06/22/21

Drugs Do Not Fix Chemical Imbalances

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

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

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

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

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

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

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

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

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

Consequences of Believing in a Chemical Imbalance

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12/22/20

Psychiatry Is Different, Not Irrelevant

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

01/8/19

Antidepressant Fall From Grace, Part 2

In 1995 Irving Kirsch and Guy Sapirstein set out to assess the placebo effect in the treatment of depression. Like most people, Kirsch used to think that antidepressants worked—the active ingredient in the antidepressant helped people “cope with their psychological condition.” They weren’t surprised to find a strong placebo effect in treating depression; that was their hypothesis and the reason to do the study. What did surprise them was how small the drug effect was—the difference between the response to the drug and the response to the placebo. “The placebo effect was twice as large as the drug effect.”

Along with Thomas Moore and others, Kirsch then did an analysis of data submitted to the FDA for approval of the six most widely prescribed antidepressants approved between 1987 and 1999: fluoxetine (Prozac), paroxetine (Paxil), sertaline (Zoloft), venafaxine (Effexor), nefadozone (Serzone) and citalopram (Celexa). The researchers found that 80% of the response to medication was duplicated in placebo control groups. The mean difference between drug and placebo was clinically negligible. You can read more about this study in Prevention & Treatment, “The Emperor’s New Drugs.”

When they published their findings, Kirsch sad he was pleasantly surprised by the consensus about their findings. “Some commentators argued that our analysis had actually overestimated the real effect of antidepressants.” One group of researchers said the minimal difference between antidepressant treatment and controls was a “dirty little secret” that had been known all along. “The companies that produce the drugs knew it, and so did the regulatory agencies that approve them for marketing. But most of the doctors who prescribe these medications did not know it, let alone their patients.”

According to Irving Kirsch, pharmaceutical companies have used several devices to present their products as better than they actually are. First they will withhold negative studies from publication. While publication bias effects all areas of research, it is acutely problematic with drug trials. “Most of the clinical trials evaluating new medications are sponsored financially by the companies that produce and stand to profit from them.”

The companies own the data that come out of the trials they sponsor, and they can choose how to present them to the public — or withhold them and not present them to the public at all. With widely prescribed medications, billions of dollars are at stake.

Positive studies may be published multiple times, a practice known as “salami slicing.” Often this is done in ways that makes it difficult for reviewers to recognize the studies were done on the same data. The authors may be different. References to the previous publication of the data are often missing. Sometimes there are minor differences in the date used between one publication and another. Sometimes positive data is cherry-picked from a clinical trial and published, giving the impression that the drug seemed more effective than it really was. For more information on this issue, see: The Emperor’s New Drugs: Exploding the Antidepressant Myth by Irving Kirsch.

Published in 2004, the STAR*D study (Sequenced Treatment Alternatives to Relieve Depression) was a multisite, multistep clinical trial of outpatients with nonpsychotic major depression. It was designed to be more representative of the real world use of antidepressants than typical clinical trials; and to show the effectiveness of antidepressants in the best of circumstances. STAR*D was funded by the NIMH at a cost of $35 million dollars and took six years to complete. It was hailed as the “largest antidepressant effectiveness trial ever conducted.” Robert Whitaker described it as follows:

The STAR*D trial was designed to test whether a multistep, flexible use of medications could produce remission in a high percentage of depressed outpatients. Those who didn’t get better with three months of initial treatment with an SSRI (citalopram) then entered a second stage of treatment, in which they were either put on a different antidepressant or given a second drug to augment an antidepressant. Those who failed to remit in step two could go on to a step three, and so on; in total, there were four treatment steps.

According to the NIMH, in level 1, about one-third of participants became symptom-free. In level 2, about 25% of participants became symptom-free. So a half of the participants in the STAR*D study became symptom-free after two treatment levels. “Over the course of all four treatment levels, almost 70 percent of those who did not withdraw from the study became symptom-free.” However, there was a progressive dropout rate: 21% withdrew after level 1; 30% after level 2; and 42% after level 3.

An overall analysis of the STAR*D results indicates that patients with difficult-to-treat depression can get well after trying several treatment strategies, but the odds of beating the depression diminish with every additional treatment strategy needed. In addition, those who become symptom-free have a better chance of remaining well than those who experience only symptom improvement. And those who need to undergo several treatment steps before they become symptom-free are more likely to relapse during the follow-up period. Those who required more treatment levels tended to have more severe depressive symptoms and more co-existing psychiatric and general medical problems at the beginning of the study than those who became well after just one treatment level.

The message communicated to doctors and the public was that STAR*D showed that antidepressants enabled 67% of depressed patients to recover. Robert Whitaker said an article in The New Yorker commented this “effectiveness rate” was “far better than the rate achieved by a placebo.” But this “cumulative” remission rate of 67% was in fact a theoretical rate that assumed those who dropped out of the study would have the same remission rates as those who remained. “They [also] included remission numbers for patients who weren’t depressed enough at baseline to meet study criteria, and thus weren’t eligible for analysis.” Irving Kirsch said the STAR*D symptom remission was temporary for most: “Approximately 93 percent of the patients who recovered relapsed or dropped out of the trial within a year.”

Recently, Kirsch and others acquired the STAR*D raw data through the MIMH and reanalyzed the HRSD (Hamilton Rating Scale for Depression) results. The HRSD was identified by the original as the primary outcome measure for STAR*D. “Yet the outcome that was presented in almost all the study papers was the QIDS (Quick Inventory of Depressive Symptomatology), a measure made up especially for the STAR-D study, with no prior or subsequent credentials.” The QIDS was devised as a way of tracking symptoms during the course of treatment NOT as an outcome measure. And the original study protocol stated it should not be used as an outcome measure.

Analysis of the HRSD data in STAR*D failed to reach the threshold required for a minimal improvement. “It is also below average placebo improvement in placebo-controlled trials of antidepressants.” The STAR*D results were about “half the magnitude of those obtained in standard comparative drug trials.” Commenting on STAR*D in his book, The Emperor’s New Drugs, Irving Krisch said:

This is a rather bleak picture of the effects of antidepressant treatment. In the best of circumstances—which is what the trial was designed to evaluate—only one out of three depressed patients showed a lasting recovery from depression, and since there was no evaluation of what the recovery rate might have been with placebo treatment, there was no way of knowing whether their recovery was actually due to the medication they had been given.

In her review of the Kirsch reanalysis of the STAR*D study, Joanna Moncrieff said STAR*D suggests that in real life situations, people who take antidepressants do not do very well. “In fact, given that for the vast majority of people depression is a naturally remitting condition, it is difficult to believe that people treated with antidepressants do any better than people who are offered no treatment at all.” She thought this might be the reason the results of the main outcome measure (the HRSD) remained unpublished for so long—and also an explanation for the substitution of the QIDS as an outcome measure. In the original STAR*D analysis:

Whether this was deliberate on the part of the original STAR-D authors or not, it was certainly not made explicit. There should surely be uproar about the withholding of information about one of the world’s most widely prescribed class of drugs. We must be grateful to Kirsch and his co-authors for finally putting this data in the public domain.

According to data gathered by the CDC, 10.7% of all U.S. adults in 2011-2014 reported using an antidepressant in the past 30 days. This is 5.9 times the reported usage for 1988-1994. Demographically, the percentages of U.S. adults who used antidepressants increased with age. The percentages of women using antidepressants were also consistently higher then men for all age groups. Yet their effectiveness in treating depression has been shown to be little better than a placebo. And given that they have a multitude of adverse effects—even the SSRIs—in most cases, no medication may be better than an antidepressant.

See “Dirty Little Secret” and “Do No Harm with Antidepressants” on this website for more information on the antidepressant research of Irving Kirsch. See “The Lancet Story on Antidepressants,” Part 1 and Part 2 for more on the ongoing debate over the effectiveness of antidepressants. See “Antidepressant Fall From Grace, Part 1” for a brief history of antidepressants.

