06/13/23

Overdiagnosing Depression with the PHQ

According to PsychCentral, in 2020 there were more than 252 million prescriptions prescribed for mental health conditions. The total cost spent on psychiatric medications was more than $15.6 trillion. Zoloft (sertraline) was the most prescribed psychiatric medication with 38.22 million prescriptions, but only made Pfizer $523 million. This is because Pfizer’s patent on Zoloft expired in June of 2006. In its last full year of patent exclusivity, Pfizer’s sales for Zoloft totaled $3.3 billion. And it seems Zoloft’s popularity as an antidepressant can be credited at least in part to the introduction of the Patient Health Questionnaire (PHQ-9), which was developed by Pfizer shortly after Zoloft came on the market.

Writing for Insider, Hilary Bruek said Pfizer was persuaded to invest in the research necessary to develop what became the PHQ-9 by Howard Kroplick, one of their marketers. Kroplick told STAT: “It wouldn’t have happened if it wasn’t for me.” The PHQ-9 became a quick and easy tool that made many primary care doctors more comfortable prescribing antidepressants. Once Pfizer decided to underwrite the development of the PHQ-9, they contracted with Robert Spitzer and his wife Janet Williams, who were central figures in the revisions of the DSM-III.

In September of 2001, Kurt Kroenke, Robert Spitzer and Janet Williams published “The PHQ-9” in the Journal of General Medicine. The authors thought brief measures like the PHQ-9 were more likely to be used in the busy setting of primary care clinical practice. “Brevity coupled with its construct and criterion validity makes the PHQ-9 an attractive, dual-purpose instrument for making diagnoses and assessing severity of depressive disorders.” Note that the creators of the nine item PHQ-9 thought it could be used to diagnose depression. STAT reported the PHQ-9 has become an omnipresent tool, being cited in more than 11,000 scientific papers and routinely used in primary care and other routine visits.

Prescribing antidepressants in primary care based upon a PHQ-9 score of 10 or greater appears to be a sensible medical decision. There have been multiple studies such as Moriarty et al in General Hospital Psychiatry, that find the cutoff point of 10 on the PHQ-9 to have “acceptable diagnostic properties” for major depression. Studies, such as Negeri et al in the BMJ find the PHQ-9 has a combined sensitivity of 85% at the standard cutoff value of ≥10. A referral to a psychiatrist to confirm a depression diagnosis means a delay in treatment, meaning a delay in prescribing an antidepressant. Why not just recommend to the patient that they try a SSRI if their PHQ-9 score is equal to or greater than 10?

Malpass et al noted their concern that self-administered questionnaires like the PHQ-9 were regularly used in clinical practice to guide prescribing or to measure recovery and response to treatment. They thought when patients were given the PHQ-9, they were not interpreting the question items in the same way. They used a research technique called cognitive interviewing to identify ‘interpretive measurement error’ (IME). They found a wide range of comprehension and answer-mapping difficulties on the PHQ-9 that persisted over time.

Clinicians have expressed uncertainty about the PHQ-9’s validity and utility, and in the management and diagnosis of depression within primary care have a strong preference for clinical judgement over scores on severity measures. In light of the numerous ways the PHQ-9 may be missing the presence and/or intensity of certain symptoms that are meaningful to patients, clinicians should continue to adopt caution when using and interpreting questionnaire scores. The study raises the question that longer assessments may be better in providing opportunities for distinguishing frequency and severity.

Writing for Mad in America, Peter Simons commented on a meta-analysis study by researchers in the Journal of Epidemiology that concluded the PHQ-9 did not accurately estimate the prevalence of depression. The researchers concluded that that the PHQ-9 “substantially overestimates depression prevalence. There is too much heterogeneity to correct statistically in individual studies.” Simons said they found it was twice as likely to diagnose depression as the SCID, a semi-structured interview guide for making diagnoses according to the diagnostic criteria published in the DSM. 24.6% of participants in the study were found to be depressed by the PHQ-9, while only 12.1% met the criteria for depression on the SCID.

In primary care settings doctors will likely consider a positive score of ten or higher (the standard cut-off for depression screening with the PHQ-9) as indicating the presence of depression and consider it good enough to diagnose patients with depression and recommend antidepressant treatment. “This could lead to massive inflation of the estimates of how many people ‘have’ depression in the population.” The PHQ-9 is technically not a diagnostic measure of depression (despite what its creators said), but when it is used that way, the result is overdiagnosis.

Estimates of depression prevalence should be based on validated diagnostic interviews designed for determining case status; users should evaluate published reports of depression prevalence to ensure that they are based on methods intended to classify major depression.

The bottom line is that when screening tools like the PHQ-9 are used alone to assess depression in a person, clinicians are likely to misdiagnose it. And there are additional problems if the misdiagnosed person begins using an antidepressant to “treat” this so-called depression.

The general public widely believes depression is the result of a chemical imbalance, which shapes how people understand their moods. It may also discourage them from discontinuing a prescribed antidepressant medication, potentially leading to lifelong dependence on these drugs. An umbrella study by Moncrieff et al found “there is no convincing evidence that depression is associated with, or caused by, lower serotonin concentrations or activity.” The researchers said most studies did not find evidence of reduced serotonin activity in people with depression when they were compared to people without depression. The chemical imbalance theory of depression is now seen as an urban legend, “never a theory seriously propounded by well-informed psychiatrists,” according to pro-medication psychiatrist Ronald Pies.

Moncrieff and others have also noted there are adverse effects from taking antidepressants. In “Persistent adverse effects of antidepressants, she said we are not clear about the nature of the neurochemical and physiological changes that occur when we take an antidepressant. “We are even less certain about how the body, including the brain, adapts to the long-term presence of these drugs.” We also do not know whether the changes produced by the drugs in the brain return to normal when the drugs are stopped; or if the changes persist.

Moncrieff then pointed to the withdrawal effects with long-term antidepressant use. She said the evidence suggests a picture similar to benzodiazepine withdrawal. There is a range of duration and intensity, where not everyone experiences noticeable or debilitating symptoms, but there are numerous reports of “withdrawal symptoms being severe and protracted.”

Moncrieff also referred to a 2006 article by David Healy and others that associated antidepressants and violence in some individuals. Healy said mechanisms that linked antidepressant treatment (rather than the depression itself) to violent behavior included akathisia, emotional disinhibition, emotional blunting, and manic or psychotic reactions. “There is good evidence that antidepressant treatment can induce problems such as these and a prima facie case that akathisia, emotional blunting, and manic or psychotic reactions might lead to violence.”

A group of researchers from the Nordic Cochrane Center in Denmark, including Peter Gøtzsche, published a meta-analysis in 2016 that confirmed Healy et al’s findings, according to Moncrieff. They found the risk of aggressive behavior doubled with the use of antidepressants. They also said akathisia was under-reported. Although akathisia occurred more often with study participants who used antidepressants, the difference was not significant. While they found no significant differences in mortality or suicidality, “our data confirmed the increased risk of suicide in children and adolescents.”

A 2016 literature review of long-term newer antidepressant use (SSRIs and SNRIs) by Carvalho et al noted over 12 adverse effects from antidepressants, that included weight gain, bleeding, sleep disturbance, diabetes, osteoporosis and others. The findings of this review suggest that long-term treatment with SSRIs and SNRIs “should be avoided if alternative treatments are available.” The authors noted there is a tendency to extend antidepressant treatment for long periods of time, believing that it protects against recurrence. However, that was not true in all cases. “This finding indicates that in patients with chronic recurring MDD, recurrences are difficult to prevent with [antidepressant] use only.”

It seems that the PHQ-9 depression scale has contributed to the overdiagnosis of depression and the overuse of antidepressants. One might even suggest this was exactly what it was developed to do. The PHQ-9 helped Pfizer (and eventually other pharmaceutical drug companies) reach into the untapped market of primary care physicians and gave them a tool they felt comfortable using in order to prescribe antidepressants to their patients. Unfortunately for the PHQ-9, the evidence that antidepressants have limited efficacy and multiple adverse side effects is growing.

02/7/23

Paradigm Shift Needed with Depression

There has been a study published in Molecular Psychiatry, “The serotonin theory of depression: a systematic umbrella review of the evidence,” that debunked the chemical imbalance theory of depression. Wonder of wonders, it led to conversations in the general public about depression and the use of antidepressants. Was the theory just an urban legend, or is it just a shorthand explanation of how antidepressants work, “even if it’s not entirely accurate.” It also resulted in what seemed to be as much a personal attack to the lead author of the study, Joanna Moncrieff, by Rolling Stone: “Who Is the Psychiatrist Behind the Antidepressant Study Taking Over Right-Wing Media?”

She and the other researchers were ridiculed for doing an umbrella review of “outdated” studies. One professor of psychiatry was quoted as saying: “Wow, next she’ll tackle the discrediting of the black bile theory of depression.” The term originated in the humoral theory of Hippocratic medicine, where an excess of black bile was thought to result in a melancholic temperament and lead to symptoms of depression. This was the dominant theory for depression, or melancholia, from antiquity through the 19^th century.

Responding to the Rolling Stone article on her blog, Moncrieff said ignoring her critique was no longer working. So, “champions of big Pharma and mainstream psychiatry have gone into attack mode.” In what she referred to a “a time-honoured tactic,” she described how Rolling Stone attempted to discredit her by associating her with the right-wing media coverage of their research.

