuals with depression. Despite this, very little is known about how these beliefs interact with the treatment process and outcomes in a psychiatric treatment setting. They wanted to know if the language used affected treatment protocols and patient expectations. They found that believing depression was caused by a chemical imbalance was related to poorer treatment expectations.

In fact, they found that more depressed individuals showed a stronger relationship between chemical imbalance beliefs and lower treatment expectations. In “The dangers of the chemical imbalance theory of depression,” Derek Beres noted while the chemical marker serotonin is correlated with depression, it does not cause depression. “Decade after decade, however, we’ve been marketed the idea that chemical imbalance is the culprit behind depression.”

Instead of doctors diagnosing patients, they increasingly confirm what the patient suspected all along. The patients self-diagnose because they saw an advertisement or listened to a friend. Doctors too often comply without further investigating of the reasons for their reported distress. Medicalizing mental health softens the stigma of depression, but it also disempowers the patient. In “Stressors and chemical imbalances: Beliefs about the causes of depression in an acute psychiatric treatment sample,” the McLean researchers wrote:

More recent studies indicate that participants who are told that their depression is caused by a chemical imbalance or genetic abnormality expect to have depression for a longer period, report more depressive symptoms, and feel they have less control over their negative emotions.

Doctors, media, and advertising come together with a similar message. Everyday blues is a real medical condition, everyone is susceptible to clinical depression, and drugs correct the underlying physical conditions. Counseling aimed at self-insight seems to serve little purpose. The McLean team of researchers found patients expected little from psychotherapy and a great deal from pills. “When depression is treated as the result of an internal and immutable essence instead of environmental conditions, behavioral changes are not expected to make much difference.”

Doctor Ronald Pies referred to and cited “Stressors and chemical imbalances” in his January article in Psychiatric Times, “What We Tell Patients about Depression, and What They Say They Have Been Told.” Pies said the study found that the most commonly endorsed explanations for depression were psychosocial explanations, not “the chemical imbalance notion.” He said popular beliefs about the cause of depression could be adopted from a variety of sources, including television advertisements and anti-stigma campaigns promoting biogenetic explanations. These beliefs could also come from individual treatment experience. “All of this is simply to note that popularization of the chemical imbalance canard is almost certainly an over-determined effect, in which the role of psychiatrists (or other clinicians) is but 1 possible causal factor.”

But he seems to have glossed over the primary finding of “Stressors and chemical imbalances.” Patients who believe a chemical imbalance or genetic abnormality caused their depression do worse. The results of the study’s abstract said:

We found that although psychosocial explanations of depression were most popular, biogenetic beliefs, particularly the belief that depression is caused by a chemical imbalance, were prevalent in this sample. Further, the chemical imbalance belief related to poorer treatment expectations. This relationship was moderated by symptoms of depression, with more depressed individuals showing a stronger relationship between chemical imbalance beliefs and lower treatment expectations. Finally, the chemical imbalance belief predicted more depressive symptoms after the treatment program ended for a 2-week measure of depression (but not for a 24-hour measure of depression), controlling for psychiatric symptoms at admission, inpatient hospitalizations, and treatment expectations.

“Stressors and chemical imbalances” was not critiquing psychiatry for spreading the chemical imbalance theory, which Pies has called a kind of urban legend. The researchers examined etiological beliefs about depression and studied how they were related to treatment expectations and outcomes. If you believed in the chemical imbalance theory of depression, you tended to have poorer treatment outcomes. But that isn’t the only problem with believing in this “urban legend.”

Consequences of Believing in a Chemical Imbalance

Dutch researchers interviewed people who were given medical advice to discontinue antidepressants. The participants’ use of antidepressants was determined to be “not indicated” based upon clinical practice guidelines. This meant that participants had no current mental health diagnoses, no history of recurring mental health problems, and they had been taking antidepressants longer than nine months. Reporting on the study for Mad in America, Peter Simons said that despite receiving advice to discontinue, more than half refused to stop taking their antidepressant. The researchers identified two significant barriers to discontinuation.

The first was fear that if they ever stopped taking antidepressants, they would not be able to cope with the rebound depression. One of the participants said: “That’s my biggest fear. The misery I was in, before I got these medicines. I never want to relive that. I never want to go back to how I felt then. And because of this fear, I just can’t attempt to stop them.” Another person said if she would remain well, she would quit tomorrow. “But . . . to go through the hell I went through again? No.”

The second barrier was a belief in the serotonin deficiency theory, the chemical imbalance theory. The participants described their antidepressant use as supplying a deficient substance they needed to function normally. This resulted in their acceptance of a lifelong dependency. “I just need it. For me, this isn’t a psychological illness, it’s physical. And my body isn’t able to make enough serotonin, so I take the pill to supply it.”

There was a comparison to diabetes by her doctor reported by one participant.

She (the GP) told me, you should see it like you have a deficiency in your brain, you miss a certain substance and the medicine supplies it. She told me it’s just like someone with diabetes who needs insulin for the rest of their life. Well, I kind of believe that, so never questioned my use since.

The Dutch researchers said the biological model for depression seemed to backfire:

Another important barrier was the notion that antidepressants are necessary to supply the deficient serotonin. This serotonin deficiency resulted in patients expecting continued use of their medication. Presumably this is the result of the explanation the GPs gave to their patients at first prescription, or at least what patients (choose to) remember. The biological model for depression seems to backfire, making it difficult to persuade the patient to discontinue the drug. This is an important and new finding. GPs must keep this in mind while explaining the course of treatment for depressive and anxiety disorders. On the other hand, uneasiness with the perception of a biological cause could enhance attempts to stop antidepressants.

The chemical imbalance theory of depression is a false, unfounded report. For decades, the idea has been falsely marketed to consumers that a chemical imbalance is the culprit behind depression. Even psychiatrists, as seen with Dr. Pies, want to distance themselves from this “canard.” This urban legend is associated with poorer treatment outcomes and leads individuals with no apparent clinical need to remain on antidepressants instead of tapering off of them. We need to ask, how did we get here?

In his interview for Scientific American, “Has the Drug-Based Approach to Mental Illness Failed?”, Robert Whitaker described his journey away from the conventional understanding that depression and schizophrenia were caused by chemical imbalances in the brain, to founding the webzine, Mad in America.

Whitaker said he is convinced that psychiatric medications cause net harm when used over the long term. “I wish that weren’t the case, but the evidence just keeps mounting that these drugs, on the whole, worsen long-term outcomes.” Increasingly, he is not sure the medications provide real a short-term benefit either. “When you look at the short-term studies of antidepressants and antipsychotics, the evidence of efficacy in reducing symptoms compared to placebo is really pretty marginal, and fails to rise to the level of a ‘clinically meaningful’ benefit.” His concern and the concern of Mad in America has grown beyond studies with psychiatric medications:

Mad in America’s mission is to serve as a catalyst for rethinking psychiatric care in the United States (and abroad). We believe that the current drug-based paradigm of care has failed our society, and that scientific research, as well as the lived experience of those who have been diagnosed with a psychiatric disorder, calls for profound change.