05/1/18

Psychiatric Scientism

There is a curious phenomena within the debate over the evidence base of psychiatric drug treatment, namely whether psychiatry itself ever promoted or supported the chemical imbalance theory. Ronald Pies, an emeritus editor for Psychiatric Times, has repeatedly claimed that the chemical imbalance theory “was always a kind of urban legend—never a theory seriously propounded by well-informed psychiatrists.” Further, Pies said that to his knowledge, “No professional psychiatric organization has ever publically promoted a ‘chemical imbalance theory’ of mental illness in general.” But it seems his statements are incorrect.

The two above quotes by Ronald Pies were from blog articles he posted on the Psychiatric Times website in “Psychiatry’s New Brain-Mind and the Legend of the Chemical Imbalance,” and “Serotonin: How Psychiatry Got Over Its ‘High School Crush’”. He claimed “the ‘chemical imbalance’ trope” has been used by the opponents of psychiatry and erroneously attributed to psychiatrists themselves. Yet Robert Whitaker commented in his response to “Serotonin: How Psychiatry Got Over Its ‘High School Crush’” that it is quite easy to find numerous instances where prominent psychiatrists, including leaders of the APA [American Psychiatric Association], informed the public that “mental illnesses—such as depression or schizophrenia—are not ‘moral weaknesses’ or ‘imagined’ but real diseases caused by abnormalities of brain structure and imbalances of chemical in the brain.” This quote was in a 2001 Family Circle article, “Unlocking the Brain’s Secrets,” by the president of the APA, Richard Harding.

Another example given by Whitaker was in a 2005 brochure published by the APA, “Let’s Talk Facts About Depression.” In the section “How Is Depression Treated?” it says: “Antidepressants may be prescribed to correct imbalances in the levels of chemicals in the brain.” In 2005 APA press release, “Mental Illness Stigmas Are Receding, But Misconceptions Remain,” the results of an APA survey indicated that although 75% of consumers believe mental illnesses are usually caused by a chemical imbalance in the brain, they are more likely to consult a primary care physician rather than a psychiatrist—“a specialist specifically trained to diagnose and treat chemical imbalances and other determinants of mental illness.”

Whitaker’s thesis is that since the publication of the third edition of the DSM in 1980, the APA has been committed to the position that mental disorders are diseases of the brain; and that drugs for those diseases are safe and effective. “The chemical imbalance story comprised the heart of this disease-model narrative: Psychiatric researchers were discovering the pathology of mental disorders, and its drugs fixed that pathology, like insulin for diabetes.” He sees this narrative as serving psychiatry’s interests as a guild.

It told of how its disorders in DSM III had been “validated” as real diseases.
It told of a medical specialty that was making great scientific progress, which elevated its power and authority in our society.
It told of a medical specialty that had a product—e.g. drugs—that was of great worth in treating those diseases.
Most important of all, this narrative provided a reason for psychiatry, as a medical specialty, to have authority over this part of our lives.

Whitaker said our society has responded to this narrative by organizing itself around it, and assuming it is the legitimate “story of science.” In “The Scientism of Psychiatry,” Sami Timimi said this tendency has led mainstream psychiatric literature to prefer rhetoric to scientific accuracy. Psychiatric research and discourse, according to Timimi, “are now dominated and infected by scientism — the promotion of a belief … that because what you do and talk about sounds and looks like ‘science,’ it is ‘scientific’”.

In “What Is Scientism?” Thomas Burnett said philosopher Tom Sorell defined scientism as putting too high a value on natural science in comparison with other branches of learning. A more precise and extreme definition by physicist Ian Hutchinson was also quoted from his book: Scientism: Philosophy and the Infatuation with Science: “Scientism is a matter of putting too high a value on natural science in comparison with other branches of learning or culture.” Hutchinson also said the health of science was jeopardized by scientism.

Burnett gave a brief history of scientism up through the logical positivism embodied in The Vienna Circle. “In this system, there are only two kinds of meaningful statements: analytic statements (including logic and mathematics), and empirical statements, subject to experimental verification. Anything outside of this framework is an empty concept.” However Karl Popper pointed out there were very few statements that could be completely verified in science. “A single observation has the potential to invalidate a hypothesis, and even an entire theory.” So he proposed that instead of experimental verification, “the principle of falsifiability should demarcate what qualified as science, and by extension, what can qualify as knowledge.” Timimi noted how this has been incorporated into scientific methodology as a process of rejecting or disproving the null hypothesis.

Science uses a methodological approach involving hypothesis generation and then testing the hypothesis through empirical methods. The best scientists can live with and accept uncertainty as a prerequisite to being objective in the pursuit of knowledge. Knowledge develops and builds through generating a hypothesis (often using results from previous research) and then carrying out an investigation aimed at proving that something called a ‘null hypothesis’ can’t be true. The null hypothesis is a general statement or default position that there is no relationship between certain measured phenomena. Rejecting or disproving the null hypothesis — and thus concluding that there are grounds for believing that there is a relationship and the actual hypothesis may be true — is a central task in the modern practice of science.

He then said one of the major problems with the current concepts used in psychiatry traces back to the basic assumptions on which much of psychiatric research rests. In order to scientifically evaluate a proposition that there is a natural category of dysfunction/disorder, we must start with the null hypothesis. Until proven otherwise, there is no characteristic relationship between what we are investigating (put the disorder of your choice here) and some measurable biological/neurological feature. “This is a foundational assumption behind the development of knowledge through the scientific method.” ADHD, Depression and essentially all other psychiatric disorders fail to meet this standard. “Until we have demonstrated that this basic null hypothesis can’t be true, then scientifically, we cannot proceed with research that assumes that ADHD [or any other diagnostic category] as a concept has explanatory power for the behaviours it describes.”

Mainstream psychiatry has been afflicted by at least two types of scientism. Firstly, it parodies science as ideology, liking to talk in scientific language, using the language of EBM [evidence based medicine], and carrying out research that ‘looks’ scientific (such as brain scanning). Psychiatry wants to be seen as residing in the same scientific cosmology as the rest of medicine. Yet the cupboard of actual clinically relevant findings remains pretty empty. Secondly, it ignores much of the genuine science there is and goes on supporting and perpetuating concepts and treatments that have little scientific support. This is a more harmful and deceptive form of scientism; it means that psychiatry likes to talk in the language of science and treats this as more important than the actual science.

Contrasting medical and psychiatric diagnosis, Timimi then said:

In medicine, diagnosis is the process of determining which disease or condition explains a person’s symptoms and signs. Diagnosis therefore points to causal processes. Making an accurate diagnosis is a technical skill that enables effective matching of treatment to address a specific pathological process. Pseudodiagnoses, like for example ADHD, cannot explain behaviours as there are only ‘symptoms’ that are descriptions (not explanations) of behaviours. Even using the word ‘symptom’ may be problematic, as in medicine ‘symptoms’ usually refers to patients’ suffering/experience as a result of an underlying disease process and is therefore associated in our minds with a medical procedure leading to an explanation for the ‘symptom.’ But psychiatric diagnoses do not explain symptoms.

Using ADHD as am example, Timimi said once we start interrogating basic assumptions like the validity of psychiatric diagnoses, it should be easy to see that much of the psychiatric literature is built on assumptions lacking validity. Since ADHD is a descriptive classification and not a medical diagnosis, we have no reliable empirical method for defining what qualifies as a case of ADHD. Determining what qualifies as a case of ADHD is then arbitrary and depends on the standards used by the person doing the diagnosis, “influenced by whatever prevailing ideology concerning diagnosis they have been exposed to.” So as a consequence, we cannot eliminate wide variation in ‘diagnostic’ practice.

Timimi said in Western culture, science has become a cosmology—“an ideology/faith that believes that science has an undeniable primacy over all other ways of seeing and understanding life and the world.” This makes us vulnerable to scientism. He suggested psychiatry keeps faith in scientism despite its flaws because of the value we place in our culture on technology and technological achievement; and because, “this connects with that broader ‘cosmology’ that wants to use ‘science’ to explain everything.” In order to have credibility and leverage in our society, “we are inclined to use technological/scientific-sounding language.” Michael Foucault and others have pointed out, “this is how institutional power builds up and get authority to create ‘regimes of truth’.” Robert Whitaker said if psychiatry is ever going to reform itself in a way that will serve the public, “rather than its own guild interests,” it has to confront its past.