The article accuses me of ‘promoting widely disputed beliefs about the dangers of various mental health interventions such as antidepressants or alternative forms of treatment’. This is not accurate. Most of the adverse effects I have highlighted in my research are widely recognised, and those that are less well-recognised (such as post SSRI sexual dysfunction- which is now recognised officially by the European Medicines Agency) have not been ‘widely disputed,’ or indeed disputed at all.

Psychiatric Times also used the black bile slur asking its physician readers what they would think if they saw the headline: “Depression Probably Not Caused by Excessive Black Bile.” The authors condescendingly said they believed that Moncrieff et al thought they were publishing something “extraordinarily newsworthy or controversial.” They concluded that “depression is a complex, heterogenous disorder with biological, psychological and sociological determinants and risk factors.” Placebo-controlled studies offered “ample evidence that serotonergic agents are safe and effective in the treatment of acute major depressive disorders.” They hoped that patients and clinicians were not deterred from using antidepressants by the review.

These ad hominem attacks were not the only coverage. On Point, a pod cast on NPR radio, featured Daniel Carlat, the chair of psychiatry at Melrose Wakefield Hospital, part of the TuftsMedicine network, Joanna Moncrieff and Anne Harrington, a professor of the history of science at Harvard University. The host for “Behind the new study changing how doctors view depression” noted while antidepressants work for some people, Pfizer and other pharmaceutical companies don’t know how they work to relieve depression symptoms, “especially SSRIs.” Meghna Chakrabarti said some studies show that as many as 85% of the public believe the chemical imbalance theory of depression. “People have been told for three decades now, that depression is due to a chemical imbalance, and that they need to take antidepressant treatment to put that imbalance right.”

The program explored the gap between what the medical community knows about antidepressants, what the public knows, and why that gap exists. Dr. Carlat said many of the studies reviewed by Moncrieff et al were ones he had read before he wrote his 2010 book, Unhinged: The Trouble with Psychiatry – a Doctor’s Revelations about a Profession in Crisis. He thought their study pulled the data together “in a nice way” that made it very clear: “People have been led to believe that there is a chemical imbalance theory of depression.” Listen to the 40-minute program to hear more from Dr. Carlat.

The overall message seems to be yes, the public believed there was a chemical imbalance theory of serotonin deficiency for depression, but that’s old news. Researchers and academic psychiatrists have never believed this urban legend. Nevertheless, antidepressants still work and are safe and effective, so don’t be deterred from using them. However, that effectiveness rate is only slightly better than a placebo in the clinical trials approved by the FDA. And that difference—around two points on the 52-point Hamilton D depression scale—is “clinically imperceptible.”

Marc Stone was the lead author of a new study published in the BMJ, the British Medical Journal, in August of 2022. He is the Deputy Director for Safety with the FDA. Irving Kirsch, the principal investigator, is the Associate Director of the Program in Placebo Studies at Harvard Medical School, noted for his work on placebo effects with antidepressants. See “Dirty Little Secret” and “Do No Harm with Antidepressants” for more on Kirsch’s work on antidepressants and placebos.

Stone et al again replicated the less-than-two-point difference between drug and placebo across all 73,388 participants. “We found a drug effect among adults equivalent to 1.82 points, with a standardized mean difference of .24.” The response distributions did not appear to be unimodal to the researchers. Further analysis of the data found the optimal model for drug and placebo responses was “a combination of three overlapping normal distributions,” which they referred to as Large responses, Minimal responses and Non-specific. About two thirds of participants had a Non-specific response; and about 15% had a substantial antidepressant effect.

Reviewing the BMJ study for Mad in America, Peter Simon said:

The drug and placebo groups both had extremely high rates of symptom improvement: 84.4% of the placebo group found their depression symptoms improved, while 88.5% of the drug group improved. However, in many cases, this “improvement” was small.

More important is the number of people who experienced a large improvement. This improvement is more likely to be clinically relevant. The researchers found that those taking the drug were more likely to experience this level of improvement—24.5% of the antidepressant group experienced large improvement, versus 9.6% of the placebo group.

Based on these numbers, there seems to be a small group—about 15% of people—who experience a large response to the drug who would not otherwise improve to this level.

Unfortunately, the researchers found no way to predict who, exactly, is in this 15%. They write that if everyone with a depression diagnosis is given an antidepressant, about seven people need to be given the drug (and thus be exposed to the harmful effects with no benefit) before one person benefits.

Only one in seven people who use antidepressants will notice a clear improvement and researchers can’t predict who those individuals will be. That means 85% of individuals using antidepressants will not have a clinically noticeable improvement. Stone et al said the effectiveness of all placebo-controlled antidepressant efficacy trials submitted to the FDA between 1979 and 2016 was 1.82 points on the HAMD17, ranging from 1.62 to 2.56. It is generally agreed that drug-placebo differences greater than 3 points are necessary for a clinician to detect a minimal improvement with a patient. See “Fighting or Fueling Suicide with Antidepressants?”

It doesn’t seem that placebo-controlled studies of antidepressants offer ample evidence that they are “safe and effective” in treating acute major depression. The findings and conclusions of “The serotonin theory of depression: a systematic umbrella review of the evidence” cannot be easily ignored or dismissed.

One final research article to consider is by Peter Sterling, a professor of Neuroscience at the Perelman School of Medicine, University of Pennsylvania. He is a self-described “hard core” neuroscientist. His article, “A Neuroscientist Evaluates the Standard Biological Model of Depression,” concluded that current evidence does not support the hypothesis that depression is “a localized, disordered neural circuit.” Neuroimaging cannot identify “the mental disturbance” we call depression; nor can it be predicted in individuals by analyzing their genetic makeup.

“Chemical imbalance” theories of depression have not been supported, thereby removing any scientific rationale for “antidepressant” drugs. The drugs are not specific but rather affect myriad neurotransmitter systems, offering little advantage for most individuals, but commonly causing long-term harm. The brain adapts to antidepressant drugs, just as it adapts to drugs of abuse, and so for both withdrawal can be extremely difficult.

Depression is far better predicted by levels of childhood trauma, life stress, and lack of social supports. Depression in individuals is significantly reduced by physical repairs to their depressed communities and by psychological repairs through shared experience of childhood trauma and chronic domestic abuse.

If researchers and academic psychiatrists never believed the chemical imbalance theory of depression, why weren’t they as assertive challenging this urban legend as they have been at minimizing the significance of “The serotonin theory of depression: a systematic umbrella review of the evidence?” Does an effectiveness rate of 15% with antidepressants justify 85%—6 of 7 who use them—receiving ineffective, marginally better treatment effectiveness than placebo? Supporters of the current paradigm of depression and its treatment dismiss or minimize evidence that challenges it. There needs to be a paradigm shift in how we think about depression and its treatment.

12/20/22

Business as Usual with Antidepressants

Van Gogh | in the public domain{{PD-US}}

In “Serotonin or Not, Antidepressants Work” for Psychiatric Times, Drs. Ronald Pies and George Dawson wrote a critique of an article in Molecular Psychiatry by Moncrieff et al, “The serotonin theory of depression: a systematic umbrella review of the evidence.” They were puzzled with the article’s claim, that there was “no support for the hypothesis that depression is caused by lowered serotonin activity or concentrations.” They said it was like seeing an article in 2022, that said depression was probably not caused by excessive black bile.

Pies and Dawson dismissed the review as nothing more than “old wine in new bottles.” Then they listed 7 ways they thought the review and its conclusions were amiss. The role of serotonin in mood disorders was not settled science and there may be a role for it “in some types of depression, which is almost certainly a heterogeneous group of disorders.” They quoted Dr. Michael Bloomfield who said: “The problem with the review [by Moncrieff et al] is that…it has lumped together depression as if it is a single disorder, which from a biological perspective does not make any sense.”

Yet it does make sense when you do an umbrella review of studies where depression was assessed as the singular disorder of Major Sepressive Disorder, according to the DSM—which is published by the American Psychiatric Association.

Depression is a complex, heterogeneous disorder with biological, psychological, and sociocultural determinants and risk factors. Very few—if any—US psychopharmacologists and academic psychiatrists have ever endorsed a sweeping chemical imbalance theory of mood disorders. Historically, psychiatrists have never explained clinical depression solely in terms of reduced serotonin or any specific neurotransmitter. Many drugs in clinical medicine work through unknown or multiple mechanisms, as SSRIs do, and this does not affect their safety, efficacy, or approval for medical use. Results of placebo-controlled studies offer ample evidence that serotonergic antidepressants are safe and effective in the treatment of acute major depressive episodes. If serotonergic agents are not helpful, antidepressants from other classes (eg, noradrenergic/dopaminergic agents) may be considered.

Their final word was they hoped patients and clinicians would not be deterred from using antidepressants by the review, “or by the fact that SSRIs’ mechanism of action is complex and not completely understood.” So, the bottom line of their critique was whether or not we understand how serotonin influences depression, SSRIs work. In other words, the serotonin theory of depression may be wrong, but there must be a biochemical connection because antidepressants work. The effectiveness of SSRIs and other antidepressants is evidence of such a relationship. We just haven’t discovered what it is yet.

The Moncrieff et al article has received a significant amount of support as well as critique since it was published. The Rolling Stone wrote how the article “went viral,” but then essentially attempted to marginalize Moncrieff and dismiss her research.

In an email to Rolling Stone, Moncrieff said, “I see our research as linked with the way we understand and evaluate antidepressants, and it logically follows from my other work on the nature of drug action.” I think this statement by Moncrieff is the center of the dispute, but that was not where Rolling Stone went. It went off on a tangent, noting how the Church of Scientology organization, CCHR, frequently promoted her work. Also, that ‘far-right’ commentators like Matt Walsh and Tucker Carlson were promoting its findings. They suggested she was dabbling in conspiratorial thinking. If you conclude that antidepressants don’t work after reading her paper, then you got the wrong message.