He thinks our society organized itself with regard to mental illness around a false narrative presented as a narrative of science. In the early 1980s, we began to hear that psychiatric disorders were cause by chemical imbalances in the brain; and that like insulin did for diabetes, there was a new generation of psychiatric medications that could fix those imbalances. “We came to believe that there was a sharp line between the ‘normal’ brain and the ‘abnormal’ brain, and that it was medically helpful to screen for these illnesses, and that psychiatric drugs were very safe and effective, and often needed to be taken for life.”

But what can be seen clearly today is that this narrative was a marketing story, not a scientific one. It was a story that psychiatry, as an institution, promoted for guild purposes, and it was a story that pharmaceutical companies promoted for commercial reasons. Science actually tells a very different story: the biology of psychiatric disorders remains unknown; the disorders in the DSM have not been validated as discrete illnesses; the drugs do not fix chemical imbalances but rather perturb normal neurotransmitter functions; and even their short-term efficacy is marginal at best.

The above quotes from participants in the Dutch study and the quote on how the biological model for depression backfired, are found in the research article published in Therapeutic Advances in Psychopharmacology, “Patients’ attitudes to discontinuing not-indicated long-term antidepressant use.”

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?

05/25/21

Reading Rorschach’s “Tea Leaves”

In 1904, a twenty-year-old medical student at the University of Zurich had a dream. After seeing his first autopsy, he dreamt that his brain was being cut. The dream was so vivid, that after he woke, he could still feel the sharp piercing of the knife. The powerful imagery of the dream captured his imagination and reinforced the medical student’s decision to specialize in psychiatry. That student was Hermann Rorschach, the creator of the inkblot test that bears his name.

The Rorschach inkblot test presents the test taker with a series of ten inkblots and asks them, “What might this be?” What was important to Rorschach was not what they saw, but how they approached the task. “What parts of the image did they focus on or ignore? Did they see the image moving? Did the color on some inkblots help them give better answers, or distract and overwhelm them?” The test taker’s responses are assumed to reflect underlying personality traits as well as unconscious conflicts, motives and fantasies.

The Rorschach is a projective test, where the psychologist writes down everything the participant says or does, no matter how trivial. Administrators of the test typically sit side-by-side in order to ensure they do not influence the test takers answers. There are ten official inkblots, each printed on a white card. Five inkblots are of black ink, two are of black and red ink and three are multicolored. Rorschach said, “The experiment is very simple, so simple that at first it provokes interest and head-shaking everywhere.”

The general goal of the test is to provide data about cognition and personality variables such as motivations, response tendencies, cognitive operations, affectivity, and personal/interpersonal perceptions. The underlying assumption is that an individual will class external stimuli based on person-specific perceptual sets, and including needs, base motives, conflicts, and that this clustering process is representative of the process used in real-life situations.

The general hypothesis underlying projective tests like the Rorschach Inkblot test is that when individuals attempt to understand vague or ambiguous stimuli, their interpretation reflects their needs, feelings, experience, prior conditioning and thought processes. The problem is identifying which needs, feelings, experience prior conditioning or thought processes are reflected in the test. “Projective tests can, by their own claim, draw equally upon the imagined and real, the conscious and unconscious, the recent and old, the important and trivial, the revealing and obvious.” This leaves a significant amount of room for interpretation, making validation of projective tests almost impossible.

Bsed on the belief of a Freudian defense mechanism, projection, they were widely used during the psychoanalytic era of 1940-1960. There are no hard and fast rules in scoring a Rorschach test. Most scoring is qualitative. “All but the most ardent proponents suggest the protocol be analyzed in the context of other tests and clinical information.” Validity and reliability are rendered meaningless by the open-ended, multiple possibilities that are allowed and by the lack of universally-accepted and standardized instructions, administration protocol and scoring procedure. Other evidence suggests there may be cultural biases, as several different cultures produce Rorschach scores different than those from the Exner norms.

The Rorschach Comprehensive System (RCS), also known as the Exner scoring system, is the standard method for interpreting the Rorschach test. Developed in the 1960s, it became the universal standard, “taught in universities, applied by researchers and used by psychologists to this day.” In 1998, Exner was recognized by the American Psychological Association: “Exner has almost single-handedly rescued the Rorschach and brought it back to life.” Today the Rorschach is administered hundreds of thousands of times each year. According to Annie Murphy Paul, 93% of all graduate programs approved by the American Psychological Association taught the test and 90% of clinical practitioners in the field believed psychology students should be trained in Rorschach assessment.

Among mental health professionals, it is the second most popular personality test available; in a recent survey, eight of ten clinical psychologists said they included it in their test batteries at least “occasionally,” and four out of ten reported that they “frequently” or “always” used it.

But, in the words of Annie Murphy Paul, the Rorschach was headed for a “near-death experience.” A psychology professor named James Wood coauthored a highly critical article in Psychological Science, “The Comprehensive System for the Rorschach: A Critical Examination.” The authors alleged, “Basic issues regarding the reliability and validity of the Comprehensive System have not been resolved.” They said the interrater reliability of most scores in the system have never been adequately demonstrated. The important scores and indices in the system were of questionable validity. The research basis of the system consisted mainly of unpublished studies that were often unavailable for examination.

In “The Scientific Status of Projective Techniques,” Lilenfield, Wood and Garb said that despite its widespread use by clinicians, the Rorschach Inkblot Test remained problematic from a psychometric standpoint. They said the scientific status of the RCS appeared to be less then convincing. The RCS norms for many variables appear to misclassify normal individuals as pathological. The possibility of cultural bias has not been excluded. “The substantial majority of Rorschach variables have not demonstrated consistent relations to psychological disorders or personality traits.”

Another article critical published in Psychological Assessment, “The Clinical Utility of the Rorschach: Unfulfilled Promises and an Uncertain Future,” concluded “there is little scientific evidence to support the clinical utility of the Rorschach.” The authors said even if the Rorschach could provide valid information about personality dynamics and treatment outcome, “There is currently no replicated evidence to indicate that this information has any meaningful bearing on services provided to clients and no evidence to substantiate claims of improved treatment outcomes accruing from this information.” They said the Rorschach has the dubious distinction of being, simultaneously, “the most cherished and the most reviled of all psychological assessment tools.”

Given the meager support from thousands of publications to date, the history of disagreements among proponents about the proper use of the Rorschach, and the uncertain acceptance by psychologists of a psychometrically and scientifically sound approach to Rorschach scoring and interpretation, we doubt that there will ever be sufficient evident to suggest that the Rorschach or the Comprehensive System can contribute, in routine clinical practice, to scientifically informed psychological assessment.

As Erica Goode noted in “What’s in an Inkblot,” there has been controversy with the Rorschach almost since its creation. She said early critics called it “cultish.” Later critics, as illustrated above, said it was “scientifically useless.” There is essentially no evidence that the Rorschach can accurately diagnose depression, anxiety, post-traumatic stress disorder or other emotional problems. Yet it has been used in custody disputes to help determine the emotional fitness of parents fighting over child custody and as a diagnostic tool in therapy.

The Rorschach is such a common feature of custody disputes that Fathers’ Right to Custody, a nonprofit organization, includes advice on its Web site on the best ways to respond to the inkblots. Describing one Rorschach card, for example, the site counsels, “This blot is supposed to reveal how you really feel about your mother.” In another case it advises, “Schizophrenics sometimes see moving people in this blot.”