Why did it tell this false narrative—of drugs that fixed chemical imbalances in the brain—to the public? Perhaps then it could understand that its duty, as a medical specialty, is to tell a narrative to the public that is consonant with the relevant science. If that were so, then the public would be hearing that the biological causes of psychiatric disorders remain unknown, and that its drug treatments are of marginal efficacy over the short term, and that over the long-term, outcomes for medicated patients are very poor.

06/9/17

Worse Results with Psych Meds

Psych meds are popular. One in six U.S. adults (16.7% of 242 million) reported filing at least one prescription for a psychiatric medication in 2013. That increased with adults between the ages of 60 and 85, where one in four (25.1%) reported using psych meds. Only 9% of adults between the ages of 18 and 39 reported using one or more psych drugs. Most psychiatric drug use was long-term, meaning patients reported taking these meds for two years or more; 82.9% reported filling 3 or more prescriptions in 2013. “Moreover, use may have been underestimated because prescriptions were self-reported, and our estimates of long-term use were limited to a single year.”

The above findings were reported in a research letter written by Thomas Moore and Donald Mattison in JAMA Internal Medicine. Their findings got a fair amount of media attention, including articles in Live Science (here), The New York Times (here), Mad in America (here), Psychology Today (here) and even Medscape (here).

Moore said the biggest surprise was that 84.3% of all adults using psychiatric medication (34.1 million) reported using these meds long-term, meaning over two years. He said the high rates of long-term use of psych meds raises the need for closer monitoring and a greater awareness of the potential risks.

Both patients and physicians need to periodically reevaluate the continued need for psychiatric drugs. . . This is a safety concern, because 8 of the 10 most widely used drugs have warnings about withdrawal/rebound symptoms, are DEA Schedule IV, or both.

The ten most commonly used psychiatric drugs in ranked order were:

Sertraline (Zoloft, an SSRI antidepressant)
Citalopram (Celexa, an SSRI antidepressant)
Alprazolam (Xanax, a benzodiazepine for anxiety)
Zolpidem tartrate (Ambien, a hypnotic prescribed for sleep)
Fluoxetine (Prozac, an SSRI antidepressant)
Trazodone (an antidepressant often prescribed for sleep)
Clonazepam (Klonopin, a benzodiazepine for anxiety)
Lorazepam (Ativan, a benzodiazepine for anxiety)
Escitalopram (Lexapro, an SSRI antidepressant)
Duloxetine (Cymbalta, an SNRI antidepressant)

Drawing on data from a different source in “Drugs on the Mind” for Psychology Today, Hara Estroff Marano said the Institute for Healthcare Informatics (IMS) reported there were 4.4 billion prescriptions dispensed in 2015, with total spending on medicines reaching $310 billion. “Over a million of the prescriptions written for a psychiatric drug were to children 5 years of age or younger.” There were 78.7 million people in the U.S. using psychiatric meds. Within this group, 41.2 million were prescribed one or more antidepressants; 36.6 million were given anti-anxiety medications; and 6.8 million were given antipsychotics.

These figures were different than the percentages reported above from the Moore and Mattison study. Moore and Mattison found that 12% (29 million) reported using antidepressants; 8.3% (20 million) reported using anxiolytics and 1.6% (3.9 million) reported using antipsychotics. Their 1 in 6 (16.7%) figure would then be 40.4 million people using at least one psychiatric medication. Regardless of which data source you use, there are millions of U.S. citizens taking at least one psychiatric drug and therefore at risk of experiencing the adverse effects associated with these drug classes.

Anatomy of an Epidemic by Robert Whitaker described how psychiatric drugs seem to be contributing to the rise of disabling mental illness rather than treating those who suffer from it. What follows is a sampling of comments from Anatomy that he made about benzodiazepines (anxiolytics), which are widely used to treat anxiety and insomnia. Whitaker said long-term benzodiazepine use can worsen the very symptoms they are supposed to treat. He cited a French study where 75 percent of long-term benzodiazepine users “. . . had significant symptomatology, in particular major depressive episodes and generalized anxiety disorder, often with marked severity and disability.”

In addition to causing emotional distress, long-term benzodiazepines usage also leads to cognitive impairment (137). Although it was thirty years ago that governmental review panels in the United States and the United Kingdom concluded that the benzodiazepines shouldn’t be prescribed long-term … the prescribing of benzodiazepines for continual use goes on (147).

In her article for Medscape, Nancy Melville pointed out the CDC found zolpidem (a so-called “Z” drug) was the number one psychiatric linked to emergency department visits. As many as 68% of patients used it long-term, while the drug is only recommended for short-term use. Up to 22% of zolpidem users were also sustained users of opioids.

Among the concerns with antidepressants are that they are not more effective than placebos (see discussions of the research of Irving Kirsch, starting here: “Do No Harm with Antidepressants”). In some cases they contribute to suicidality and violence (see “Psych Drugs and Violence” and “Iatrogenic Gun Violence”) and they have a risk of withdrawal symptoms upon discontinuation.

In a systematic review of the literature, Fava et al. concluded that withdrawal symptoms might occur with any SSRI. The duration of treatment could be as short as 2 months. The prevalence of withdrawal was varied; and there was a wide range of symptoms, encompassing both physical and psychological symptoms. The table below, taken from the Fava et al. article, noted various signs and symptoms of SSRI withdrawal.

The withdrawal syndrome will typically appears within a few days of drug discontinuation and last for a few weeks. Yet persistence disturbances as long as a year after discontinuation have been reported. “Such disturbances appear to be quite common on patients’ websites but await adequate exploration in clinical studies.”

Clinicians are familiar with the withdrawal phenomena that may occur from alcohol, benzodiazepines, barbiturates, opioids, and stimulants. The results of this review indicate that they need to add SSRI to the list of drugs potentially inducing withdrawal phenomena. The term ‘discontinuation syndrome’ minimizes the vulnerabilities induced by SSRI and should be replaced by ‘withdrawal syndrome’.

Updating his critique of the long-term use of antipsychotics in Anatomy of an Epidemic, Robert Whitaker made his finding available in a paper, “The Case Against Antipsychotics.” There are links to both a slide presentation and a video presentation of the information included in his paper. The breadth of material covered was difficult to summarize or select out some of the more important findings. Instead, we will look at what Whitaker said was the best long-term prospective study of schizophrenia and other psychotic disorders done in the U.S. The Harrow study assessed how well an original group of 200 patients were doing at various time intervals from 2 years up until 20 years after their initial hospitalization for schizophrenia. In his paper, Whitaker reviewed the outcome for these patients after 15 and 20 years of follow up.

Harrow discovered that patients not taking medication regularly recovered from their psychotic symptoms over time. Once this occured, “they had very low relapse rates.” Concurrently, patients who remained on medication, regularly remained psychotic—even those who did recover relapsed often. “Harrow’s results provide a clear picture of how antipsychotics worsen psychotic symptoms over the long term.” Medicated patients did worse on every domain that was measured. They were more likely to be anxious; they had worse cognitive functioning; they were less likely to be working; and they had worse global outcomes.