Joseph Comaty, a Medical Psychologist, thought the paper didn’t undermine the efficacy of antidepressants. “But we just don’t know the biochemical theory of depression.” As we learn more about mental illness, things will change. According to Comaty: “if what we once believed is no longer tenable, then yeah, we’ll move along and come up with a new one.” That is just the process of scientific inquiry.

However, the mythical nature of the serotonin hypothesis of depression doesn’t seem to have been translated into the marketing and public discussion of antidepressants just yet. And why is it psychiatrists are referring to the Moncrieff et al study as old wine in new wine skins, saying it is akin to declaring depression is not caused by an excess of black bile? If they’ve known the chemical imbalance theory of depression was an error for several years, why did they not correct that false impression in the public media that is now discussing the Moncrieff et al review?

In a blog article, Moncrieff responded to some of the inaccuracies and distortions in the Rolling Stone article. She said apparently their finding was so obvious that it was met with yawns by the psychiatric community. “Yet the public were kept in the dark about the lack of evidence for a chemical imbalance for three decades in what an Australian psychiatrist recently called a ‘scourge on our profession’. And the public is very interested.” Their original paper is in the top 500 most shared scientific papers—of the 21 million that have ever been tracked—and their article in The Conversation (the one Pies and Dawson referred to) had over a million hits by August 3^rd.

She noted the attempt to discredit her by association to the Scientologists and the ‘right-wing media.’ The article said she promoted the belief that SSRIs were linked to aggressive behavior, which was said to be a fringe view used by right wing media to argue against gun control in the US. She did comment on research published in the British Medical Journal (BMJ) that found a link between antidepressants and aggressive behavior, as well as suicide, in young people. Her comments were published in an invited editorial in the BMJ.

The journalist does present my response to these issues, but bringing them up seems to suggest that because of this we should never have publicised or maybe even done our research. This amounts to the suggestion that millions of people should be denied information about the drugs they put in their body every day because the message might be taken up by the ‘wrong’ people.

The ’right’ people seem to be the ones who have known for thirty years that the chemical imbalance theory was disproved. They’ve known it was an urban myth, yet did not speak up and correct the wrong impression given to the public. Now that the public is paying attention, they say the news about serotonin is old hat. It seems they want you to ignore the conclusions of the Moncrieff et al study and just return to business as usual with antidepressants.

For more information on the Moncrieff et al study its implications, see “The Death of the Chemical Imbalance Theory?” and “The Myth of the Serotonin Theory of Depression.”

10/25/22

The Myth of the Serotonin Theory of Depression

A research article by Joanna Moncrieff, Mark Horowitz and others, “The serotonin theory of depression: a systematic review of the evidence”, published in the journal Molecular Psychiatry in July of 2022, continues to draw media attention to its findings. The researchers did a systematic umbrella review of the principle relevant areas of research and concluded that the main areas of serotonin research provide no consistent evidence of an association between serotonin and depression. “We suggest it is time to acknowledge that the serotonin theory of depression in not empirically substantiated.” In other words, it’s a myth.

The response from many psychiatrists to the article was that the serotonin imbalance theory has not been treated seriously within the field for many years. Neuroscience News & Research quoted several who thought the findings were not surprising. Dr. Michael Bloomfield a consultant psychiatrist and head of the translational psychiatry research group at University College London said he didn’t think he’d met any serious scientists or psychiatrists who thought that “all causes of depression are cause by a simple chemical imbalance in serotonin.” Allan Young, the director of the Centre for Affective Disorders at King’s College London said, “Most psychiatrists adhere to the biopsychosocial model with very few people subscribing to a simple ‘chemical imbalance’ theory.”

According to Ang, Moncrieff and Horowitz in Is the chemical imbalance theory an ‘urban legend’?, historically there was a considerable promotion of the serotonin hypothesis of depression in both the psychiatric and the psychopharmacology literature. Research papers supporting it were widely cited. While some textbooks were more nuanced, others could be seen to unreservedly indorse it. The American Psychiatric Association (APA) published a patient leaflet in 2005 that said, “antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” See, “The Death of the Chemical Imbalance Theory?” on this website.

It is often assumed that the effects of antidepressants demonstrate that depression must be at least partially caused by a brain-based chemical abnormality, and that the apparent efficacy of SSRIs shows that serotonin is implicated. Other explanations for the effects of antidepressants have been put forward, however, including the idea that they work via an amplified placebo effect or through their ability to restrict or blunt emotions in general.

Moncrieff et al said surveys suggest that 80% of the general public now believe depression is caused by a ‘chemical imbalance.’ They said many general practitioners also subscribe to this view and popular website commonly cite the theory.

The chemical imbalance theory of depression is still put forward by professionals, and the serotonin theory, in particular, has formed the basis of a considerable research effort over the last few decades. The general public widely believes that depression has been convincingly demonstrated to be the result of serotonin or other chemical abnormalities, and this belief shapes how people understand their moods, leading to a pessimistic outlook on the outcome of depression and negative expectancies about the possibility of self-regulation of mood. The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.

Writing for The Conversation, Moncrieff and Horowitz said the serotonin theory of depression has been one of the most influential and extensively researched biological theories of depression. Most antidepressants now in use are presumed to work through their effects on serotonin or noradrenaline. Yet their study shows that is not supported by scientific evidence. “It also calls into question the basis for the use of antidepressants.”

It is important that people know that the idea that depression results from a “chemical imbalance” is hypothetical. And we do not understand what temporarily elevating serotonin or other biochemical changes produced by antidepressants do to the brain. We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.If you’re taking antidepressants, it’s very important you don’t stop doing so without speaking to your doctor first. But people need all this information to make informed decisions about whether or not to take these drugs.

The organization, Inner Compass Initiative, was able to get Joanna Moncrieff, Mark Horowitz and Irving Kirsch together for an online discussion in “Moving Beyond Myth: A Postmortem Analysis of Chemical Imbalances and Antidepressants Efficacy.” On its website Inner Compass Initiative said it is an organization that is “dedicated to helping people make more informed choices about taking and withdrawing from psychiatric medications.”

Irvin Kirsch has published several studies of the placebo effect and antidepressants, demonstrating that most of the efficacy with antidepressants is from the placebo effect. For more information on Irving Kirsch and his research, see, “Dirty Little Secret,” and “Antidepressant Fall From Grace, Part 2” on this website.

The Inner Compass Initiative moderator, Laura Delano, said the use of antidepressants in the West more than doubled between 2000 and 2015. One in seven Americans and one in six in England take an antidepressant. In October of 2004 the FDA issued a black box warning, indicating an increased risk of suicidal ideation and behavior in children and adolescents treated with SSRIs. However, their off-label use with children and adolescents has increased. In “Antidepressants in Children and Adolescents”, Boaden et al said: “From 2005 to 2012, the prevalence of antidepressant use has increased from 1.3% to 1.6% in the USA, from 0.7% to 1.1% in the UK.”

While the overall percentages are low, keep in mind that at least in the U.S. those increases took place after the FDA required a black box warning of an increased risk of suicidality with children and adolescents treated with SSRIs. In the UK, it represents an increase of over 36%; in the USA, by almost 19%.

“Moving Beyond Myth” begins with a description of how serotonin is measured within the body and a review of the history of the chemical imbalance theory. Joanna Moncrieff said it is not the case that there is a set normal level of serotonin against which people’s serotonin can be judged. She went on to say that the chemical imbalance theory of depression was one of a number of chemical imbalance theories of mental disorders that arose in the 1960s, “in the context of thoughts about drugs that are used to treat these disorders. So, they’re always directly related to the use of drug treatments.” Psychiatrists and researchers came to think that the drugs are working by targeting the underlying abnormality.

Initially they thought that noradrenaline might be relevant in depression. They hypothesized that depression might be due to lower levels of noradrenaline. But when the drugs that selectively target serotonin came out, “people started to think that the underlying abnormality was an abnormality of serotonin, rather than noradrenaline. And that is what the pharmaceutical industry took hold of and ran with in the 1990s when they started to market SSRIs.”

Her point is that chemical imbalance theories have always been dreamed up in the context of the use of different drugs to treat mental disorders. “They are based on the assumption that drugs are working by targeting the underlying abnormality, and that you can deduce the abnormality from the opposite of what the drugs do.” Mark Horowitz goes on to describe the findings of “The serotonin theory of depression: a systematic review of the evidence.”

An added bonus in “Moving Beyond Myth” is to hear Irving Kirsch describe his research into antidepressant efficacy and its relationship to the placebo effect. His most recent research was published in August of 2022 in the BMJ (British Medical Journal). Kirsch and the other researchers did a participant level analysis of randomized, placebo-controlled trials of acute monotherapy for the treatment of major depressive disorder submitted to the FDA between 1979 and 2016. The Conclusions section of the article said:

Patients with depression are likely to improve substantially from acute treatment of their depression with drug or placebo. Although the mean effect of antidepressants is only a small improvement over placebo, the effect of active drug seems to increase the probability that any patient will benefit substantially from treatment by about 15%. Further research is needed to identify the subset of patients who are likely to require antidepressants for substantial improvement. The potential for substantial benefit must be weighed against the risks associated with the use of antidepressants, as well as consideration of the risks associated with other treatments that have shown similar benefits. Because the benefits and risks might be categorically different (eg, reduced sadness v anorgasmia), weighting should be done at the individual level, jointly by patients and their care providers.