Equally problematic is its use in parole and sentencing hearings to evaluate whether individuals are prone to violence or prone to commit future crimes. Research suggesting a correlation between Rorschach indicators and psychopathic tendencies and violent behavior has been challenged by other studies. “It just doesn’t work for most things it’s supposed to.” In some studies, the ability to predict behavior or diagnose mental disorders went down when data from Rorschach tests were added to information gleaned from other tests. It has become a synonym for “anything ambiguous enough to invite multiple interpretations.”

Dr. Exner, the developer of the RCS scoring system for the Rorschach, acknowledged the test could be unwittingly misused. He also said he was uncomfortable with its use in adversarial settings like custody disputes. “The strength of the test is that it helps the really capable interpreter to develop a picture of an individual.” If you’re only looking to diagnose someone, he didn’t think it was worth doing. On the other hand, if your intention was to treat someone, he thought the Rorschach was a helpful instrument.

Advocates like the author of Principles of Rorschach Interpretation argue that a diagnosis should never be made on the basis of the test alone. If it was going to be used effectively, you would take several factors into consideration. No single test makes the diagnosis. “Tests don’t ‘overpathologize.’ That’s done by the person who interprets them.”

In “The Scientific Status of Projective Tests,” the authors recommended that practitioners stop using the tests for purposes other than research. Alternatively, they suggested the interpretations of the tests be limited “to the very small number of indexes derived from these techniques that are empirically supported.” And that seems to be what further Rorschach research suggested.

In “The validity of individual Rorachach variables,” Mihura et al evaluated the peer-reviewed literature for the 65 main variables in the RCS scoring system. They found 13 variables had excellent support; 17 had good support; 10 had modest support; and 13 had little or no support. The variables with the strongest support were those that assessed cognitive and perceptual processes. Those with the least support tended to be very rare or more recently developed scales. “Our findings are less positive, more nuanced, and more inclusive than those reported in the CS [RCS] test manual.”

In “A second look at the validity of widely used Rorschach indices,” Wood et al agreed there was compelling evidence that 4 categories of cognitive scores in the Rorschach were related to cognitive ability/impairment and thought disorder. They were now comfortable endorsing the use of these scores in some applied and research settings. Unlike Mihura et al, they included unpublished dissertations in their analysis. Wood et al concluded that while the meta-analysis done by Mihura et al reflects the published literature, their neglect of unpublished studies resulted in overestimates of validity for many Rorschach scores. “Therefore, the evidence is presently insufficient to justify using the CS to measure noncognitive characteristics such as emotionality, negative affect, and bodily preoccupations.”

Mihura et al responded to Wood et al in “Standards accuracy, and questions of bias in Rorschach meta-analyses.” They said Wood et al used procedures that contradicted their standards and recommendations for sound Rorschach research and as a result, found lower effect sizes. They also said they found numerous methodological errors, data errors, and omitted studies. Many of their conclusions were said to be based on a narrative review of individual studies and post hoc analyses rather than their meta-analytic findings. “In short, one cannot rely on the findings or conclusions reported in Wood et al.”

So, is the Rorschach Inkblot test worth the time and trouble of administering and taking? Irving Weiner, a clinical professor of psychiatry and behavioral medicine at the University of South Florida, said:

The test can give you objective data, like a blood work. But we all know that some physicians, for whatever reason, are skillful diagnosticians beyond the tests, in seeing the way the patient looks or moves. The Rorschach is a stimulus that generates a lot of information. You may generate hypotheses that aren’t in the hard data yet, but that doesn’t mean this is the same thing as reading tea leaves.

Information presented here was also gleaned from the Online Rorschach Inkblot Test, the “Rorschach test,” and The Cult of Personality Testing by Annie Murphy Paul. You can see representations of the standard ten Rorschach inkblots on Online Rorschach Inkblot Test.

05/18/21

Support and Defend Against Suicide

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.

04/27/21

Death, Taxes and Dementia

Are you 55 or older and do you take an antidepressant or an antipsychotic medication? What about an antiepileptic drug? How about an antiparkinson or an antimuscarinic medication for an overactive bladder? These medications are probably anticholinergic drugs and if you use them regularly, you could be at a 50% higher risk of dementia. However, before looking at the evidence showing how anticholinergic medications could lead to dementia, we need to first understand a few things about these drugs.

Older adults with multiple co-occurring medical conditions are likely to be prescribed medications with anticholinergic properties, drugs that block the action of the neurotransmitter acetylcholine (Ach). These drugs are associated with many side-effects and are consistently shown to be associated with the later development of cognitive problems and dementia. Given the association between anticholinergic exposure and adverse effects, accurate quantification of anticholinergic burden (the cumulative effect over time) is needed to assess the risks versus benefits of prescribing these medications. There are a number of scales and measures that have been developed to assess anticholinergic burden.

“A review of published anticholinergic scales and measures” in Archives of Gerontology and Geriatrics found that the Anticholinergic Cognitive Burden (ACB) Scale was well suited to use in observational studies where anticholinergic exposure needed to quantified because it considered a large number of medications. The ACB Scale was developed by Malaz Boustani of the Aging Brain Program of Indiana University. Drugs were given a score of 1 if lab tests indicated possible anticholinergic effects, but there was no evidence of clinically relevant cognitive effects. A drug was given a score of 2 or 3 if it has established, clinically relevant anticholinergic effects.

A study by Coupland et al, “Anticholinergic Drug Exposure and the Risk of Dementia” concluded that regular use of some anticholinergic medications increased your risk of developing dementia by 50%. The researchers found significant increases in dementia risk for anticholinergic antidepressants, antiparkinson drugs, antipsychotics, antiepileptics, and urological/antimuscarinic drugs. According to Peter Simons, who reviewed the study for Mad in America, “The researchers estimated that 10% of all new dementia cases are due to the adverse effects of these medications.” The increased risk of dementia was projected from a total anticholinergic exposure equivalent to “3 years’ daily use of a single strong exposure medication at the minimum effective dose recommended for older people.” These findings were consistent with 3 other studies and the coherence of their findings provided strong evidence for the study’s reliability.

One of these studies was “Anticholinergic drugs and risk of dementia: case control study” by Richardson et al. The researchers said while middle aged and older adults are increasingly taking multiple anticholinergic drugs, the potential adverse effects of long-term use were not well understood. The researchers selected patients with a new diagnosis of dementia and compared their prescriptions of anticholinergic medications 4-20 years before the diagnosis of dementia with a matched group of patients without dementia. They found a noticeable association between an increasing anticholinergic burden over the previous 4-20 years and the occurrence of dementia. This dose-response effect was only evident for certain classes of anticholinergic drugs, antidepressants and urologicals/antimuscarinics. Significantly these relations were seen even when the drugs were used 15-20 years before the dementia diagnosis.

“The association with dementia increases with greater exposure to these types of medication,” said George Savva, who was one of the researchers. He cautioned that the study only showed an association, not a cause. “But because our research shows that the link goes back up to 15 or 20 years before someone is eventually diagnosed with early dementia symptoms, probably isn’t the case.” Fortunately, there is no apparent risk with anticholinergic drugs used to treat common conditions, like hay fever, travel sickness and stomach cramps. “The risk of dementia increased with greater exposure for antidepressant, urological, and antiparkinson drugs with an ACB score of 3.”