There is one other comparison that can be made. Throughout the study, there were, in essence, four major groups in Harrow’s study: schizophrenia on and off meds, and those with milder psychotic disorders on and off meds. Here is how their outcomes stacked up:

As Whitaker himself noted, his findings have been criticized from several individuals. However, he answered those critiques and demonstrated how they don’t really hold up. Read his paper for more information. But his conclusions about the use of antipsychotic medications are not unique. In the article abstract, for “Should Psychiatrists be More Cautious About the Long-Term Prophylactic Use of Antipsychotics?” Murray et al. said:

Patients who recover from an acute episode of psychosis are frequently prescribed prophylactic antipsychotics for many years, especially if they are diagnosed as having schizophrenia. However, there is a dearth of evidence concerning the long-term effectiveness of this practice, and growing concern over the cumulative effects of antipsychotics on physical health and brain structure. Although controversy remains concerning some of the data, the wise psychiatrist should regularly review the benefit to each patient of continuing prophylactic antipsychotics against the risk of side-effects and loss of effectiveness through the development of supersensitivity of the dopamine D₂ receptor. Psychiatrists should work with their patients to slowly reduce the antipsychotic to the lowest dose that prevents the return of distressing symptoms. Up to 40% of those whose psychosis remits after a first episode should be able to achieve a good outcome in the long term either with no antipsychotic medication or with a very low dose.

All three classes of psychiatric medications reviewed here have serious adverse effects that occur with long-term use. In many cases, they lead to a worsening of the very symptoms they were supposed to “treat.” Increasingly, it is being shown that the psychiatric drug treatments are often worse than the “mental illness” they allegedly treat.

04/28/17

Huffing and Puffing at Anti-Psychiatry

For awhile now I’ve been aware of the ongoing dispute between mainline psychiatry and what is disparagingly referred to as the “anti-psychiatry” movement instead of the critical psychiatry movement. Over time I have come to identify with the “anti-psychiatric” types. The term sets up a false dichotomy, implying you can only be “for” or “against” psychiatry. Critiques of psychiatric diagnosis or the use of psychiatric medications are regularly dismissed out-of-hand by mainline psychiatry. One of the ongoing dialogues of dispute occurs between the author and journalist Robert Whitaker and the eminent psychiatrist Ronald Pies.

Robert Whitaker is the author of three books that relentlessly drive their readers to question the narrative for mental illness and psychiatry verbalized by mainline psychiatrists like Ronald Pies. These books are: Mad in America, Anatomy of an Epidemic and Psychiatry Under the Influence. His articles on the mentally ill and the drug industry have won several awards. A series he wrote for The Boston Globe was a finalist for the Pulitzer in 1998. Anatomy was the 2010 winner for best investigative journalism by Investigative Reporters and Editors, Inc. Mad in America is also the name of a nonprofit organization and webzine, madinamerica.com, whose mission is “to serve as a catalyst for rethinking psychiatric care in the United States (and abroad).”

Ronald Pies is a noted psychiatrist, a Clinical Professor of Psychiatry at Tufts University and SUNY Upstate Medical University, Syracuse NY. He is also Editor in Chief Emeritus of Psychiatric Times. A bit of a Renaissance man, he’s published poetry: The Heart Broken Open, a novel: The Director of the Minor Tragedies, nonfiction: Becoming a Mensch: Timeless Talmudic Ethics for Everyone, as well as psychiatry: Psychiatry on the Edge, Handbook of Essential Psychopharmacology and psychotherapy: The Judaic Foundations of Cognitive-Behavioral Therapy. He has authored or coauthored several other books as well.

Whitaker and Mad in America authors have disagreed with Pies on several issues. For example, they disagreed on whether psychiatrists widely promoted the chemical imbalance theory (see “Psychiatry DID Promote the Chemical Imbalance Theory” and “My Response to Dr. Pies” on madinamerica.com); or whether the long-term use of antipsychotics is helpful (see “Dr. Pies and Dr. Frances Make a Compelling Case that Their Profession is Doing Great Harm on madinamerica.com).

Into this mix Pies has written three articles for Psychiatric Times: “Is There Really an ‘Epidemic’ of Psychiatric Illness in the US?,” “The Bogus ‘Epidemic’ of Mental Illness in the US” and “The Astonishing Non-Epidemic of Mental Illness.” He’s clearly playing off of Whitaker’s book: Anatomy of an Epidemic. In his third article, “The Astonishing Non-Epidemic of Mental Illness,” Pies said that the epidemic of mental illness narrative is (with a few qualifications) “mostly fear-mongering drivel.” It sells books and makes for good online chatter, but “The so-called epidemic of mental illness among adults in the US proves largely illusory.”

He did some rhetorical sleight-of-hand, stating that by pulling out the bottom card of the epidemic narrative, the entire house of cards of the anti-psychiatry movement would collapse. In order to do this, he first quoted what he said was the CDC definition of epidemic: “ . . . an increase, often sudden, in the number of cases of a disease above what is normally expected in that population in that area . . .” Pies then said the CDC definition of epidemic applied to actual cases of disease; not to changing rates of diagnosis, which are subject to many socio-cultural variables. The distinction was critical,

Since psychiatry’s critics do not claim merely that there is more diagnosis of schizophrenia or major depression; rather, they claim there are actually more people sick with these illnesses, owing to misguided or harmful psychiatric treatment.

Remember that in psychiatric diagnosis, there are relatively few diagnoses that can be confirmed by medical tests. The vast majority of psychiatric disorders are assessed by a diagnostic process alone. If you demonstrate to a clinician that you meet the diagnostic criteria for a psychiatric disorder, you are treated as if you actually have the disorder. So Pies seems to be splitting hairs with his distinction between actual cases and diagnoses. And I don’t think he has made as telling a point as he thought.

It would seem he is suggesting that psychiatric diagnostic rates for a disorder are overstated from the actual cases because of the influence of socio-cultural variables. Yet how can you distinguish the actual cases from the false positives due to socio-culturally influenced diagnosis? The same diagnostic criteria are used. Is there an unstated assumption that diagnostic inflation is due to factors beyond psychiatry? Namely, that if a trained psychiatrist follows the structured clinical interview process, only actual cases of a psychiatric disorder will be identified?

Pies also said the “epidemic” claim was largely based on the increasing US rates of psychiatric disability over the past 50 years. Here he cited an article by Whitaker without mentioning Whitaker’s name. He dismissed the validity of using disability determinations, saying they cannot be used as “a legitimate index of disease incidence or prevalence.” He then shifts the focus to affirm there is a growing population of “persons with serious psychiatric illness who are not receiving adequate treatment.” Here he named two well-known psychiatrists who have written of their concerns with the “epidemic” of neglect with our most severely impaired citizens. But one of the persons he mentioned, Dr. Fuller Torrey, wrote The Invisible Plague about the rise of mental illness from 1750 to the present!

In the Introduction to The Invisible Plague Torrey described what he saw as “the epidemic of insanity.” He said a major impediment to understanding the epidemic of insanity was that its onset occurred over so many years. Few people fully appreciated what was happening. “Those who did raise an alarm were largely ignored.” He said the suggestion today that we are living in the midst of an epidemic of insanity strikes most people as unbelievable.

Insanity is an invisible plague. There are no body counts with which one can compare the present with the past. In most countries, there are remarkably few statistics that can be used to assess insanity’s prevalence over time. Professional textbooks assume that insanity has always been present in approximately the same numbers as now.

Fuller Torrey is a believer in insanity as an epidemic of brain dysfunction. And he blames the likes of Michel Foucault, Thomas Szasz, Ronald Laing and others for emptying the insane asylums that have been “the mainstay for containing the epidemic for a century and a half,” without insuring these individuals received the treatment needed to control the symptoms of their illness.

When looking at the costs of this epidemic, Torrey said the combined costs in 1991 for the US were $110 billion. “And this included the single largest disease category for federal payments under the Supplemental Security Income (SSI) and Social Security Disability Insurance (SSDI) programs.” So in quantifying the cost of the epidemic of insanity, Torrey used the same statistic to make his point that Whitaker did. Pies either didn’t realize this, or ignored it in his critique of Whitaker. I wonder if Pies sees what Torrey said as fear-mongering drivel or one of the few qualifications?

Pies dismissively cited two articles written by Marcia Angell for The New York Review of Books in 2011 (“The Epidemic of Mental Illness: Why?” and “The Illusions of Psychiatry”) in all three of his articles as an example of the promotion of the false narrative of “the raging epidemic of mental illness.” Her articles discussed three books and their implications for psychiatry: The Emperor’s New Drugs, Anatomy of an Epidemic, and Unhinged: The Trouble with Psychiatry. Angell’s review of Whitaker’s book drew it to the attention of a wide audience; so it seems this may be at least partly why Pies is dismissive of it.