The belief that a chemical imbalance underlies depression and other mental disorders has begun to unravel. For some time, it has been set aside by researchers and some psychiatrists as an urban legend. The pharmaceutical industry may continue to hold on to the notion that drugs work by targeting an underlying abnormality and that you can identify the abnormality “from the opposite of what the drugs do.” But it is time the public became aware that the chemical imbalance theory of depression is just a myth.

09/20/22

The Death of the Chemical Imbalance Theory?

There was an article published recently in the journal Molecular Psychiatry that is getting a lot of attention online. The Hill, Psychology Today, Neuroscience News and other new outlets highlighted an umbrella review by researchers that questioned the serotonin theory of depression and the value treating depression with antidepressants. In an article for The Conversation, two of those researchers wrote, “Our study shows that this view is not supported by scientific evidence. It also calls into question the basis for the use of antidepressants”; and the chemical imbalance theory of depression.

Joanna Moncrieff and Mark Horowitz wrote that the serotonin theory of depression was widely promoted by the pharmaceutical industry in the 1990s with its marketing a then new class of antidepressant medications, selective serotonin-reuptake inhibitors (SSRIs). This strategy became known as the “chemical imbalance theory of depression.” The theory was endorsed by institutions like the American Psychiatric Association. But this has changed, with psychiatrists like Ronald Pies, saying as early as 2011 that, “the chemical imbalance notion was always a kind of urban legend.”

Pies said in another more recent article for Psychiatric Times that he influenced the APA to replace a statement on its public education website that referred to “imbalances in brain chemistry,” with: “While the precise mechanism of action of psychiatric medications is not fully understood, they may beneficially modulate chemical signaling and communication within the brain, which may reduce some symptoms of psychiatric disorders.” The statement quoted by Dr. Pies is in article titled, “What is Psychiatry?”

Moncreiff and Horowitz pointed to another article on the same website, “What is Depression?”, where it said while several factors can play a role in depression—biochemistry, genetics, personality and environment. For biochemistry, it said: “Differences in certain chemicals in the brain may contribute to symptoms of depression.”

Looking at these articles, the chemical imbalance theory may have been weakened, but I don’t think it was defeated. It seems that when medications can “beneficially modulate” and when “differences in certain chemicals” may contribute to symptoms of depression, the imbalance theory is present implicitly. That is why the new study by Moncrieff et al, “The serotonin theory of depression: a systematic review of the evidence,” in Molecular Psychiatry is so important.

Despite the fact that the serotonin theory of depression has been so influential, no comprehensive review has yet synthesised the relevant evidence. We conducted an ‘umbrella’ review of the principal areas of relevant research, following the model of a similar review examining prospective biomarkers of major depressive disorder. We sought to establish whether the current evidence supports a role for serotonin in the aetiology of depression, and specifically whether depression is associated with indications of lowered serotonin concentrations or activity.

Their comprehensive review indicated there is no convincing evidence that depression is related to or caused by lower serotonin concentrations or activity. Yet surveys suggest 80% or more of the general public believe depression is caused by a ‘chemical imbalance.’ This belief shapes how people understand their moods, leading to a pessimistic view on what they can expect from treatment. “The idea that depression is the result of a chemical imbalance also influences decisions about whether to take or continue antidepressant medication and may discourage people from discontinuing treatment, potentially leading to lifelong dependence on these drugs.”

Moncrieff and Horowitz said in The Conversation article that it was important for people know the idea that depression as a chemical imbalance is hypothetical. Moreover, we don’t understand what temporarily elevated serotonin or other biochemical changes produced by antidepressants do to the brain. “We conclude that it is impossible to say that taking SSRI antidepressants is worthwhile, or even completely safe.” And yet, the serotonin theory of depression has formed the basis for a significant amount of research over the past few decades.

Along with Benjamin Ang, Moncrieff and Horowitz explored the serotonin theory of depression in the scientific literature in, “Is the chemical imbalance an ‘urban legend’? They noted where the chemical imbalance theory was first proposed in the 1960s, focusing initially on the neurochemical noradrenaline instead of serotonin. “What came to be known as the ‘monoamine hypothesis’ (noradrenaline and serotonin are both classified as monoamines), was stimulated by the belief that certain prescription drugs targeted the basis of mood, particularly drugs that were named ‘antidepressants’.”

Following the introduction of the selective serotonin reuptake inhibitor (SSRI), the ‘serotonin hypothesis’ became embedded in the popular and professional consciousness. The pharmaceutical industry promoted the idea that depression was a result of an imbalance or deficiency of serotonin in the brain. SSRIs, which were just being brought to the market, were said to be the ‘magic bullets’ that could reverse this abnormality. In an advertisement for Zoloft, Pfizer said “while the cause is not known, depression may be related to an imbalance of natural chemicals between nerve cells in the brain” and that “prescription Zoloft works to correct this imbalance.”

Ang, Moncrieff and Horowitz more fully documented how the American Psychiatric Association (APA) supported the pharmaceutical company rhetoric from a patient leaflet produced in 2005, which said: “antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” Despite what Dr. Pies said, it seems that the APA did not have many psychiatrists who knew this was a kind of urban legend.

The marketing of SSRIs and the serotonin theory led to a dramatic global increase in their use. Prescriptions in England tripled between 1988 and 1998; and then tripled again between 1998 and 2018. Similar increases took place throughout Europe, with some Eastern European countries where use was previously low, increasing 5-6 times since 2000. In the U.S., antidepressant prescriptions quadrupled between the late 1980s and the mid-2000s.

There is evidence that increasing numbers of people are taking antidepressants on a long-term basis. Research has shown that believing depression is caused by a chemical imbalance is widespread among antidepressant users, encourages people to ask for antidepressants and discourages them from trying to stop.

In 2005, Jeffrey Lacasse and Jonathan Leo published a paper in PLOS Medicine that received a lot of attention. It was the first time the media grasped that the serotonin theory might not be supported by the evidence. Their paper provoked a response by the chair of the FDA psychopharmacology committee, who admitted evidence for a neurochemical deficiency in people with depression was elusive. He thought it could be a ‘useful metaphor,’ but one he would not use with his own patients. While an SSRI may work well with an individual, that “doesn’t prove that there is an underlying imbalance, defect or dysfunction in the person’s serotonin system.”

Responding to a report published by the Citizens Commission on Human Rights, a Church of Scientology organization, Ronald Pies called the chemical imbalance theory an urban legend that no well-informed psychiatrist had ever believed. He claimed the theory was spread by the pharmaceutical industry, and opponents of psychiatry attributed the belief to psychiatrists themselves. A few months later, he wrote an article for Psychiatric Times admitting that there were psychiatrists and other physicians who used the term ‘chemical imbalance’ when explaining psychiatric illness to a patient.

My impression is that most psychiatrists who use this expression feel uncomfortable and a little embarrassed when they do so. It’s a kind of bumper-sticker phrase that saves time, and allows the physician to write out that prescription while feeling that the patient has been “educated.” If you are thinking that this is a little lazy on the doctor’s part, you are right. But to be fair, remember that the doctor is often scrambling to see those other twenty depressed patients in her waiting room. I’m not offering this as an excuse–just an observation.

In 2019 Pies said while some prominent psychiatrists have used the term ‘chemical imbalance’ in public comments about antidepressants, and possibly in their clinical practices, “there was never a unified, concerted effort within American psychiatry to promote a chemical imbalance theory of mental illness.” A good bit of psychiatric opinion follows Pies’ lead and says the idea that depression is caused by brain chemical imbalances is an over-simplified explanation that should not be taken seriously. The attempt by leading psychiatrists to deny that the serotonin theory was ever influential seems to be a tactic to deflect criticism, and allow it to continue in some modified form.

Ang, Moncrieff and Horowitz concluded that during the period 1990-2010, there was considerable coverage of, and support for, the serotonin hypothesis of depression in the psychiatric and psychopharmacological literature. Research papers on the serotonin system were widely cited, and most strongly supported the serotonin theory. Textbooks took a more nuanced approach, but at other points were unreservedly supportive of the theory. Critics of the theory were either ignored or marginalized as antipsychiatry. Yet it seems in 1987 at least one critic, the Irish psychiatrist David Healy, astutely described the neurochemical theory of depression as an exhausted Kuhnian paradigm in “The structure of pharmacological revolutions.” He said it was perpetuated because it served the professional purpose of convincing patients that depression is a biological condition.

Healy was referring to the seminal work by Thomas Kuhn on the philosophy and history of science, The Structure of Scientific Revolutions. According to Kuhn, normal science referred to research firmly based on one or more past scientific achievements that a particular scientific community “acknowledges for a time as supplying the foundation for its further practice.” The process of normal science takes place within a paradigm—like the monoamine hypothesis—where research occurs within the context of a scientific community committed to the same rules and standards for scientific practice. “That commitment and the apparent consensus it produces are prerequisites for normal science.”

Any new interpretation of nature, whether a discovery or a theory, emerges first in the mind of one or a few individuals. It is they who first learn to see science and the world differently, and their ability to make the transition is facilitated by two circumstances that are not common to most other members of their profession. Invariably, their attention has been intensely concentrated upon the crisis-provoking problems; usually, in addition, they are men [or women] so young or so new to the crisis-ridden field that practice has committed them less deeply than most of their contemporaries to the world view and rules determined by the old paradigm. How are they able, what must they do, to convert the entire profession or the relevant professional subgroup to their way of seeing science and the world? What causes the group to abandon one tradition of normal research in favor of another?