Although Richardson et al did not find the risk of dementia increased with exposure to antipsychotics, it should be noted that several antipsychotics, including Thorazine, Zyprexa, Trilafon, Seroquel, Mellaril, and Stelazine have an ACB score of 3. The antidepressants amitriptyline (Elavil) and paroxetine (Paxil) have an ACB score of 3 and were among the five most commonly prescribed drugs in the study. Less popular antidepressants with an ACB score of 3 included Anafranil, Tofranil, Sinequan, and Surmontil. Antidepressants with an ACB scores of 1 (Wellbutrin, Luvox, Effexor, Trazodone), were associated with dementia, but the association was greater when these antidepressant prescriptions were given close to the timing of the dementia diagnosis. Abilify, an antidepressant and Effexor, an antidepressant, were given a score of 1 in a 2012 update to the ACB Scale.

The organization Health in Aging Foundation, created by the American Geriatrics Society, adds some additional medications that older adults should be wary of. There is a helpful Tip Sheet on its HealthinAging.org website, “Ten Medications Older Adults Should Avoid or Use With Caution.” The noted medications expand the adverse side effects for older adults from certain medications beyond just the risks for cognitive decline and dementia. They also underscore some of the warnings given above. For instance, the caution against antipsychotics was in bold: “If you are NOT being treated for psychosis, use antipsychotics WITH CAUTION.” Antipsychotics are commonly used to treat behavioral problems in older adults with dementia, where they increase the risk of stroke and even death.

Avoiding medications for anxiety (such as benzodiazepines) or insomnia such as Sonata (zaleplon), Ambien (zolpidem) and Lunesta (eszopiclone) was suggested. These drugs increase the risk of falls and can cause confusion. “Because it takes your body a long time to get rid of these drugs, these effects can carry into the day after you take the medication.” Muscle relaxants such as Flexeril (cyclobenzaprine; ACB score of 2), Robaxin (methocarbamol, ACB score of 3) and Soma (carisoprodol) can leave you feeling groggy and increase your risk of falls as well. “Plus, there is little evidence that they work well.” Women should avoid estrogen pills and patches prescribed for hot flashes and other menopause-related symptoms, as they can increase the risk of breast cancer and blood clots.

Psychiatric Times published a literature review, “Benzodiazepine Use and the Risk of Dementia,” that evaluated the evidence benzodiazepine use may increase the risk of dementia in older adults. They found 15 studies that assessed the association between benzodiazepine use and the development of dementia. Of the 15 studies, 8 showed a positive association between benzodiazepine use and dementia. The authors said given the prevalence of benzodiazepine use among older adults, the association between benzodiazepines and the development of dementia is a major cause of concern.

A study among older adults in the province of Quebec, Canada published in the BMJ, “Benzodiazepine use and risk of Alzheimer’s disease: case-control study,” found that benzodiazepine use was associated with an increased risk of Alzheimer’s disease. “The risk of Alzheimer’s disease was increased by 43-51% among those who had used benzodiazepines in the past.” There was a dose-effect relationship between benzodiazepine use and increased risk of Alzheimer’s disease in older people treated previously for more than three months. There was also a higher risk with long-acting formulas.

These medication concerns overlap an existing and growing problem as Americans grow older. In the United States, the number of Americans 65 and older was projected to nearly double from 53 million in 2018 to 95 million by 2060. That age group’s share of the total population is supposed to rise from 16% to 23%. The aging baby boomer generation may also fuel a 50% increase in the number of Americans requiring nursing home care. “Demand for elder care will also be driven by a steep rise in the number of Americans living with Alzheimer’s disease, which could more than double by 2050 to 13.8 million, from 5.8 million today.” So, an increase of older adults living with Alzheimer’s disease (not counting those with dementia) of over 200% is expected by 2050.

The word at this point seems to be that the influence of anticholinergic medications on the rates of dementia in older adults cannot be proven with certainty. Yet the evidence suggests there is a relationship. Maybe by 2050 we will have found a cure for dementia and Alzheimer’s; maybe not. However, there was a Dutch study suggesting that dementia and Alzheimer’s disease may not be an inevitable part of aging. Dr. Richard Isaacson, the director of the Alzheimer’s Prevention Clinic at Weill Cornell Medicine and New York-Presbyterian Hospital told ABC News that dementia and Alzheimer’s tend to have multifactorial conditions. This means “that a mix of genetics, age, environment, lifestyle behaviors and medical conditions that coexist together and can lead a person toward or away from cognitive decline.”

The takeaway seems to be we can be certain of cognitive decline from dementia or Alzheimer’s with older adults, but we can’t be certain of what causes it. Benjamin Franklin said, “in this world nothing can be said to be certain, except death and taxes.” Perhaps we can suggest in this world nothing can be certain except death, taxes and dementia.

03/23/21

The Trickery of Drug Approval

From all that the public is hearing and seeing about the COVID vaccines, both the pharmaceutical companies and the FDA have done an amazing job bringing the first two vaccines to market. In order to alleviate public mistrust of the “warp speed” development process, Dr. Anthony Fauci and NIH director Francis Collins publicly received their first dose of the Moderna vaccine. Dr Fauci said it was remarkable to be receiving it less than a year after the virus it treated was discovered. “What we’re seeing now is the culmination of years of research which have led to a phenomenon that has truly been unprecedented.” But will the pharmaceutical companies continue this standard of fast, safe and effective drug development?

In January 2020, just before the emergence of the pandemic, Harvard Medical School researchers published a study in JAMA that found the FDA is approving new drugs more quickly than ever before and using less stringent standards to determine if the drugs actually work. The lead author of the study told NPR “There has been a gradual erosion of the evidence that’s required for FDA approval.” As a result, patients and doctors “should not expect the new drugs will be dramatically better than older ones.” The use of expedited programs (Accelerated Approval, Fast-Track, and Priority Review) for new drugs increased over time, with 81% of new drugs benefiting from at least one such program in 2018. NPR reported the study found the median review time for standard drug applications was just over 10 months in 2018 compared to 2.8 years for standard and priority applications from 1986 through 1992.

The proportion of new approvals supported by at least 2 pivotal trials decreased from 80.6% in 1995-1997 to 52.8% in 2015-2017, based on 124 and 106 approvals, respectively, while the median number of patients studied did not change significantly (774 vs 816). FDA drug review times declined from more than 3 years in 1983 to less than 1 year in 2017. But total time from the authorization of clinical testing to approval has remained at approximately 8 years over that period.

Drug makers began to pay FDA fees to fund the review process as a result of AIDS activists protesting the slowness of the agency in the 1980s. In 1993, the first year after Congress passed the Prescription Drug User Fee Act, the FDA collected $29 million in fees. That amount rose to $908 million in 2018. The industry fees amounted to around 80% of the money spent on FDA employee salaries for drug reviews that year. The lead author of the JAMA study said: “There is some concern about the incentives that this created within the FDA … And whether it has created a culture in the FDA where the primary client is no longer viewed as the patient, but the industry.”