However, read her articles. They will give you a thumbnail sketch of issues Pies goes to great lengths to deny and minimize. Then read the books she discusses. Remember that Marcia Angell is a Senior Lecturer at Harvard Medical School and was the first woman to serve as editor-in-chief of the New England Journal of Medicine. Don’t be dismissive of what she has to say; she has great credibility.

There is one final point to be made with regard to Pies’ third article. In the conclusion, he references Thomas Kuhn’s idea of “paradigm,” saying it is misleading and unfair to suggest that psychiatry is laboring under a “failed paradigm.” This was, he said, because “there is no one paradigm the defines all of psychiatry or that dictates practice on the part of all psychiatrists.” But I wonder if he truly understood the implications to his comment. If you apply Kuhn’s notion of paradigm (“a paradigm is what members of a scientific community share”) with Pies’ application of the term to psychiatry, then you would have to conclude that psychiatry as it’s practiced, is NOT a science. Rather, it would either be what Kuhn called a “pseudoscience” or pre-scientific. He also seems to be oblivious to the possibility of an implicit paradigm generated in psychiatric practice with DSM diagnosis—that it classifies a real “illness” or “disease” of the brain.

I’m reminded of what Robert Whitaker pointed out in his review of Jeffrey Lieberman’s book Shrinks, “The Untold Story of Psychiatry.” Whitaker noted how speeches given by the presidents of the American Psychiatric Association at their annual meetings regularly sounded the same theme: “Psychiatrists are true heroes.” He said it struck him that Shrinks served as an institutional self-portrait of psychiatry. “What you hear in this book [Shrinks] is the story that the APA and its leaders have been telling to themselves for some time.” Similarly, it seems Pies is preaching to the psychiatric choir—a message that there really isn’t an epidemic increase in mental illness; the argument that the anti-psychiatry movement is just a house of cards. Yet it seems to me that house is still standing despite the huffing and puffing of Pies and others.

04/7/17

Souless Psychiatry

A psychiatric resident at Stanford University School of Medicine wrote an essay on the crisis with psychiatry that appeared in a Scientific American blog. The author said the field was in decline as fewer medical students sought to specialize in psychiatry. He stated psychiatry was looked down upon by nearly every segment of society; and patients avoided treatment because of the stigma related to the field. His solution was to change the name of the field—call it something else.

The crisis, in his view, stems largely from a misunderstanding of what psychiatry is. He said it was “the medical field where doctors incorporate neuroscience and medical research to treat patients with diagnosable mental disorders.” But his friends seem to think he interprets dreams and administers Rorschach tests. Administering Rorschach tests and interpreting dreams are activities associated with psychoanalytic practice that dominated psychiatry up until the 1970s. While “mental health” has made great strides raising awareness (i.e., May is now National Mental Health Awareness Month), “psychiatry has been left behind as its anachronistic forebear.” So he asked, “Would renaming the field help?”

The word psychiatry evokes thoughts of dated medical practices, like Freudian analysis and ice-pick lobotomies. Its sordid history turns away patients, providers, and the public from the progress of mental health care today.

He acknowledged where relabeling could be seen as a Band-Aid. A mere name change ignores the root causes of the problem, which from his perspective is the stigma attached to psychiatry and mental illness. However, citing studies of name changes within the U.S. and other countries, he suggested these language shifts helped psychiatry sound more reputable. He imagined most people would rather have a mental health disorder than a psychiatric disorder, “even if it were the same thing.”

“Mental Health Care” would be a simpler name for the field instead of psychiatry. Psychiatrists would then become “mental health physicians.” Medical centers could create departments of mental health, combining specialties such as internal medicine, psychiatry, psychology and social work. “By uniting these fractured disciplines under one roof, clinicians could provide more comprehensive care to patients without the stigma associated with aging terminology.” Mental health units were said by the author to be far less frightening than psychiatric wards.

In conclusion, he noted how the term psychiatry meant: “healing of the psyche,” drawn from the Greek goddess of the soul—Psyche. “It’s a romantic notion, but we don’t treat patients’ souls. We treat diagnosable diseases of the brain. Perhaps it’s time to rename the field.”

In reading this essay, I was reminded of what psychiatrist Jeffrey Lieberman wrote in his book, Shrinks about psychiatry. He commented that in the 1970s, “the majority of psychiatric institutions were clouded by ideology and dubious science,” mired in a pseudomedical Freudian landscape. But now in the twenty-first century, psychiatry offered scientific, humane and effective treatments. “Psychiatry is finally taking its rightful place in the medical community after a long sojourn in the scientific wilderness.” You can read about the fallacies of “Freudian analysis and ice pick lobotomies” in Shrinks, but you won’t hear the complete and unvarnished truth about psychiatry.

Robert Whitaker astutely commented that Shrinks is more of a story of how psychiatry sees itself as an institution, than it is an accurate history of psychiatry. And I see the same approach here. I wonder if the Stanford psychiatric resident who wrote “Maybe We Should Call Psychiatry Something Else” is simply rehashing the received view of psychiatric history.

If you want a truly unvarnished look at psychiatry, read Whitaker: Mad in America, Anatomy of an Epidemic, and Psychiatry Under the Influence. You can read more about Lieberman and Shrinks on this website. Do a search for “Lieberman.”

The term “psychiatry” was originally coined by Johann Reil—a German physician—in 1808. And it does literally mean the medical treatment of the soul. Another German physician, Johann Heinroth was the first person to hold a chair of psychiatry. He also staked out working with the mentally ill as medical territory. Since there was little or no knowledge within the medical tradition to equip doctors to deal with mental disturbances, he proposed the creation of a new branch of medicine—psychiatry.

In his 1818 Textbook of Mental Disturbances, Heinroth said: “Since we are speaking of medical art and science, we should think that nobody but a doctor should have a right to make mental disturbance the object of his studies and treatment.” In The Myth of Psychotherapy, Thomas Szasz said of this time:

The birth of psychiatry occurs when the study of the human soul is transferred from religion to medicine, when the “cure of souls” becomes the “treatment of mental diseases,” and, most importantly, when the repression of the heretic-madman ceases to be within the jurisdiction of the priest and becomes the province of the psychiatrist.

There have been some radical shifts in how psychiatrists function since the early 1800s. Initially they were administrators of large institutions for the insane. Under Freud’s influence, psychiatrists began to consult with individuals living in society rather than working solely with those within institutions. Then in 1909, Freud was invited to give a series of lectures on psychoanalysis by Stanley Hall, the president of Clark University.

The cover photo for “Maybe We Should Call Psychiatry Something Else” shows seven men from the time of that conference, but only identified Sigmund Freud and Carl Jung. At the time, Jung was still friendly with Freud. The photo credit said the others were “pioneers in psychiatry,” but that is not entirely accurate. The photo shows Sigmund Freud and Carl Jung on either side of Stanley Hall in the front row. In the back row from left to right are Abraham Brill, Ernest Jones and Sandor Ferenczi.

Stanley Hall was a well-known American psychologist in addition to the then president of Clark University. He had an interest in Freud’s psychoanalytic theories and invited him to be part of a “galaxy of intellectual talent” to celebrate the twentieth anniversary of the founding of Clark University. Jung and Ferenczi were invited as the leading European disciples of Freud. Ernest Jones, another protégé of Freud, was then in Toronto Canada, building a private psychoanalytic practice and teaching at the University of Toronto. Jones would later become a biographer of Freud. Brill was the first psychoanalyst to practice in the U.S. and the first translator of Freud into English. In 1911 he founded the New York Psychoanalytic Society.

So these individuals are better seen as pioneers of Freudian psychoanalytic practice —the approach dismissed by the author of “Maybe We Should Call Psychiatry Something Else” as a dated medical practice, which he placed alongside ice pick lobotomies.