So in “The serotonin theory of depression: a systematic review of the evidence,” by Moncreiff at al, we may be witnessing the death of the old paradigm for depression.

Kuhn went on to observe that the proponents of competing paradigms are always at least slightly at cross-purposes. “Neither side will grant all the non-empirical assumptions that the other needs in order to make its case.” While each may hope to “convert” the other to his or her way of seeing science and its problems, the dispute is not one “that can be resolved by proofs.” Kuhn quoted the theoretical physicist Max Planck who said: “A new scientific truth does not triumph by convincing its opponents and making them see the light, but rather because its opponents eventually die, and a new generation grows up that is familiar with it.”

04/12/22

The Psychedelic Pendulum and Psychiatry, Part 2

On October 12, 1955 psychiatrist Sidney Cohen took LSD for the first time. Expecting to feel catatonic or paranoid because LSD was then thought to produce a temporary psychosis, he instead felt an elevated peacefulness, as if the problems and worries of everyday life had vanished. “I seemed to have finally arrived at the contemplation of eternal truth.” He immediately began his own LSD experiments, even exploring whether it could be helpful in facilitating psychotherapy, curing alcoholism and enhancing creativity. But on July of 1962 in The Journal of The American Medical Association, he warned of the dangers of suicide, prolonged psychotic reactions, and said: “Misuse of the drug alone or in combination with other agents has been encountered.”

The history of psychedelics seems have followed this pendulum swing from hope and promise, to disappointment and warnings, and then back again to hope and promise. In Part 1 of this article, we looked at the current promise of psychedelic therapy and treatment and mentioned its use to supposedly enhance creativity. Here we’ll take a closer look at the present-day concerns and reservations with the proposed use of psychedelics as therapeutic tools. Tellingly, they haven’t change much since Cohen co-authored “Complications Associated with Lysergic Acid Diethylamide (LSD-25).”

In “Psychedelics—The New Psychiatric Craze,” Joanna Moncrieff acknowledged the “increasingly fashionable” interest in psychedelics as a medical treatment, but wondered if they weren’t just “a powerful form of snake oil.” She noted the ever-lengthening list of problems they were recommended to treat, which included PTSD, depression, anxiety, addiction, chronic pain and distress associated with having a terminal illness. The rationale behind the trend was said to be confusing and contradictory.

On the one hand, psychedelics are promoted as assisting the process of psychotherapy through the insights that the ‘trip’ or drug-induced experience can generate – on the other they are claimed to represent a targeted medical treatment for various disorders, through correcting underlying brain deficiencies.

Increasingly, the use of these drugs is portrayed as if they work by targeting underlying dysfunctional brain processes (i.e., resetting brain processes by acting on 5-HT2A receptors). Moncrieff said claims by David Nutt, a psychopharmacologist and psychedelic researcher that psychedelics “turn off parts of the brain that relate to depression” and reset the brain’s thinking processes by their actions on the 5-HT2A receptors were “pure speculation.” She made the same judgment on a John Hopkins website that said researchers hoped to “create precision medicine treatments tailored to the specific needs of individual patients.” The charity, Mind Medicine Australia’s claim that psychedelic treatments were curative and only required 2-3 dosed sessions, that they were “antibiotics for the mind”, Moncrieff thought was a sales pitch for an expensive therapy.

In reality, psychedelics do not produce the miracle cures people are led to expect, as experience with ketamine confirms. Some people may feel a little better after a treatment, and then the effect wears off and they come for another one and another one, and get established on long-term treatment just as people do on antidepressants.

Official research also over-plays the drug’s benefits. A study published in The New England Journal of Medicine, “Trial of Psilocybin versus Escitalopram for Depression,” found no significant difference between groups in their primary outcome. The study’s discussion then pointed out that secondary outcomes had small differences, but did not consider the placebo effect of participants having a drug-induced experience. The participants were also not typical of those with depression, consisting of mainly well-educated men, almost a third of whom had tried psychedelics before. The study’s researchers said:

The patients in the trial were not from diverse ethnic or socioeconomic backgrounds. Strategies to improve recruitment of more diverse study populations are needed in studies of psilocybin for depression. Also, average symptom severity scores at baseline were in the range for moderate depression, thus limiting extrapolations to patients with severe depressive symptoms or treatment-resistant depression.

The current craze for psychedelics means adverse effects are being minimized, according to Moncrieff. Whether or not people find the effects of psychedelics enlightening or not depends on how the drug-induced experience is interpreted. This highlights the importance of staff as support people while clients are under the influence. Yet she worried that when, and if, psychedelics obtain a medical license, psychotherapy would be dropped or minimized. “The tendency of all psychedelic treatment will be towards the provisions of the drug in the cheapest possible way, which means the minimum of supervision and therapy.”

In “When Drugs of Abuse Become Psychiatric Medications,” Sara and Jack Gorman noted that some commentators have been suggesting we’re on the cusp of a new era in psychopharmacology with the potential of ketamine, MDMA and psilocybin as psychiatric treatments for depression, PTSD and other disorders. They noted how we have information about the biological mechanisms of action for all three of them. Ketamine works mainly through interaction with the brain’s glutamate neurotransmission system. MDMD and psilocybin enhance the brain’s serotonin receptors—the same system affected by SSRI antidepressants.

Unfortunately, however, we still have no firm idea if derangements in any of these neurotransmitter systems are actually the cause of any mood or anxiety disorder. There are many theories linking abnormal glutamate neurotransmission to depression, for example, and some solid data from animal studies suggesting such a link, but no definitive proof that any abnormality in glutamate neurotransmission is part of depression yet exists. We cannot say that any of these drugs work by remediating a known abnormality in the brains of people with psychiatric illnesses any more than we can say that about any of the traditional psychiatric medications.

One final issue is that regardless of the fact that currently approved medications for depression and PTSD are only partially effective for many patients, they are not usually abused or addictive. Yet ketamine, psilocybin and MDMA have long histories as recreational street drugs that can be addictive for some people. In the clinical trials done to date adverse side effects have been minimal, and with the doses and manner in which they are given, addiction is unlikely. Moreover, there are widely used, FDA-approved, psychiatric drugs with known histories of misuse—benzodiazepines and ADHD medications.

Then the Gormans asked a telling question: Is psychiatry following solid science, or going in the direction of approving the use of mind-altering street drugs as medications—and I’d add—because they have no other potential medications on the horizon?

In the journal, JAMA Psychiatry, Joshua Phelps and two others expressed concerns with the growth of industry-sponsored drug development and the assessment of psychedelic drug effectiveness. They noted the market for psychedelic substances was projected to grow from $2 billion in 2020 to $10.75 billion by 2027, “a growth rate that may even outpace the legal US cannabis market.” They said the interest in psychedelic medicine seems to hope that psychedelics will be the next blockbuster class of medicines and has led to efforts to decriminalize psychedelics at the local level, as with Oregon (see Part 1) and other locations. Their concern is that these regulatory changes will adversely affect the quality and rigor of biomedical research with psychedelics.

Although popular excitement, policy momentum, and financial investment in psychedelics continue to increase, it is imperative that research maintains scientific rigor and dispassion to outcomes in the pursuit of improved therapeutics and new insights into the mind, brain, and consciousness that this class of molecules may well afford in the coming years. The presence of large-scale, newly established public companies as an unprecedented category of stakeholder may help to further understanding of these molecules and their possible clinical applications, but these firms also have a unique set of self-interests that must be understood and considered. Research enabled by these firms must still meet the same rigorous standards that are expected elsewhere, even if breakthrough status is warranted.

Then there is another concern described by Will Hall on “Ending the Silence Around Psychedelic Therapy Abuse.” He made his decision to write about therapy abuse when he read Michael Pollan’s best-selling book on psychedelics, How to Change Your Mind. Hill thought Pollan was overly enthusiastic and largely uncritical. “All the new hype about miracle psychiatric treatments and the next wave of cures for mental disorders leaves out the risk of therapy abuse.”

He said from his perspective, as far as drugs go, psychedelics were relatively safe—safer than benzodiazepines or SSRIs. He even acknowledged that reported healings from emotional pain with psychedelics did happen. By raising an alarm about therapy abuse he said he wasn’t exaggerating the dangers of psychedelics, rather: “I’m calling for more honesty about the implications of putting psychedelics in the hands of therapists.”

He noted the inherently imbalanced power relationship of therapist and client, where there is already the potential danger of authority being misused. The therapist has too much influence over a client, and the consequences for clients are too severe to see each side as equal, according to Hall. “And so we protect clients from therapists in the same way we protect children from adults, especially from the most exploitive and extreme violation of therapist trust, sex with clients.” The risks are magnified when you add psychedelics.

Drugs affect judgment, drugs can enhance idealization, drugs can promote risk taking, drugs can lower defenses, drugs can amplify suggestibility, drugs can lead to dissociation… all drugs. Imagine if you heard therapists were giving their clients alcohol to get them talkative, lines of cocaine to get them confident, or cannabis to get them relaxed? You would easily recognize that even if some clients do benefit, the client is also put into a heightened and more easily exploited state. Despite their many unique and often positive qualities, this is still true of psychedelics. And the influence is magnified when the therapist is supplier of and expert about the drug, when the drug has a taboo cultural aura of esoteric healing powers, the media are hyping miracle cures, and scientific experts are waving their hands and calling it “medical treatment.” Add that psychedelic therapists are typically also themselves users of and true believers in these substances. The dangers are obvious.