The Pharma Marketing Blog tracked the relationship of fees paid to the FDA by the pharmaceutical industry and the push for less rigorous scientific proof in clinical trials (and therefore faster drug approvals). He noted that there was a negative correlation between the rise in user fees and a drop in the number of warning letters sent out by the FDA to companies. There was also a positive correlation between drug user fees and adverse event reports, which track drug safety. See the following graphs taken from the Pharma Marketing Blog.

This hasn’t been the only recent evidence of how the pharmaceutical industry seems to be replacing patients as the FDA’s primary clients. Researchers published a study of the “Association between FDA and EMA [European Medicines Agency] expedited approval programs and therapeutic value of new medicines” in the October 2020 issue of the BMJ. The study sought to characterize the therapeutic value of new drugs approved by the FDA and EMA and how these ratings were associated with the regulatory approval process of the expedited programs of the FDA and EMA.

Over the past few decades both agencies have established programs to expedite drug development for serious conditions. The four main expedited programs of the FDA are: fast track (introduced in 1987), accelerated approval (1992), priority review (1992), and breakthrough therapy (2012). Emergency use authorization, under which the COVID-19 vaccines have been expedited, technically isn’t an FDA approval of the drug, but it authorizes the FDA to facilitate an unapproved product during a declared state of emergency. Its latest update occurred in 2017. The EMA has two expedited programs, accelerated assessment (2005) and conditional marketing authorization (2006). The EMA instituted a third program, PRIME, the priority medicines scheme, in 2016.

These expedited programs were intended to prioritize the most important medicines for faster access to patients, and are increasingly the route by which new medicines are approved. For example, the FDA approved 60% of new drugs through at least one expedited program in 2019, while only 34% of drug approvals in 2000 were expedited. The FDA and EMA guidance indicated that an expedited program should be reserved for drugs that are expected to show an improvement over the available therapies. “However, neither the FDA nor the EMA specifically requires data on, or makes regulatory approval contingent on, comparative effectiveness; most new drugs are approved on the basis of placebo-controlled trials or single arm studies.”

This means the therapeutic value of medicines that benefitted from the FDA and EMA expedited programs is uncertain. Using ratings of therapeutic value published by health authorities in four countries and an independent non-profit organization, the researchers “evaluated the association between expedited programs and ratings of therapeutic value for all new drugs approved by the FDA and EMA from 2007 through 2017.”

We found that less than a third of all new drugs approved by the FDA and EMA were rated by any of five independent organizations as having high therapeutic value—that is, providing moderate or better improvement in clinical outcomes for patients. Most of the increase in the number of new drug approvals over the past decade was driven by drugs rated as having low therapeutic value, which calls into question the common practice of using simple counts of new drug approvals as a measure of innovation. Rather, a more nuanced view of innovation is needed that takes into account the clinical benefits and relevance to patients of new medicines.

The study’s findings suggest that after FDA regulatory approval, there is a widening gap between the drug’s approval and the clinical and public health priorities of health systems, payers and patients in drug safety and efficacy. Contributing to this gap is the varying quality of clinical evidence available at the time of approval. This leads to uncertainty around the extent of clinical benefit of the respective drug. The study’s data emphasizes the importance of robust post marketing evaluation for expedited drugs. “Such an evaluation would confirm early evidence of efficacy and help to elucidate findings from several previous studies suggesting that accelerated approval, priority review, and fast track drugs were associated with increased safety related reports or labeling changes.”

The researchers suggested one step leading to greater assurance of timely completion of post marketing study requirements for expedited drugs could be to require that certain mandated studies enroll patients before the FDA or EMA grants approval. They also suggested that regulatory agencies explore whether additional explanations were necessary. These explanations could include elaboration in product labeling, press releases, or approval documents. They could provide more realistic expectations of benefit for expedited drug approvals by patients and clinicians. Their findings also had implications for the controversy around drug prices.

In the US, the largest public payers are required by law to cover most (Medicaid) or a substantial number (Medicare) of drugs approved by the FDA, regardless of the quality of the evidence supporting their approval or their therapeutic value. Previous studies of cancer drugs have found no association between clinical benefit and drug prices and reimbursement.

In conclusion, the researchers said while the FDA and EMA are increasingly using expedited programs to facilitate drug development, the absolute value of highly rated drugs approved by the FDA and EMA over the past decade was low. Policy makers could explore implementing therapeutic value ratings more widely for new drug approvals. This would align the evidentiary needs of regulatory approval and reimbursement decisions with informing patients and doctors about the benefits and risks of new drugs, particularly those approved by expedited programs.

It’s not so surprising, then, that so many Americans are hesitant to say they plan to get a coronavirus vaccine. It seems that the above discussed results of research into new drug development by the pharmaceutical companies is at least partly to blame. Many people do not trust the claims drug companies make about their products.

The Pew Research Center conducted a survey of Americans at the end of November 2020. Sixty percent said they would definitely or probably get a vaccine for the coronavirus, which was up from 51% in September. Thirty-nine percent say they will definitely or probably not get a coronavirus vaccine. About half of this group, 18%, said it’s possible they would decide to get vaccinated once people start getting vaccinated and there is more information available. “Yet, 21% of U.S. adults do not intend to get vaccinated and are ‘pretty certain’ more information will not change their mind.”

While public intent to get a vaccine and confidence in the vaccine development process are up, there’s considerable wariness about being among the first to get a vaccine: 62% of the public says they would be uncomfortable doing this. Just 37% would be comfortable.

Public confidence has increased since September that the research and development process will yield a safe and effective vaccine for COVID-19. Seventy-five percent of individuals now have a great deal or fair amount of confidence in the R&D process. However, one of the factors influencing whether someone intends to get a vaccine for COVID-19 is mistrust of the vaccine development process. Sixteen percent of Americans do not have much confidence in the process; 8% have no confidence that the R&D process will produce a safe and effective vaccine for COVID-19. Confidence in scientists remains slightly higher than before the pandemic.

With scientists and their work in the spotlight, 39% of Americans say they have a great deal of confidence in scientists to act in the public’s best interest, an uptick from 35% who said this before the pandemic took hold. Most Americans have at least a fair amount of confidence in scientists. However, ratings of scientists are now more partisan than at any point since Pew Research Center first asked this question in 2016: 55% of Democrats now say they have a great deal of confidence in scientists, compared with just 22% of Republicans who say the same.

Pharmaceutical companies have an opportunity when they resume the research and development process for new drug applications after the pandemic. Will they continue to use external committees of scientists vetting the data for new drug applications and produce truly independent recommendations and rejections? If pharmaceutical companies can maintain an open and transparent R&D process and develop drugs with a truly high therapeutic value, the confidence level of patients and their doctors would be higher than ever. For more on COVID, see “Learning from COVID Drug Development.”

03/9/21

Weighing the Risks with ADHD Medication

Did you know that millions of children in the US have been diagnosed with ADHD? The CDC said in “Data and Statistics About ADHD,” that the number of US children diagnosed with ADHD increased from 4.4 million in 2003 to 6.4 million in 2011. It decreased to 6.1 million in 2016. Sixty-two percent of the children diagnosed with ADHD are taking medication. And yet, the prominent Harvard psychologist Jerome Kagan believes ADHD is an invention.

