Tag: Ronald Pies

09/20/22

The Death of the Chemical Imbalance Theory?

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

04/28/17

Huffing and Puffing at Anti-Psychiatry

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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.

02/16/16

Nearsighted Drug Development

© Antonio Gravante | Dreamstime.com
© Antonio Gravante | Dreamstime.com

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.