Psychedelics present some of the same risks as any drugs. Hall said we need to name those risks, and be especially vigilant about them. Otherwise, even though some people will be helped, others will be harmed. “And as the history of psychedelic therapy abuse shows, they already have.” Hall then gave specific historical examples and details from past abuse as well as his own personal experiences.

He wasn’t alone in pointing to this safety concern with psychedelic therapy. In her article on Oregon’s experiment with legalizing psychedelics for STAT, Olivia Goldhill noted that sexual abuse has historically been a problem with psychedelic therapy. “All the usual power imbalances of patients and therapists are exacerbated in a setting where drugs can create feelings of sexual arousal.”

Hall also pointed out that with psychedelics or any other drug, “it’s called getting high for a reason—we lose our feet on the ground.” Gaining a new perspective can be illuminating, but avoidance could come instead of insight. Psychedelics also increase suggestibility, a tendency to accept the beliefs of others illustrated in hypnotic trance states and situations where there is social pressure for conformity. Psychedelics can make some people more dependent on outside influence and more reluctant to consider they may have misjudged their safety when using the drugs.

There is more Will Hall has to say about the potential for therapy abuse with psychedelics, but what we’ve reviewed lays out the concerns. I don’t agree entirely with what seems to me to be a “laissez faire” approach to people who want to use psychedelics for healing or illumination. I’d say there is as much of concern with their use as with benzodiazepines or SSRIs. And given the pendulum swing evident in the history of psychedelics as therapeutic agents, there is a swing back to disappointments and concerns ahead. As Hall astutely said,

All medical treatment outcomes are driven in part by expectation and placebo: eventually the hype around new psychiatric products wears off, and then we are on to the next marketing wave—with iatrogenic harm to patients left in the wake.

STAT said that Washington, New York, Colorado and California are all considering some form of legalizing psychedelics. Other states are enacting decriminalization measures. If Oregon-style legislation spreads to other states, the potential market for legalization will get bigger. Field Trip, a company with a series of clinics used for ketamine therapy plans to set up clinics in Oregon. “Oregon is just the first step. But there’s a big wave coming almost certainly.”

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.”

08/11/20

Throwing Down the Gauntlet for ECT, Part 1

Effective on December 26, 2018, the FDA issued a final order that required a premarket approval application for most uses of electroconvulsive therapy (ECT) devices. It also reclassified using ECT devices to treat catatonia or a severe major depression episode or bipolar disorder from Class III (higher risk) to Class II (moderate risk) with special conditions. This meant ECT manufacturers would have to submit information to the FDA demonstrating their ECT device complied with special controls that diminish known risks and provided an assurance of safety. These special controls were requirements about the technical limitations of the ECT device, about the labeling of potential adverse effects, about necessary practitioner training and a few aspects of clinical practice with the device. Carlos Pena, director of the Division of Neurological and Physical Medicine Devices for the FDA, said: “We remain committed to ensuring patients have access to reasonably safe and effective medical devices using the most current and scientifically robust information available.”

The reclassified uses for ECT devices into Class II are limited to the treatment of catatonia or a severe major depressive episode associated with major depressive disorder or bipolar disorder in patients age 13 years and older who are treatment-resistant or who require a rapid response treatment due to the severity of their psychiatric or medical condition. The safe use of ECT for treatment of these conditions has been well studied and is better understood than other uses. Therefore, sufficient information exists to establish special controls that mitigate known risks and provide a reasonable assurance of safety and effectiveness for these two uses of ECT devices. Manufacturers of ECT devices for the indications above will now need to submit information to the agency to demonstrate their devices are in compliance with these special controls.

A Premarket Approval (PMA) application is the scientific and regulatory review process the FDA uses to evaluate the safety and effectiveness of Class III medical devices. Class III devices support or sustain life, are of significant importance in preventing the impairment of human health, or they “present a potential, unreasonable risk of illness or injury.” PMA is based on the FDA determining there is sufficient, valid scientific evidence in the PMA application to assure the device is safe and effective for its intended use(s). The FDA determined that general and special controls alone were not sufficient to assure the safety and effectiveness of Class III devices.

For that reason, they required a PMA application from manufacturers to obtain marketing approval for their devices. A PMA application is required for all uses of an ECT device not specified as Class II, including disorders like schizoaffective disorder and bipolar manic states. This is because the FDA said it does not have sufficient information to establish special controls to provide a reasonable assurance of the safety and effectiveness of ECT devices for these indications.

In Psychiatric Times, Doctor Charles Kellner, who is the Chief of ECT Therapy ay New York Community Hospital, said the FDA’s final order was very good news in that it allowed for the ongoing availability of ECT devices in the US, but had “slightly less good news” in that what he referred to as “on label” indications was shorter than it had been in the past. With regard to the implications of the FDA order, he said most importantly moving depression into Class II ensures the majority of ECT patients will not have any change in their care. The way the order is written closely mirrors existing clinical practice. He estimated that major depression and catatonia account for 60% to 70% of current American ECT practice.

He emphasized that the FDA order does not regulate medical, clinical practice, meaning “practitioners are free to continue to prescribe ECT for any patient, regardless of diagnosis, whom they feel would benefit from the treatment.” Choosing to leave schizophrenia, schizoaffective disorder and mania in Class III was perplexing and disappointing to him, as he said schizophrenia was the leading indication globally for ECT and “the clinical and research evidence base support ECT as safe and effective for this illness.” He believed ECT devices will continue to be a small, but important part of psychiatric tools. From his contacts with other ECT practitioners around the country, he believed ECT use was increasing.

Dr. Kellner has spent most of his professional career in the study of ECT, especially with geriatric patients and can be understood as having a more positive view on the practice and future of ECT. But is his assessment accurate? Is the use of ECT increasing? Is the FDA final report good news and slightly less good news with regard to ECT or is it an overly optimistic view of both ECT and the FDA final rule?

Psychologist Phillip Hickey pointed out some inconsistencies in previous statements made by Dr. Kellner with regard to ECT that suggests his apparent optimism was at least partly playing to his perceived audience, other psychiatrists and medical doctors. In an editorial which he co-authored for the Journal of ECT, he said: “Despite its widespread acceptance in the medical community, ECT remains surrounded by ‘controversy.’” Yet in an earlier article for New Scientist, Kellner was quoted as saying “ECT ‘remains in the shadows’”, and described it as the second most controversial medical procedure after abortion. In the US and UK, only a tiny fraction of people whose depression doesn’t respond to medication are offered ECT.

Philip Hickey asked if only a tiny fraction of eligible patients were referred, “doesn’t this suggest that they [psychiatrists and other medical specialists] are, as a group less supportive of electric shocks” then Kellner claimed? He then cited a supporter of electric shock, George Kirov, a professor at Cardiff University who supervises ECT treatment in the city of Cardiff, Wales. Kirov acknowledged there are mixed feelings about ECT, even among psychiatrists. “If I speak to medical professionals outside of psychiatry, there is almost disbelief that we are using such an archaic practice.”

Joanna Moncrieff is a psychiatrist with reservations about the use of ECT in psychiatry. In her 2008 book, The Myth of the Chemical Cure, she acknowledged that ECT is still an accepted part of psychiatric clinical practice, but she thought its use was waning. She said it was the most controversial of current psychiatric treatments. The efficacy of ECT for depression in the short-term was still regarded as well-established, but she said it had no long-term effect. “In other words, a few weeks after the ECT has taken place, people are no better than they would have been if they had never had it.” She added:

The state produced by ECT offers several explanations for the apparent therapeutic effects of ECT. Firstly, the acute cognitive effects may temporarily override underlying emotional states and reduce people’s ability to express their emotions. The fact that the beneficial effects of ECT do not persist beyond the period of treatment would support this idea (Ross 2006).

Ross said the burden of proof is on ECT advocates to show that ECT can be prescribed ethically and rationally. He suggested a research study be conducted involving a randomized, prospective, double-blind, placebo-controlled design be done in which the placebo was sham ECT. But he wondered whether a true double blind was even possible in sham ECT research. “In the absence of such a study, whatever its outcome, the sham ECT literature supports the conclusions that: real ECT is no more effective than placebo, except during the period of time ECT is being administered; even that difference is modest.” He noted how the effectiveness of ECT was over-endorsed repeatedly in the psychiatric literature.

Moncrieff said other possible explanations for the apparent therapeutic benefit of ECT include the sedative and calming effects of ECT may produce improvement, particularly in people with agitated depression. The organic behavioral cycle produced by ECT, with its euphoria and disinhibition, can be mistaken as improvement. This is often misdiagnosed as mania, even in people with no history of manic depression. Lastly, ECT may work psychologically. In other words, patients may be able to break the double-blind methodology of the ECT control trials since the sham procedure cannot replicate the acute cognitive effects of ECT. Particularly if they have previously had ECT and believed ECT worked for them, they could be disappointed if they determined they had received the sham procedure. Conversely, they may do better if they received the real ECT treatment and were able to perceive it.

These explanations offered a more compelling explanation of the effects of ECT than the idea it was a specific treatment for major depression, according to Moncrieff. In addition, there is no currently accepted coherent theory of the efficacy of ECT or what it does to the brain that might help in depression:

(The jury is still out on ECT. Its use has survived much longer, despite widespread opposition from some psychiatric survivors and the fact that it is widely acknowledged that its effects are not persistent. Its effects can be explained by the acute cognitive impairment it causes, sometime amounting to a brain injury-like state that can be mistaken for recovery from depression.