Kagan made this claim in a 2012 interview with Spiegel, when he was asked if he was saying ADHD was just an invention, he said: “That’s correct; it is an invention.” Every child who does not do well in school is sent to a pediatrician who then says: “It’s ADHD; here’s Ritalin.” The neurologist Steven Novella said in “The ADHD Controversy,” that such a characterization was irresponsible. He acknowledged the fact that ADHD is a fuzzy clinical entity, but said progress has been made in understanding what is happening in the brains of most people with ADHD.

The current consensus is that ADHD is a deficit of executive functions. The frontal lobes carry out many critical functions, some considered executive functions: they include being able to focus your attention, maintain focus, switch among tasks, filter out distractions, and impulse control. Executive function includes the ability to weigh the probable outcomes of your behavior and then make high-level decisions about how you will behave.

He went on to say that convergent data from neuroimaging, neuropsychology, genetics and neurochemical studies point to the involvement of a part of the brain known as the frontostriatal network contributing to the pathophysiology of ADHD. “At this point there is no reasonable disagreement about the fact that ADHD is a disorder of brain function.” He referred to an article by David Tuller, whose concerns were more nuanced than Kagan’s. Tuller interviewed Richard Scheffler, co- author of The ADHD Explosion with Stephen Hinshaw. He said the issue was a spike in ADHD diagnoses, not that ADHD was an invented disease.

ADHD is real—it’s not made up. But it exists on a continuum. There’s no marker or white line that says you’re in the “definite” or “highly likely” group. There’s almost unanimous agreement that five or six percent clearly have enough of these symptoms for an ADHD diagnosis. Then there’s the next group, where the diagnosis is more of a judgment call, and for these kids, behavioral therapy might work. And then there’s a third group, on the borderline. These are the ones we’re worried about being pushed into an inaccurate diagnosis.

Scheffler said the research done for their book found that in general, there was a relationship between the rates of ADHD diagnoses and changes in the 1990s with how many states budgeted schools. Money was provided based upon the number of students making positive movement towards performance measures like graduation rates and test scores. Then in the early 2000s, President Bush tied federal dollars to the same kind of budgeting for performance. “We were able to show that these moves were highly correlated with spikes in various states in the diagnosis of ADHD.”

In an opinion article for The New York Times, Hinshaw and Scheffler said that unless we were careful, we faced an epidemic of 4- and 5-year-olds being wrongfully told they have ADHD. Their research showed skyrocketing ADHD diagnoses, especially among the nation’s poorest children. Their research data seems to reflect that reported above in the first paragraph by the CDC in “Data and Statistics About ADHD.”

For example, we found that in public schools, A.D.H.D. diagnoses of kids within 200 percent of the federal poverty level jumped 59 percent after accountability legislation passed, compared with under 10 percent for middle- and high-income children. There was no such trend in private schools, which are not subject to legislation like this.

By the age of 17, nearly one in five American boys and one in ten girls will be told they have ADHD. This is a 40 percent increase over the last ten years and double the rate of 25 years ago. They see this leading to more prescriptions despite the guidance from organizations like the American Academy of Pediatrics that behavioral therapy, not medication, should be the first-line treatment for children under 6. Accurate diagnosis requires reports of impairment from home and school, and a thorough child and family history to rule out abuse or unrelated disorders. “Too many kids are identified and treated after an initial pediatric visit of 20 minutes or even less.”

The CDC data indicated 77% of the children diagnosed with ADHD between the ages of 2 and 17 were receiving treatment. Thirty percent were treated with medication alone; 15% received behavioral treatment alone; and 32% received both. Around 23% were receiving neither medication nor behavioral treatment. approximately 5 in 10 children with ADHD also had a behavior or conduct problem; 3 in 10 with ADHD had anxiety. Seventeen percent were said to be depressed and 14% had autism spectrum disorder.

So there seems to be a problem with accurate diagnosis and overdiagnosis of ADHD leading to medication treatment. What are the implications of these diagnostic problems? And what are the long-term consequences for the children who are medicated?

A Norwegian article, “Drug Treatment of ADHD—tenuous scientific basis,” said that recent systematic reviews indicated there was a weak evidence base for the use of methylphenidate (Ritalin, Concerta) when treating children and adolescents with an ADHD diagnosis. The authors began with an examination of the MTA study (Multimodal Treatment Study of ADHD), stating it was crucial to understanding the current state of knowledge on ADHD treatment. The MTA study showed a reduction in ADHD symptoms in the medication groups at 14 months. But that significance disappeared over the next two years.

After six years, participants in the MTA study who received behavioral therapy but no medication had lower rates of anxiety and depression. The latest results were published in 2017, 16 years after the start of the study. After evaluating the data, the conclusion of the researchers was that the long-term use of central nervous system stimulants was associated with a suppression of adult height, on the average of 1-2 cm. But there was no reduction in ADHD symptoms.

There is no doubt that children with ADHD have genuine and serious problems. However, we cannot ignore the fact that research has yielded only weak evidence to support the extensive use of medication that occurs today. This state of affairs should trigger renewed public and expert discussion on the pharmacological treatment of ADHD in children and adolescents.

There was a further investigation of participants in the MTA study, this time of adolescents and young adults without childhood ADHD: “Late-Onset ADHD Reconsidered.” The purpose of the study was to investigate an influx of adolescents and young adults who present at clinics with complaints of inattention and/or hyperactivity/impulsivity complaints and inquire about stimulant medication. “It remains unclear whether this trend is driven by typically developing individuals seeking stimulant medication for cognitive enhancement or by individuals with late-onset ADHD that warrants medical treatment.” The results indicated that when assessing adolescents and young adults for first-time ADHD diagnoses, clinicians should obtain a thorough psychiatric history and assessment of current functioning.

After using a diagnostic procedure that considered multi-informant data, longitudinal symptoms patterns from childhood to adulthood, Co-occurring mental disorders and substance use, 95% of the individuals who originally screened positive for late-onset ADHD were excluded from diagnosis. When assessing adolescents and young adults for first-time ADHD, 53% of adolescents and 83% of adults who met all the late-onset criteria for ADHD were excluded because their symptoms “were better explained by heavy substance use or another mental disorder.”

SAMHSA, the Substance Abuse and Mental Health Services Administration, noted in “Adults with Attention Deficit Hyperactivity Disorder and Substance Use Disorders” studies that have found adults with ADHD are more likely than their peers without ADHD to develop a substance use disorder (SUD) sometime in their lives. One large epidemiological study found that 15.2% of adults with ADHD also met the criteria for an SUD, compared to 5.6% of adults without ADHD. Research has also indicated that as the severity of ADHD increases, so may the SUD risk. “In a recent analysis of data from the National Epidemiologic Survey on Alcohol and Related Conditions, each additional ADHD symptom before age 18 was associated with a greater lifetime chance of developing substance dependence.”