By the 1940s, psychoanalytic theory had not only taken over American psychiatry, it had become part of our cultural psyche. Alfred Hitchcock’s 1945 film, Spellbound is an example of how influential psychoanalytic thinking was. The opening credits of the film announce that it wanted to highlight the virtues of psychoanalysis in banishing mental illness and restoring reason. Look for the Freud look-a-like character as Ingrid Bergman’s psychoanalyst and mentor.

Psychoanalytic thought dominated the field until the 1970s when the birth of biological psychiatry was ushered in by Robert Spitzer and his reformulation of psychiatric diagnosis. After Spitzer was appointed to do the revisions for the 3^rd edition of the DSM in 1974, he was able to appoint whomever he wanted to the committees. He made himself the chair of all 25 committees and appointed individuals who he referred to as the “young mavericks” psychiatry. In other words, they weren’t interested in Freudian analysis. Spitzer said: “The feeling was that the same techniques that were useful in medicine, which is you describe something, you do laboratory studies; that those same kind of studies were appropriate for psychiatry.” Except it didn’t happen because in the 1970s, there just wasn’t a lot of psychiatric research. So the decisions of the committees were based on the expertise of the committee members.

David Chaffer was part of the process back then. He said committee members would gather together into a small room. Spitzer would sit with a mid 1970s “portable” computer and raise a provocative question. “And people would shout out their opinions from all sides of the room. And whoever shouted loudest tended to be heard. My own impression was … it was more like a tobacco auction than a sort of conference.” So much for using the same techniques as those used in medicine. Listen to the NPR story, “The Man Behind Psychiatry’s Diagnostic Manual” for the above information on Spitzer and the DSM.

But the real driving force behind the revisions made by Spitzer and others was because a “psychopharmacological revolution” couldn’t begin with the diagnostic process that existed before Spitzer and the DSM-III. Allen Frances, the chair of the next revision, the DSM-IV, acknowledged as much in his comments before the American College of Neuropsychopharmacology in 2000. Frances said the DSM-III was an innovative system that focused on descriptive diagnosis and provided explicit diagnostic criteria. “In many ways this aided, and was aided by, the knowledge derived from psychopharmacology. . . . The diagnostic system and psychopharmacology will continue to mature with one another.”

The psychopharmacological revolution required that there be a method of more systematic and reliable psychiatric diagnosis. This provided the major impetus for the development of the structured assessments and the research diagnostic criteria that were the immediate forerunners of DSM-III. In turn, the availability of well-defined psychiatric diagnoses stimulated the development of specific treatments and increasingly sophisticated psychopharmacological studies.

In the Foreword to his book, The Anatomy of an Epidemic, Robert Whitaker explained how he first wandered into the “minefield” of psychiatry by writing in the mid 1990s about research practices such as rapidly tapering schizophrenic patients off of their antipsychotic medications and then giving them a drug to exacerbate their symptoms. This “research” was done in the name of studying the biology of psychosis. Jeffery Lieberman took part in some of those studies, using methylphenidate (Ritalin, Concerta) to deliberately provoke psychotic symptoms in schizophrenic patients. Read “Psychiatry, Diagnose Thyself! Part 2” for more information on Whitaker’s articles and Lieberman. Incidentally, the series of articles Whitaker co-wrote for the Boston Globe was a finalist for the Pulitzer Prize for Public Service. Whitaker said in the Foreword to Anatomy of an Epidemic:

I began this long intellectual journey as a believer in the conventional wisdom. I believed that psychiatric researchers were discovering drugs that helped “balance” brain chemistry. These medications were like “insulin for diabetes.” I believed that to be true because that is what I had been told by psychiatrists while writing for newspapers. But then I tumbled upon the Harvard study and the WHO findings, and that set me off on an intellectual quest that ultimately grew into this book, The Anatomy of an Epidemic.

Maybe there is a stigma against psychiatry for more than just the past use of ice pick lobotomies or insulin comas or ice baths or the electroshock treatment shown in One Flew Over the Cuckoo’s Nest. But simply changing the name of what we now call psychiatry will not change the opposition against a medical specialty that no longer treats patients’ souls. And perhaps that is really why the field is in decline.

07/12/16

Common Sense with Lithium

Lithium carbonate (not the element lithium) is used as a psychiatric medication primarily with bipolar disorder. It can be used with other psychiatric disorders such as major depression and schizophrenia, when first line medications are not effective. There are several advantages to lithium, particularly when it comes to cost. Available as a generic medication, a typical daily dose costs between 90 cents and $1.20. Major downsides are that therapeutic doses are just lower than toxic doses and there is the potential of direct damage to the kidneys and thyroid.

The website drugs.com said that since the toxic levels for lithium are so close to the therapeutic levels, patients and their families should watch for early symptoms, then discontinue the drug and inform the physician should they occur. Indications of lithium toxicity may include: diarrhea, vomiting, drowsiness, muscular weakness and lack of coordination. There are a host of other potential side effects that include: confusion, dry mouth, muscle twitching or trembling, vertigo, increased urination, memory problems and weight gain. These are only a few of the side effects found in 10% or more of the persons using lithium. See drugs.com or the Wikipedia listing for a more detailed discussion of lithium side effects.

In the late 1800s lithium was a popular ingredient in elixirs and tonics. It was even added to beer and other beverages. The theory was that it dissolved uric acid, so it could break up kidney stones and the uric acid crystals associated with gout. It was found to have no such effects. Lithium was eventually banned by the FDA in 1949 when it was found to cause cardiovascular problems.

Coincidentally, that same year an Australian physician named John Cade published a paper describing his treatment of 10 patients with mania with lithium. Cade had noticed that lithium made guinea pigs docile, so he thought it could have a therapeutic effect in manic patients. He announced dramatic effects in his paper and claimed they were specific to mania. What he failed to mention was that one patient died, two others had to discontinue lithium because of severe toxicity and one patient refused to take it. None of this was reported in his paper. Side effects were noted 41 times in the clinical records, but only 1 time in the published article. See The Myth of the Chemical Cure by Joanna Moncrieff for a more detailed description of lithium as a psychiatric treatment.

In Anatomy of an Epidemic, Robert Whitaker noted that psychiatrists in the U.S. had little interest in lithium until manic-depression was distinguished into unipolar and bipolar forms. Only a few placebo-controlled trials of lithium had ever been done up to that point. In 1985 UK researchers could only identify four with any merit. But within those studies, lithium was said to have a good response rate in 75% of the patients. This was much higher than the response rate in the placebo group.

A 1994 meta-analysis of nineteen studies by J.P. Baker of patients who were on lithium and had their lithium withdrawn showed that 53.7% of the patients relapsed, versus 37.5% of the lithium-maintained patients. This was seen as clear evidence that lithium prevented relapse. However, only 29% of patients who were gradually withdrawn from lithium relapsed. Note how this rate was better than those in the drug-maintained group.

Whitaker said this wasn’t very robust evidence of lithium’s benefit to patients, especially when you considered the additional studies raising concerns about lithium’s long-term effects. There was also a high rate of patients who stopped taking lithium—over 50%—because of how the drug dulled their minds and slowed their physical movements. In 1999 Baldessarini et al. found that almost half of all patients relapsed within five months of quitting lithium, while individuals who did not use lithium took nearly three years to reach that percentage of relapse. “The time between episodes following lithium withdrawal was seven times shorter than it was naturally.” Whitaker noted:

Although lithium is still in use today, it lost its place as a first-line therapy once “mood stabilizers” were brought to market in the late 1990s.

Now there has been a growing body of evidence that suggests lithium prevents suicide. In 2003 Baldessarini and others found that long-term lithium maintenance patients had lower suicide rates than individuals who did not. Cipriani et al. found lithium was an effective treatment for reducing the risk of suicide in people with mood disorders as well as bipolar disorder. Lewitzka et al. did a comprehensive review of more than 20 years of studies investigating the anti-suicide effect of lithium in patients with affective disorders. They also concluded lithium to be “an effective treatment for reducing the risk of suicide and suicide attempts in patients with affective disorders over the long-term course.”