Dr. Kellner may have an overly optimistic view for the future of ECT in the wake of the FDA final rule. I’d like to have some clear evidence one way or the other about whether ECT use is actually increasing. And I am not sure if the FDA final report is the “good news” he thinks it is. It appears to me the FDA has thrown down a gauntlet for medical device companies. They are to demonstrate their ECT devices are in compliance with special controls that diminish the known risks of ECT for Class II conditions.

And the companies are required to meet more stringent expectations, with sufficient and valid scientific evidence, that an ECT device does not “present a potential, unreasonable risk of illness or injury” if they want to claim their device as a treatment for Class III conditions. I hope the FDA remains committed to the stated standard of science described in their final rule on ECT. It will be interesting to see what the agency does with a recent publication in the Journal of Ethical and Human Psychology, “Electroconvulsive Therapy for Depression,” that raises the possibility that past support for ECT may be based on poor quality research. We will look at the claims of that study in Part 2 of this article.

06/30/20

The Complexities and Limitations of Buprenorphine, Part 2

William White wrote “From Bias to Balance: Further Reflections on Addiction Treatment Medications” in an attempt to open a dialogue between the polarized sides of using opioid medications like buprenorphine to treat opioid addiction. In Part one of this article I expressed my belief that the impasse between the two sides is largely for philosophical, not scientific reasons. Medication advocates presume what Joanna Moncrieff calls a disease-centered model of drug action that leads to the belief and portrayal of certain medications as a panacea for opioid use disorders, something that the so-called medication haters soundly reject. I suggested that beginning instead with what Moncrieff calls a drug-centered model would allow for a more productive dialogue on the complexity and limitations of using buprenorphine to treat opioid use disorder.

In “Rethinking Models of Psychotropic Drug Action,” Joanna Moncreiff described the distinctions between two different types of drug action, the disease-centered model and the drug-centered model. She added that theoretical assumptions about how psychotropic drugs work are rarely discussed explicitly. The disease-centered model underlies orthodox psychopharmacology. It assumes that a psychotropic drug like buprenorphine helps correct a biochemical abnormality. In other words, medications are understood to work by acting on a disease process.

This notion, sometimes called the ‘chemical imbalance’ theory, is the implied view of SAMHSA, which says MAT medications (like buprenorphine) “operate to normalize brain chemistry.” But in a ‘drug-centered model’ the distinctive physiological, behavioral and subjective effects of drugs are used to define drug action. “The therapeutic value of a drug stems from the usefulness of these effects in clinical situations.”

In this approach, drugs are seen to induce characteristic physiological and subjective states that may, or may not, be experienced as useful in certain social and interpersonal situations, including clinical situations. Unlike the disease-centred model that assumes that drugs move an abnormal physiological state towards a more normal one, the drug-centred model suggests that drugs create their own characteristic abnormal states or alterations of normal states. It is these states or effects that need to be described and understood, and the potential therapeutic value of a drug is deduced from this understanding. It is therefore implied that diagnosed patients and normal volunteers’ basic physiological responses to drugs will differ only in so far as a degree of individual variation in drug response (including variation in arousal, set, biological sensitivity) always exists.

Consistent with what Moncrieff said here regarding the drug-centered model, in “From Bias to Balance,” William White said the potential risks and benefits of medication support when treating opioid addiction are not uniform. He thought recovery advocates needed to have a general knowledge of the evolving science and the clinical experience with regard to the overall benefits and risks associated when medications like buprenorphine are used in medication-assisted treatment—what the side effects are, when and for whom it is indicated and contraindicated. “The question of potential degree of help or harm of medications in the treatment of addiction is unanswerable without also asking, ‘For whom?”’ ‘For what purpose?’, ‘For how long?’, and ‘At what cost?’.” White said that despite knowing that people recover from opioid addiction with and without medication support, the addiction treatment field still has not clinically defined who would benefit most from pharmacotherapy and for whom it would be contraindicated. He thought answering that question would be a major step forward.

The potential differences between those who achieve stable recovery (five years plus of opioid abstinence) from opioid use disorder through pharmacotherapy and those who achieve stable recovery without medication support are unclear. Nearly 40% of Narcotics Anonymous (NA) members report regular use of narcotics and an average of 8.2 years of continuous recovery. This would seem to challenge the bleak prospects of recovery from opioid addiction without medication support that dominates the professional literature and popular media. “Yet such recoveries from opioid use disorders within NA remain a rare focus of scientific study.”

There is also no consensus on the optimal duration of medication-assisted support in the treatment of opioid use disorder. SAMHSA said the length of time should be tailored to each patient and could be indefinite. In SAMHSA’s TIP 63, the section “Duration of Buprenorphine Treatment,” stated there was no known duration of buprenorphine therapy where patients could be certain they would not return to illicit opioid use. “Patients should take buprenorphine as long as they benefit from it and wish to continue.” ASAM, the American Society of Addiction Medicine, echoed SAMHSA’s indefiniteness, giving the following advice in their “National Practice Guideline” for the length of treatment with buprenorphine when treating opioid use.

There is no recommended time limit for treatment with buprenorphine. Buprenorphine taper and discontinuation is a slow process and close monitoring is recommended. Buprenorphine tapering is generally accomplished over several months. Patients and clinicians should not take the decision to terminate treatment with buprenorphine lightly.

Consistent with this reluctance to define or investigate a time limit for treatment with buprenorphine, William White said there has been inadequate attention to the process of tapering when clients choose to maintain their recovery without medication. The statistics reported in the research literature on those who attempt buprenorphine treatment are not promising. Meinhofer et al reported that over one-half (55%) of individuals discontinued buprenorphine within about six months and 13% experienced at least one adverse opioid-related event within 360 days of starting with buprenorphine. Hser et al reported that only 46% of buprenorphine participants completed 24 weeks of treatment; 24.8% dropped out within the first 30 days.

White stated the reality is that many patients who begin MAT for opioid addiction stop taking the medications within a matter of months. He cited a study of adolescents and young adults, “Receipt of Timely Addiction Treatment,” that found the median retention of those who did use buprenorphine was less than six months. Could it be that the intent to limit the risk of overdose mortality by leaving the time limit for MAT with buprenorphine open-ended has led to a perceived “Hotel California” effect in buprenorphine treatment? You can check in anytime you want, but you’ll find you can never leave. Open-ended treatment protocols like the SAMHSA and ASAM recommendations for buprenorphine leads abstinence-based recovery advocates and some addicts to conclude the goal is to keep patients “parked” on medication forever.

One factor influencing the open-ended recommendations for MAT is the high risk of overdose mortality when an opioid addict resumes active use. In the four weeks following the cessation of medication maintenance, death rates as high as four times that of patients who remain in treatment have been reported, due to the lost tolerance from their abstinence. This parallels the risk of overdose mortality after the release from a prison, hospital or inpatient/residential addiction treatment program.

One of White’s suggested action steps was to expand supports available for patients during and after medication tapering. According to ASAM, factors associated with the successful termination of treatment with buprenorphine are not well described, but may include the following:

Employment, engagement in mutual help programs, or involvement in other meaningful activities.
Sustained abstinence from opioid and other drugs during treatment.
Positive changes in the psychosocial environment.
Evidence of additional psychosocial supports.
Persistent engagement in treatment for ongoing monitoring past the point of medication discontinuation. Patients who relapse after treatment has been terminated should be returned to treatment with buprenorphine.

White said long-term follow-up studies of people with opioid use disorders find that between a third and half of those who achieve stable recovery have far less problem severity and complexity and have great recovery capital (e.g., education, employment, family and social support).

The overwhelming majority of addiction medication providers assert the value of psychosocial interventions as a critical component of addiction treatment, but little more than a third report that their organizations and local communities have the resources to provide such interventions for patients using medication to support recovery from an opioid disorder.

A final complexity and limitation with buprenorphine as an opioid medication is that buprenorphine is itself an opioid. Given Moncrieff’s drug-centered model of medication action, this reality needs to be acknowledged by treatment professionals and addressed when evaluating the overall benefits and risks of buprenorphine. The potential degree of help or harm it may incur should also be discussed honestly and openly with the individual. One of the likely effects an individual should expect when tapering off of buprenorphine is the emergence of a withdrawal or discontinuation syndrome.

In Part 1 of this article, I discussed how according to the drug-centered model, when psychoactive medications like buprenorphine are taken over a long period of time, they “induce physical adaptations to the presence of the drug.” The body attempts to counteract the effects of the drug, which it sees as a foreign, exogenous substance. In time, a kind of homeostasis is reached between the effects of the medication and the body’s adaptations to it. When the medication is stopped, the body’s adaptations overpower the now weakened medication effect and symptoms of withdrawal or discontinuation are evident. I’d suggest this is likely with years of medication maintenance and even after a slow, gradual taper.

The taper event should be addressed clinically as a relapse trigger and the resulting withdrawal symptoms understood simply as that; and not as a reemergence of the ‘disease state’ that will lead back to active use if buprenorphine maintenance is not resumed. I think this discontinuation or withdrawal is best understood as the delayed manifestation of post-acute withdrawal (PAW) symptoms. The original use of an opioid recreationally was supplanted by an opioid (buprenorphine) used as a MAT and the original emergence of PAW symptoms was muted or never truly occurred.

I’ve added the thinking of Terrance Gorski on recovery and relapse to the discussion here. See “Preventing the Relapse Process,” Part 1 and Part 2 for a discussion of relapse. See “Managing Your PAWS” and “Recognizing Your PAWS” for a discussion of post-acute withdrawal. Also see the Gorski-CENAPS Corporation for his books and workbooks.