Much of the research into the misuse of prescribed stimulants has been with college students. College students were found to misuse Dexedrine and Adderall more than other prescribed stimulants. According to the 2012 National Survey on Drug Use and Health, the nonmedical use of Dexedrine and Adderall has risen among college-aged adults and adults 26 and older. Between 4 and 20 percent of college students have used a prescription stimulant without having a legitimate prescription in the past year, typically obtaining the medication from friends who either sell or give their medications away. “Roughly a third of college students with ADHD report that they have sold or given away their medication at least once.” See the following chart.

So, what are the risks with ADHD medications? There are problems with diagnosis and concerns of overdiagnosis, particularly with poor children (See “Demolishing ADHD Diagnosis”). After 2 or 3 years the positive effects of ADHD medications seem to disappear. Long-term use seems related to a suppression of adult height. There appears to be an association between ADHD and an increased risk of SUD. At least one study concluded there is weak evidence for the use of Ritalin and Concerta when treating children and adolescents with an ADHD diagnosis. ADHD was said to be a “fuzzy clinical entity” by a neurologist who believes ADHD is a disorder of brain function.

Web MD said the side effects and risks from long-term use of ADHD medication include: heart disease, high blood pressure, seizure, irregular heartbeat, abuse and addiction, and skin discolorations. Although it’s rare, ADHD medications may be tied to mental health issues like aggression and hostility; and some say they developed symptoms of bipolar disorder. “The FDA has also warned that there’s a slight risk that stimulant ADHD drugs could lead to mood swings or symptoms of psychosis—like hearing things and paranoia.”

01/26/21

Learning from COVID Drug Development

On December 11, 2020 the FDA issued an emergency use authorization (EUA) for the Pfizer-BioNTech COVID-19 Vaccine. Then on December 18^th, the FDA issued an EUA for the Moderna COVID-19 Vaccine. The FDA News Releases for both drugs said the data provided clear evidence both vaccines may be effective in preventing COVID-19. The known and potential benefits for both drugs were said to outweigh the known and potential risks. “In making this determination, the FDA can assure the public and medical community that it has conducted a thorough evaluation of the available safety, effectiveness and manufacturing quality information.”

In December of 2019, no one knew COVID-19 existed and now there are two vaccines being distributed in the US that are both around 95% effective in preventing the novel coronavirus. Despite the unprecedented speed of their development, there were not any compromises with the safety or the scientific integrity of the process. According to Dr. Anthony Fauci, the speed was “a reflection of the extraordinary scientific advances in these types of vaccines which allowed us to do things in months that actually took years before.” He wanted to settle the concerns some people have about the rush of development and approval. Despite the politicization of the process, there was an independent body of people with no allegiance to the administration or to the pharmaceutical companies who were the first ones to review and then approve the data from the companies’ late-stage clinical trials. “We need to put to rest any concept that this was rushed in an inappropriate way . . . Help is on the way.”

The FDA requires that a vaccine be at least 50% effective, according to the latest guidance. By comparison, two doses of the measles vaccine is about 97% effective, and flu vaccines range from about 40% to 60% effective, according to the Centers for Disease Control and Prevention (CDC).

The FDA just finalized the guidance for EUAs in January of 2017. The purpose of this guidance was to explain the FDA’s current thinking on the authorization of the emergency use of certain medical products under certain sections of the Federal Food, Drug and Cosmetic Act, as it was amended or added to by the Pandemic Reauthorization Act of 2013 (PAHPRA).

The provisions in PAHPRA include key legal authorities to sustain and strengthen national preparedness for public health, military, and domestic emergencies involving chemical, biological, radiological, and nuclear (CBRN) agents, including emerging infectious disease threats.

The Washington Post published an article that addressed common concerns about the COVID-19 vaccines. First, it is not just the vulnerable who should get the vaccine. Vaccines protect more than just the person who is inoculated. The more people who are vaccinated means there are fewer people the virus can infect, “lowering the infection rate and the risk for us all.” Another reason is to protect those who cannot get it. The first two approved vaccines were only approved for individuals over the ages of sixteen for the Pfizer-BioNTech COVID-19 Vaccine and 18 for the Moderna COVID-19 Vaccine.

Your decision not to get vaccinated could affect other people around you. Individuals with a weakened immune system may need to rely on the immunity of others to keep them healthy. Not getting a vaccine would be like refusing to wear a mask. We will likely have to wear masks through 2021. In fact, vaccinated people should wear masks and follow social distance guidelines. While the vaccine is effective at reducing symptomatic illness, it is not yet known whether it reduces the likelihood of contracting the coronavirus and being an asymptomatic carrier.

As more people get vaccinated and the US gets to community or herd immunity, there will come a point when we can do away with the masks. “In the meantime, vaccination is a crucial tool. It doesn’t replace other tools but is a powerful measure that can help save lives and help the economy recover.” Allergic reactions can be treated without lasting consequences, but the same is not true for COVID-19. At this time, it is not known what component of the vaccine triggers allergic reactions, but there is not reason for people with food or medication allergies to avoid the vaccine as long as they are monitored in a health-care setting.

All viruses mutate and it may turn out that people will have to receive regular booster shots, like with tetanus or the flu shot. Enough mutations could eventually reduce the potency of existing vaccines. A study of the Moderna vaccine found it was effective for at least 119 days. But some experts believe immunity should last at least a year. “The theoretical necessity of future vaccinations doesn’t override the urgency of getting one now.”

For those worried about political interference in expediting approval, it’s critical to emphasize that no shortcuts were taken in research or the approval process. Vaccine safety was tested in phase 3 trials involving tens of thousands of participants. External committees of scientists vetted the data and produced independent recommendations to support vaccine authorization.

The Allegheny Health Network (AHN) posted a series of frequently asked questions (FAQs) and answers that addressed further questions about the COVID-19 vaccines. The further information there included that no doctor’s order will be necessary to get the vaccine, but you will have to schedule an appointment. AHN said the vaccine is free to all Americans and will be available at retail pharmacies. “Remember, some vaccines require two doses to be effective. It’s extremely important you get both and follow the suggested timeline.”

Who knows where we’ll be with COVID in another twelve months! But there are some things we’ve learned through this pandemic about drug companies and hopefully will continue to insist on. Drug development can be done quickly and safely. Pharmaceutical companies can be open and transparent about their research and allow truly independent, external committees to verify their findings. People can trust the results of drug development when the clinical trial process is not statistically or methodologically manipulated to show what the researchers want to find.

The widespread mistrust of science that became evident during the pandemic seems partly due to the previous manipulation of drug development by the pharmaceutical companies. Like good illusionists, they directed our attention to what they wanted us to see and away from what they wanted to hide. Going forward, open, transparent drug development can restore the trust that is now lacking for the COVID vaccine. During the pandemic drug companies showed they could do COVID Drug Development quickly and safely. We need to remember these things and hold the drug companies accountable to these standards.

12/22/20

Psychiatry Is Different, Not Irrelevant

The Vice article, The Movement Against Psychiatry, opened with a disturbing story about two women who sought help from the mental health system, but received very different and ultimately harmful results. One woman refused to take medication or see her therapist and her condition deteriorated until she was eventually psychotic and incarcerated. The second woman served as a sergeant in the Army and sought psychiatric help while she was receiving medical care in Germany when she learned her convoy hit a roadside bomb in Iraq. “I walked straight down the hallway to the psychiatry office because I thought that’s what you do when you need help.” That began 13 years of being treated with 45 different medications, up to 18 at the same time until she said enough.