Joanna Moncrieff reviewed several meta-analyses indicating the anti-suicide effects of lithium in The Myth of the Chemical Cure and said the studies included in these analyses had conflicting results. An article on her website, “Lithium and Suicide: What Does the Evidence Show?” said the proposed effect of decreased mortality rates was inexplicable since lithium was a toxic drug that made most people feel rather depressed. She wondered if the sedating effect of the lithium sapped people of the will to act. “A closer look at the evidence, however, suggests the idea [lithium reducing suicidality] is simply not justified.”

The first issue was that the evidence supporting this idea consisted of follow-up studies with individuals on long-term lithium, as with Copper et al. Moncrieff commented how these people are a particularly compliant group with medication. “People who follow their lithium regime religiously are, in general, not likely to be the people who are chaotic, impulsive, desperate and most likely to commit suicide.” One study, by Gonzalez-Pinto et al., showed that people who were highly compliant with their lithium were five times less likely than those who were ‘poorly compliant’ to commit suicide. A second issue was that given small margin of error between therapeutic and toxic doses of lithium, people with suicidality tendencies are less likely to be given lithium.

Another confounding issue is that people with medical conditions are less likely to be given lithium. Not only can lithium cause kidney and thyroid problems, but it interacts with many commonly prescribed drugs like diuretics, ACE inhibitors and NSAIDS like aspirin and ibuprofen. This can result in dangerously high lithium levels. So caution is used when starting lithium with someone who is physically sick or taking other medication. Moncrieff said better randomized controlled trials are needed.

She thought it curious that a meta-analysis by Cipriani et al. in 2013 did not include a single placebo-controlled trial where the suicide rate was zero, so she looked more closely at its methology. Moncrieff discovered that the authors excluded any trial whose treatment arm was uninformative, namely those whose suicide rates were zero. “This decision is totally unsound, however, as it reduces the denominator (the total number of participants) and thereby makes the events included appear more common than they actually were.” She speculated this was why some well-known studies were not included in the analysis of suicides. When the studies with no suicides were included, “the number of participants would have been much larger and the proportion of suicides in the placebo group much smaller.”

So there is the evidence on lithium and suicide. The meta-analysis that has been accepted as demonstrating that lithium prevents suicide spuriously inflated the suicide rate on placebo by excluding studies in which no suicides occurred. The only double blind, prospective study designed to test whether lithium reduces suicide in people at high risk, ended up unblinding many of its participants, and in any case suicidal events were low in both groups.

The fact that studies of suicide prevention have been so difficult to recruit to, suggests patients may have more sense than researchers in this field!

05/31/16

To Be or Not to Be Bipolar

On The Oprah Winfrey Show in October 2007, Sinéad O’Connor disclosed that she had been diagnosed with bipolar disorder in 2003. The website, “Famous Bipolar People,” said Sinéad had suffered from depression and had thoughts of suicide since the age of 23. She also experienced voices urging her to harm herself. The voices got so loud, she said, she took herself to hospital. She was put on antidepressants, which helped. “These all confirmed that she had bipolar disorder.” Then a few years ago, she went public with an announcement that she had been misdiagnosed with bipolar disorder for eight years.

During her interview with Oprah, she said she didn’t think she was born with bipolar disorder. She thought her illness was caused by a number of outside pressures. “I believe it was created as a result of the violence I experienced.” She was scared to take the medication at first. But she realized that she had nothing to lose, so she tried them. “It was brilliant because I felt this huge hole. And when I took the meds, within half an hour, it was literally like I felt concrete coming in to fill the hole.” She said she thought she had died and then was ‘born again’ as a result of taking the meds.

But after spending eight years on the medications, she realized her depression was still there. Additionally, “some of the same problems she’d had before being medicated were persisting.” And she received complaints about her weight from people in the music business. By the way, weight gain is one of the side effects from antipsychotic medication. When she mentioned her weight problem to her doctors, they suggested taking her off of the bipolar meds as a remedy.

Writing for About Health, Angel Rouse said O’Connor was alarmed with the casualness of the suggestion and aware that simply stopping meds could be dangerous. So she sought outside opinions, eventually getting three additional ones. Their conclusion was that she was not bipolar. Rather, she actually suffered from PTSD. She revealed that when she cancelled her tour in 2012, she had tried to stop taking her medication cold turkey. Ironically, as a result of that attempt, she struggled with bipolar problems of mania and depression for nearly a year. Interviewed for the Irish Mirror, she said:

The illness was in fact what happens when you don’t go about coming off these meds properly. I’m delighted to be able to say that after ten years of poisoning myself with these drugs and having to live with the extremely difficult side-effects of them I can shortly begin the very, very slow indeed, process of getting them out of my system and my life and getting my life back.

Sinéad O’Connor is not a unique case. The NAMI (National Alliance on Mental Illness) website claims that 2.6% or 6.1 million American adults have a bipolar disorder. NAMI referenced this “mental health fact” on data they took from the National Institute of Mental Health (NIMH), which in turn cited this article by Kessler et al. from JAMA Psychiatry on the prevalence, severity and comorbidity of DSM-IV disorders. See Table 1 in the article for the reported percentage. But if Sinéad O’Connor could be misdiagnosed as having a bipolar disorder and mistakenly placed on potentially harmful medications that are seen as necessary to stabilize and control the bipolar ‘illness,’ how many others are similarly misdiagnosed? Regarding the medications she was on, O’Connor told the Irish Mirror:

They are extremely debilitating drugs. Tiring to the extreme. Ironically, extremely depressing. They can cause suicidal or self-harm type thinking. They can mess up your menstrual cycle very badly and cause you to be incapacitated for a week before. . . . [They] f**k up your liver, your kidneys, your eyes, your appetite, your entire way of thinking and generally your entire life.

Within his seminal book, Anatomy of an Epidemic, Robert Whitaker described “The Bipolar Boom” in chapter nine. He related a talk given by Fredrick Goodwin at the 2008 annual meeting of the American Psychiatric Association (APA). Goodwin said the illness has been altered since 1990. There was more rapid cycling; more mixed states; more lithium treatment failures than when he’d coauthored Manic-Depressive Illness. “The illness is not what Kraepelin described anymore, and the biggest factor, I think, is that most patients who have the illness get an antidepressant before they ever get exposed to a mood stabilizer.” Whitaker said not everyone speaking agreed that antidepressants had been disastrous for bipolar patients, but no one questioned Goodwin’s assessment that bipolar outcomes had noticeably worsened since 1990.

On his website, Whitaker noted that before 1955, bipolar illness had been a rare disorder. Only 12,750 people were hospitalized with the disorder that year. There were only about 2,400 “first admissions” that year in the country’s mental hospitals. Outcomes were fairly optimistic. Seventy-five percent of these first-admissions were projected to recover within 12 months. And only 15% of first-time admissions were expected to become chronically ill. And at least 70% were projected to return to work and have active social lives.

Today, bipolar illness is said to affect one in every 40 adults in the United States. A rare disorder has become a very common diagnosis. There are several reasons for this. First, many drugs–both illicit and legal–can stir manic episodes, and thus usage of those drugs leads many to a bipolar diagnosis. Second, the diagnostic boundaries of bipolar illness have been greatly broadened.

Allen Frances is a psychiatrist and the author of Saving Normal. He was also the chair for the DSM-IV, which expanded the criteria in diagnosing bipolar diagnosis by adding the bipolar II category. In Saving Normal, he described a dilemma when the APA was revising bipolar diagnosis for the fourth edition of the DSM. Patients with “hypomania,” less-than-full-manic episodes, didn’t fit neatly into the unipolar or bipolar depression categories. The bipolar II category was seen as a compromise that would lessen the dangers of classifying them as having unipolar depression and treating them with antidepressant medication that could trigger a manic episode.

We knew that bipolar II would expand the bipolar category somewhat into unipolar territory, but we did not think that it would double. Undoubtedly, our decision resulted in more accurate diagnosis and safer treatment for many previously missed truly bipolar patients. But like all fads, it overshot and had led to unnecessary medication for many unipolar patients who have been misdiagnosed as bipolar on very flimsy grounds and are now receiving unnecessary mood stabilizing drugs.