I think there can be productive dialogue between the two opposing views of medication-assisted treatment. A necessary first step is to see buprenorphine and opioid use disorder through the lens of the drug-centered model of medication action. Then there can be discussions of the complexities and limitations of treating opioid use disorder with an opioid. Research won’t have to ignore that elephant in the methodology. And then we can begin to do the truly important work of answering the questions—for whom, for what purpose, for how long and at what cost—as we assess the potential help or harm of buprenorphine as a treatment for opioid use disorder.

06/23/20

The Complexities and Limitations of Buprenorphine, Part 1

William White said he has for years tried to build bridges of communication across the polarized debates surrounding the use of medications in the treatment of addiction. He wrote “From Bias to Balance: Further Reflections on Addiction Treatment Medications” with a two-part goal in mind that I have borrowed and revised to frame my discussion here regarding the use of buprenorphine to treat opioid use disorder. The first part of White’s goal in “From Bias to Balance” was to help recovery advocates understand the positions of some who reject the use of medications as a pancea for opioid use disorders. The second part was to understand the complexities and limitations involved in the use of buprenorphine to treat opioid use disorders. For what it’s worth, I think I largely agree with White, even if I approach the issue more from the side of abstinence-based recovery.

Seeing medication-assisted treatment (MAT) as a polemic of medication haters and medication advocates muddies the waters by lumping different medications with radically different effects into the same category of MAT. According to SAMHSA in “Medication and Counseling Treatment,” the FDA has approved methadone, buprenorphine and naltrexone to treat opioid use disorder. Both methadone and buprenorphine are themselves scheduled substances by the DEA, meaning they each have a potential for misuse. This should be kept in mind when they are used to treat opioid use disorder, and be seen as a limitation of the respective medication. The other FDA-approved medications used for MAT, including those used to treat alcohol use disorder, are not scheduled substances and do not have the same limitation.

SAMHSA said a common misconception with MAT is that it substitutes one drug for another. According to SAMHSA, these medications are said to relieve the withdrawal symptoms and psychological cravings “that cause chemical imbalances” in the body. The phrase, “that cause chemical imbalances,” implies that the medications help correct an abnormal brain state, an assumption of what psychiatrist Jonanna Moncrieff called the disease-centered model of drug action in The Myth of the Chemical Cure. Buprenorphine and methadone do not balance or correct an abnormal brain state, in my opinion. They are as much exogenous, foreign bodily substances, as heroin or fentanyl are. I think Moncrieff’s alternative model, the drug-centered one, more appropriately captures both the effects of the originally misused drug and the medication used to treat it.

Joanna Moncrieff developed her drug-centered and disease-centered models of drug action to describe how psychiatric medications work, but they also apply to all psychoactive substances, all mind-altering and mood-changing chemicals. The disease-centered model of drug action seems to underlie the uncritical advocacy of medications for opioid use disorders. “Psychiatric drugs [including methadone and buprenorphine] are psychoactive drugs which, by their neurophysiological effects alter ‘mental and emotional life and behaviour for the duration of the treatment.’” Along with their immediate and sometime euphoric effects, when psychoactive medications are taken over a long period of time on a regular basis, they “induce physical adaptations to the presence of the drug.” These adaptations have several consequences, including the following.

When a psychoactive medication is used on a regular, frequent basis, the body attempts to counteract the effects of the drug, which it sees as an invading, foreign substance. In time, a kind of homeostasis is reached between the effects of the psychoactive medication and the body’s adaptations to it. This often leads to the development of tolerance, meaning that larger doses of a medication are needed to achieve the original psychoactive effects. When the medication is stopped or reduced too rapidly, the body’s adaptations overpower the weakened or absent medication effect and symptoms of withdrawal or discontinuation become evident.

When this process is viewed through the lens of a disease-centered perspective, the body’s reaction is interpreted as evidence of the reemergence of the underlying condition which the medication had “balanced.” In this case, opioid use disorder. And the recommended treatment is then a continuation of the psychoactive medication to maintain that balance, perhaps indefinitely. Instead of a disease-centered view of restoring chemical balance, I think opioid medications like methadone and buprenorphine relieve withdrawal symptoms and psychological cravings by creating their own abnormal brain state. This view is consistent with Moncrieff’s drug-centered model of drug action.

See “A Drug Is a Drug Is a Drug” or search this website for “the disease-centered model” for more on this topic. Also see “Models of drug action” on Jonna Moncrieff’s blog and “Rethinking Models of Psychotropic Drug Action.” Nevertheless, as William White said, medications can play a valuable role in addiction treatment:

Medications can play a valuable role in harm reduction, recovery initiation, and recovery maintenance for populations for whom they are indicated and acceptable, but we do a disservice to those populations, their families, and their communities if we portray medication alone as a panacea for the cure of all opioid addiction and fail to carefully communicate both the potential value and the limitations of medications. Issues like the above [see “From Bias to Balance”] need to be part of our nuanced discussions with those we serve. We similarly do a disservice if we let anti-medication polemics go unchecked within our local and national conversations.

Medications are best viewed as an integral component of the recovery support menu rather than being THE menu, and their value will depend as much on the quality of the milieus in which they are delivered as any innate healing properties that they possess. If the effectiveness of medication-assisted treatment (MAT) programs is compromised by low retention rates, low rates of post-med. recovery support services, and high rates of post-medication addiction recurrence, as this review suggests, then why are we as recovery advocates not collaborating with MAT patients, their families, and MAT clinicians and program administrators to change these conditions?

People seeking recovery from opioid use disorders and their families are in desperate need of science-grounded, experience-informed, and balanced information on treatment and recovery support options—information free from the taint of ideological, institutional, or financial self-interest.

Consistent with a drug-centered model of medication action, the potential risks and benefits of buprenorphine as a MAT need to be objectively and scientifically assessed. One of the complexities and a limitation of buprenorphine-based MAT is the fact that it is a Schedule III controlled substance, with a moderate to low potential for physical and psychological dependence. There is also a higher risk of harm, including overdose and death, when buprenorphine is combined with benzodiazepines or other sedatives like alcohol. Because of this danger, information was added to the Boxed Warning on the Medication Guides by the FDA for buprenorphine products on the risks of slowed or difficult breathing and death. Even before it was approved as a MAT, in the US, buprenorphine was known to have problems with diversion and misuse.

While the risks of misuse are lower for buprenorphine than for most other opioids in the US, this is not true in many European and Asian countries. Illicit buprenorphine use has been reported in Sweden, Scotland, Norway, Ireland and Spain. In Finland buprenorphine is the most widely abused opioid. In 2001 Finland had a sharp increase in the misuse of buprenorphine that coincided with a decrease in the availability of heroin. Seventy-three percent of a sample of participants in a Finnish syringe exchange program reported buprenorphine was their most frequently abused injection drug. Participants also used it as a self-treatment for withdrawal.

In “From Bias to Balance,” William White noted the standard practice with medications is to define the precise condition a medication is best suited to treat, and then identify patients who should not be prescribed the medication because of potential harm, meaning the risks outweigh the potential benefits for them. Yet after more than a century of attempts to treat opioid addiction with medications, there is no clinically defined protocol for who is most likely to benefit from pharmacotherapy. Additionally, “the question of potential degree of help or harm of medications in the treatment of addiction is unanswerable without also asking, “‘For whom?’ ‘For what purpose?’, ‘For how long?’, and ‘At what cost?’.”

White said the addiction treatment field has yet to reach consensus on what is the optimal duration of medical support in treatment of opioid use disorder. I think this impasse partly reflects the unacknowledged presumption of Moncrieff’s disease-centered model of drug action among medication advocates. The disease-centered model is itself a product of what is called the medical model, which sees psychopathology as the result of biology; a physical/organic problem in brain structures, neurotransmitters, etc. The over reliance on the medical model perspective (and the disease-centered model of drug action) in addiction treatment leads to an imperfect conception of substance use disorder and a distorted understanding of the risks and benefits of buprenorphine when it used to treat opioid use disorder.

Self-consciously taking a drug-centered model of drug action with buprenorphine and rejecting the medical model perspective of substance use disorders is necessary to truly reach a consensus on the potential degree of help or harm of buprenorphine in the treatment of opioid addiction. Consider what Joanna Moncrieff said in The Myth of the Chemical Cure when contrasting her two models of drug action to the use of buprenorphine in MAT:

The disease-centred model suggests that the important or ‘therapeutic’ effects of drugs are achieved by their effects on a particular disease process. By acting on the mechanisms of the disease, drugs move the human organism from an abnormal physiological state towards a more normal one. In contrast, the drug-centred model suggests that drugs themselves create abnormal bodily states. In the case of drugs that act on the brain or the nervous system, these states involve an alteration in subjective experience or consciousness. Psychiatric drugs [including buprenorphine, I would add] are psychoactive drugs which, by their neurophysiological effects alter ‘mental and emotional life and behavior for the duration of the treatment’ (Cohen & Jacobs 2007). When we consider drugs that are taken recreationally we have no trouble recognizing this fact and we refer to the altered mental state drugs produce as ‘intoxication’. But there is no fundamental distinction between drugs used for psychiatric purposes and other psychoactive drugs. They all act on the nervous system to produce a state of altered consciousness, a state that is distinct from the normal undrugged state.

The impasse between so-called medication haters and medication advocates is philosophical, not scientific. Beginning with a drug-centered model of buprenorphine can help us move forward in correctly addressing questions on the potential degree of help or harm buprenorphine brings to the treatment of addiction. We can more clearly discuss the complexity and limitations of using buprenorphine, an opioid medication, to treat opioid use disorder when that treatment is viewed through a drug-centered model of medication action.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Joanna Moncrieff