“The Movement Against Psychiatry” by Shayla Love used these two women to illustrate the contrasting position at the center of the debate of how to fix—or to do away with—the way we treat mental illness: over and under medication. At the core of this issue are the differences between psychiatry and what is called anti-psychiatry or critical psychiatry. But Love does not give a very fair presentation of the so-called anti-psychiatry position. This assessment is shared by Robert Whitaker, the journalist, author, and founder of madinamerica.com, which Love said was probably “the most active and legitimate critical psychiatry platform that exists today.”

Whitaker wrote a response to the Love’s article, “Vice, MIA and The Movement Against Psychiatry,” in which he presented a three-pronged assessment of what Love wrote. First, he gave an explanation of the mission of Mad in America. Then he addressed a common criticism made against himself and the Mad in America website that Love repeated, namely that Whitaker and his webzine distort the scientific record of psychiatry. Lastly, he saw the article as an opportunity to illustrate how the media, represented by Vice, perpetuated the conventional narrative about psychiatry.

In a section of his article titled: “Understanding Mad in America,” Whitaker gave a description of how the webzine seeks to be a forum for developing a new narrative to guide society’s thinking and care about psychiatry and its drug treatments. He then went on in “Deconstructing the Vice Article,” to describe some surprising details about what seems to be Love’s failure to remain unbiased. Love did not interview Whitaker for her article, instead she contacted him by email one week before her article was to be published. Whitaker also invited her to contact the researchers whose work he was said to have misinterpreted in order to see whether they thought his reporting of their work was inaccurate.

It seems she also failed to do that as well. Whitaker said, “All she needed to do was read the studies, call Harrow or Jobe, and she could have had a blockbuster article, anchored by research that revealed there was a scientific rationale for a “movement against psychiatry.”

Martin Harrow and Thomas Jobe had investigated long-term outcomes of patients diagnosed with psychotic disorders. They found at the 15-year mark that the recovery rate for schizophrenia patients off medication was eight times better than those who were medication compliant. Whitaker noticed in their data that even patients with milder psychotic disorders who stayed on antipsychotics had worse long-term outcomes than those with schizophrenia who got off medications. Harrow and Jobe later published further analysis of their long-term data and cited him and Joanna Moncrieff among those who questioned the received narrative for long-term outcomes for those who were using antipsychotics. Harrow and Jobe said:

Overall, the longitudinal studies cited do not provide conclusive proof of a causal relationship between being off medications and being psychosis free. They do clearly indicate that not all schizophrenia patients need continuous antipsychotics for a prolonged period, providing extensive evidence of samples of medication-free schizophrenia patients with favorable outcomes.

Whitaker’s deconstruction of “The Movement Against Psychiatry” illustrates how the article reinforces the conventional narrative of psychiatry. Read an op-ed article for MedPage Today, “Why Anti-Psychiatry Now Fails and Harms,” if you want an example of what is meant by the conventional narrative. Coincidentally, two of the three authors of the MedPage Today article were cited or quoted by Love as supporting the conventional narrative.

The Vice article was presented as an exploration of the “movement against psychiatry,” and yet you can see, once it is deconstructed, how it told a story that surely pleased the promoters of the conventional narrative, and put the “critics” on the defensive at almost every turn.

The concluding comments in Whitaker’s article appear to invite further dialogue between psychiatry and so-called “anti-psychiatry,” but he seems to be frustrated with the way many media outlets—Vice being the example here—protect and perpetuate the conventional narrative of psychiatry:

I hope that deconstructing this article—and revealing the journalistic standards that are on display—helps reveal the depth of the challenge for those who would like to see “psychiatry reimagined.” Unfortunately, this struggle is regularly hindered by the fact that media are often poised to report in ways that protect the conventional narrative, and look askance at those who would challenge it. But as is the case in any struggle, it’s always good to know what you are up against.

It also seems that Love may have misrepresented more than just Whitaker and Mad in America. Awais Aftab, a psychiatrist and author of an interview series for Psychiatric Times,” was prompted to clarify the context surrounding Love’s quotes of him the day after “The Movement Against Psychiatry” was published in: “The VICE Story: Beyond Anti-psychiatry.” Dr. Aftab appeared to be attempting a corrective against the potential for “the VICE Story” to lead too far into a “polarizing discourse.” He said he does not identify as a “critical psychiatrist,” because he does not think “critical” serves well as an identity function. He also said “anti-psychiatry” is an imperfect term because very few individuals today self-identify their views as being anti-psychiatry. Nevertheless, “one can still recognize the tremendous need for reform, and acknowledge the valid ways in which an exclusive emphasis on medical conceptualization can be harmful.”

This is a delicate and qualified position and navigating a dialogue from such a position is subject to the constant pressure for the dialogue to collapse into one polar position or another. I do not always succeed in that, but I try. That has precisely been the function of my interview series for Psychiatric Times, “Conversations in Critical Psychiatry”, where I try to engage with various critical and philosophical perspectives.

Attempting to maintain that dialogue, he noted how Love recognized the need to resist a polarizing discourse in her article. He pointed out that Love said it was nearly as useless to be steadfastly pro-psychiatry as it was to be anti-psychiatry. He concluded by saying: “One can recognize the need for meaningful criticisms and structural reform without delegitimizing the medical basis of psychiatry.”

Although Shayla Love did not interview Robert Whitaker for her article, John Horgan did interview him for an opinion piece published online for Scientific American, “Has the Drug-Based Approach to Mental Illness Failed?” When asked if he saw himself as a journalist or an activist, Whitaker said he didn’t see himself as an activist at all. He then quoted the mission statement for Mad in America, which said its mission was to serve as a catalyst for rethinking psychiatry. The current psychiatric paradigm has failed. Scientific research and the lived experience of those who have been diagnosed with a psychiatric disorder both call for a profound change.

The usual practice in “science journalism” is to look to the “experts” in the field and report on what they tell about their findings and practices. However, while reporting and writing Mad in America, I came to understand that when “experts” in psychiatry spoke to journalists they regularly hewed to a story that they were expected to tell, which was a story of how their field was making great progress in understanding the biology of disorders and of drug treatments that—as I was told over and over when I co-wrote the series for the Boston Globe—fixed chemical imbalances in the brain. But their own science, I discovered, regularly belied the story they were telling to the media. That’s why I turned to focusing on the story that could be dug out from a critical look at their own scientific literature.

Dr. Aftab’s comment above, about doing meaningful criticism and structural reform without delegitimizing the medical basis of psychiatry, may have captured the essence of the struggle between psychiatry and “anti-psychiatry.” Psychiatry wants to hold on to its identity as a medical specialty and sees the critique of Whitaker and others as a distinct threat to that identity. Perhaps the way forward lies with Lisa Cosgrove’s remarks quoted in “The Movement Against Psychiatry.” She said the fact that there are not any biomarkers doesn’t make psychiatry irrelevant as a medical discipline. “It just makes it different from other subspecialties in medicine.” Psychiatry needs to embrace its difference.

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.”

Faith Seeking Understanding

Charles Sigler, D.Phil.

Category Archives: Counseling Issues