Whether you agree with Frances’ assessment that adding bipolar II resulted in more accurate diagnosis and safer treatment for many, don’t miss that he also said it led to misdiagnosis and unnecessary medication. If you follow this link, also given above, to Robert Whitaker’s website, Mad in America, you will find a series of journal articles describing how substance abuse can be related to developing bipolar disorder; the effects of antidepressant use on bipolar disorder and how these drugs can worsen long-term bipolar outcomes; and the deterioration of bipolar outcomes in the modern era.

For a postscript, I want to return to note one last piece of information on Sinéad O’Connor. While she has cast off her diagnosis of bipolar disorder, it isn’t finished with her. Many websites, like that of “Famous Bipolar People” mentioned above, still list her as one of their own. There was a concluding note in the “About Health” article on Sinéad O’Connor that said: “In spite of her having stated clearly on several occasions that she does not have bipolar disorder, O’Connor continues to be included at many sites that compile lists of famous bipolar people.”

Famous Bipolar People, if Sinéad had said it’s over between the two of you, accept it and move on. There are plenty of more fish in the sea. You still have Kay Redfield Jamison. She’s written two books that touch on bipolar disorder, An Unquiet Mind and Touched with Fire. And both have been made into movies. The movie, Touched with Fire, is a fictional love story about two people with bipolar disorder who meet in a psychiatric hospital and fall in love. The trailer has a slight Romeo and Juliet feel to it; two young lovers who family and friends try to keep apart. So there will be plenty of new discussions about who is and who isn’t bipolar related to the movie. Just let go of Sinéad; let her go and move on.

02/16/16

Nearsighted Drug Development

I was encouraged to hear that ALKS 5461 failed in two late-stage clinical trial studies. This isn’t because I have something against Alkermes, the pharmaceutical company developing the drug. I don’t own stock in a competing company trying to bring their new fast-acting antidepressant drug to market ahead of Alkermes. I do think antidepressants are overprescribed and have potentially harmful side effects for some people, but that’s not why I was happy to hear that ALKS 5461 is in trouble. I just don’t think that putting an antidepressant drug on the market that uses a potentially addictive opioid as its active ingredient is a good idea.

Reporting for Reuters, Amrutha Penumudi said that when news of the failed clinical trails for ALKS 5461 were made public by Alkermes, the company saw its shares fall in value by 42.8%, a $3.88 billion loss for the company. ALKS 5461 is the company’s main product, so the bad news about the clinical trials was a major financial blow. William Tanner, an analyst for Guggenheim Partners was widely quoted by Reuters and others as saying that “We believe trial failures present a major setback in the evolution of the company.” Even if ALKS 5461 succeeds in a third as-yet not completed clinical trial, more studies may be required, according to Ken Cacciatore.

ALKS 5461 is a new molecular entity (NME) that has been fast tracked by the FDA for approval as a treatment of Major Depressive Disorder (MDD) with patients who didn’t respond to standard antidepressant therapies. It is a combination of buprenorphine, a Schedule IV Controlled Substance and samidorphan, a naloxone-like substance. Suboxone, which is a combination of buprenorphine and naloxone, is commonly used as an opioid substitution medication for heroin and prescription opioid addicts. The major difference between ALKS 5461 and Suboxone as far as buprenorphine is concerned is that ALKS 5461 is currently being tested in 2 mg and .5 mg doses, where standard protocols for Suboxone as an opioid substitution drug could reach 16 mg or higher. You will find more information on ALKS 5461 and my concerns about its use to treat depression in: “The Coming Depression Apocalypse,” an article I published here a few months ago.

But it doesn’t seem Alkermes is going to give up the fight. In their press release, Richard Pops, the CEO of Alkermes said:

We are steadfast in our commitment to developing new medicines for serious CNS conditions where there is a clear and compelling need for new treatment options for patients and their families. . . . Major depressive disorder is one of these conditions. We are building a large body of evidence supporting our belief in the clinical utility and the novel mechanism of action of ALKS 5461. We await the results of FORWARD-5 and will determine our next steps along the regulatory path with those results in hand.

In one of the failed trials, Alkermes did post-hoc analyses (reanalysis of the data after the fact) that indicated the 2 mg dose was more effective than a placebo. Given the results of the two failed studies, Alkermes said they plan to increase the number of patients in the ongoing trial and “update” the planned statistical analysis for FORWARD-5, the third efficacy study in the FORWARD program. The updated analysis sounds like it means they plan to use the same analysis process applied to the 2mg dose group for FORWARD-4 after the fact. This is bit like cheating if the researchers went p-hacking or data-dredging in their post-hoc analysis. See “How to Lie About Research” for more information on p-hacking.

Another factor regarding Alkermes and ALKS 5461 that concerns me is how the company describes the drug. In their above-linked press release, Alkermes said that ALKS 5461 acted “as a balanced neuromodulator in the brain;” and was “designed to rebalance brain function that is dysregulated in the state of depression.” This sounds eerily similar to the chemical imbalance theory of depression that even psychiatrists such as Ronald Pies have said was always a kind of urban legend. In an article in Psychiatric Times, he said: “To my knowledge, no professional psychiatric organization has ever publicly promoted a ‘chemical imbalance theory’ of mental illness in general.” Look at Robert Whitaker’s response to that article by Pies and the reams of additional evidence to show how Pies’ claim was clearly wrong.

But there is now another concern with the use of opioids to treat depression. A study by Scherrer et al., published in the Annals of Family Medicine, found that people who used prescription opioids for longer than a month may have an increased risk of developing depression. Scherrer was quoted by Agata Blaszczak-Boxe for Live Science as saying the researchers rigorously controlled for pain, “and we feel strongly that these results are independent of the known contribution of pain to depression.” The longer individuals were taking opioids, the greater was their risk of depression.

Citing a 2014 study by Howe and Sullivan in General Hospital Psychiatry, Scherrer et al. said that research on the efficacy of opioids in treating depression was limited by small sample sizes, short follow-up time and lack of control groups. So they do not support opioids as effective long-term treatments for depression. “This evidence, combined with the finding from the present study, supports the conclusion that opioids may cause short-term improvement in mood, but long-term use is associated with risk of new-onset depression.”

Buprenorphine was not one of the opioids studied, but the findings of the Scherrer et al. study does give me increased concern with the fast-track status the FDA has given ALKS 5461. Recent findings do suggest the risk of new onset of depression increases with a longer duration of opioid use. A replication attempt of Scherrer’s study with buprenorphine seems needed before approving ALKS 5461. The short-term projected improvements could lead to long-term problems with depression. “Patients and practitioners should be aware that opioid analgesic use of longer than 30 days imposes risk of new-onset depression.”

Hopefully the FDA will have the foresight to weigh all the potential adverse effects with ALKS 5461 before approving it. There is a very real potential for physical dependency to develop with ALKS 5461 given that its active ingredient is a Schedule IV controlled substance. Heroin addicts have told me buprenorphine was more difficult for them to come off of than heroin or methadone. And to top it all off, there seems to be evidence that using opioids longer than 30 days carries a risk of new-onset depression. This is not a very promising profile for a future treatment for depression.

Additionally, the initial statistical analysis done on the first two clinical trials failed to demonstrate that it was more effective than a placebo. Only after a post hoc analysis was there evidence of any statistically significant results. And then it was only with the higher, 2mg, dose. Will that lead to even higher doses of buprenorphine to increase its effectiveness? Read more on the concerns with outcome switching in clinical trials here.

Revising the statistical analysis (outcome switching) of the remaining clinical trial may produce statistically significant results, and if it does, it seems Alkermes intends to argue with the FDA to approve ALKS 5461. On the one hand, I can see where Alkermes would attempt to salvage their “lead product.” But I’m hoping their nearsighted focus on profits and the company’s market value will not blind the FDA to the long-term consequences of using opioids like buprenorphine to treat depression.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Robert Whitaker