04/7/17

Souless Psychiatry

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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 3rd 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.

03/28/17

Reproducibility in Science

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In 2011 a University of Virginia psychologist named Brian Nosek began the Reproducibility Project. He simply wanted to see if the reported problem with reproducing the scientific findings of published research studies in psychology was true. Nosek and his team recruited 250 research psychologists, many of whom volunteered their time to double-check what they considered to be the important works in their field. They identified 100 studies published in 2008 and rigorously repeated the experiments while in close consultation with the original authors. There was no evidence of fraud or falsification, but “the evidence for most published findings was not nearly as strong as originally claimed.”

Their results were published in the journal Science:Estimating the Reproducibility of Psychological Science.” In a New York Times article about the study, Brian Nosek said: “We see this is a call to action, both to the research community to do more replication, and to funders and journals to address the dysfunctional incentives.” The authors of the journal article said they conducted the project because they care deeply about the health of psychology and believe it has the potential to accumulate knowledge about human behavior that can advance the quality of human life. And the reproducibility of studies that further that goal is central to that aim. “Accumulating evidence is the scientific community’s method of self-correction and is the best available option for achieving that ultimate goal: truth.”

The present results suggest that there is room to improve reproducibility in psychology. Any temptation to interpret these results as a defeat for psychology, or science more generally, must contend with the fact that this project demonstrates science behaving as it should. Hypotheses abound that the present culture in science may be negatively affecting the reproducibility of findings. An ideological response would discount the arguments, discredit the sources, and proceed merrily along. The scientific process is not ideological. Science does not always provide comfort for what we wish to be; it confronts us with what is.

The editor in chief of Science said: ““I caution that this study should not be regarded as the last word on reproducibility but rather a beginning.” Reproducibility and replication of scientific studies has been a growing concern. John Ioannidis of Stanford has been particularly vocal on this issue. His best-known paper on the subject, “Why Most Published Research Findings Are False,” was published in 2005. A copy of one of his latest works, “Empirical assessment of published effect sizes and power in the recent cognitive neuroscience and psychology literature,” can be found here.  Szucs and Ioannidis concluded that false report probability was likely to exceed 50% for the whole literature. “In light of our findings the recently reported low replication success in psychology is realistic and worse performance may be expected for cognitive neuroscience. “

A recent survey conducted by the journal Nature found that more than 70% of researchers have tried and failed to reproduce another scientist’s experiments. More than half failed to reproduce their own experiments.  In response to the question, “Is there a reproducibility crisis?” 52% said there was a significant crisis; another 38% said there was a slight crisis. More than 60% of respondents thought that two factors always or often contributed to problems with reproducibility—pressure to publish and selective reporting. More than half also pointed to poor oversight, low statistical power and insufficient replication in the lab. See the Nature article for additional factors.

There were several suggestions for improving reproducibility in science. The three most likely were: a better understanding of statistics, better mentoring/supervision, and a more robust experimental design. Almost 90% thought these three factors would improve reproducibility. But even the lowest-ranked item had a 69% endorsement. See the Nature article for additional approaches for improving reproducibility.

In “What does research reproducibility mean? John Ioannidis and his coauthors pointed out how one of the problems with examining and enhancing the reliability of research is that its basic terms—reproducibility, replicability, reliability, robustness and generalizability—aren’t standardized.  Rather than suggesting new technical meanings for these nearly identical terms, they suggested using the term reproducibility with qualifying descriptions for the underlying construct. The three terms they suggested were: methods reproducibility, results reproducibility, and inferential reproducibility.

Methods reproducibility is meant to capture the original meaning of reproducibility, that is, the ability to implement, as exactly as possible, the experimental and computational procedures, with the same data and tools, to obtain the same results. Results reproducibility refers to what was previously described as “replication,” that is, the production of corroborating results in a new study, having followed the same experimental methods. Inferential reproducibility, not often recognized as a separate concept, is the making of knowledge claims of similar strength from a study replication or reanalysis. This is not identical to results reproducibility, because not all investigators will draw the same conclusions from the same results, or they might make different analytical choices that lead to different inferences from the same data.

They said what was clear is that none of these types of reproducibility can be assessed without a complete reporting of all relevant aspects of scientific design.

Such transparency will allow scientists to evaluate the weight of evidence provided by any given study more quickly and reliably and design a higher proportion of future studies to address actual knowledge gaps or to effectively strengthen cumulative evidence, rather than explore blind alleys suggested by research inadequately conducted or reported.

In “Estimating the Reproducibility of Psychological Science,” Nosek and his coauthors said it is too easy to conclude that successful replication means the original theoretical understanding is correct. “Direct replication mainly provides evidence for the reliability of a result.” Alternative explanations of the original finding may also account for the replication. Understanding come from multiple, diverse investigations giving converging support for a certain explanation, while ruling out others.

It is also too easy to conclude a failure to replicate means the original evidence was a false positive. “Replications can fail if the replication methodology differs from the original in ways that interfere with observing the data.” Unanticipated factors in the sample, setting, or procedure could alter the observed effect. So we return to need for multiple, diverse investigations.

Nosek et al. concluded that their results suggested there was room for improvement with reproducibility in psychology. Yet the Reproducibility Project demonstrates “science behaving as it should.” It doesn’t always confirm what we wish it to be; “it confronts us with what is.”

For more on reproducibility in science, also look at: “The Reproducibility Problem” and “’Political’ Science?” on this website.

03/17/17

Broken Promises with Abilify

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Based upon sales data for the world’s 15 top selling drugs, Abilify was ranked fourth, with $9.3 billion of sales in 2014. Reflect for a moment what this means; an antipsychotic drug had greater worldwide sales than Nexium (for acid reflux) and Crestor (for high cholesterol). While it is an approved medication in the US for bipolar 1 and schizophrenia, it is likely these sales figures reflect it use as an adjunct medication for major depression. Oh, and along with other antipsychotics, it is used off label to treat several other behavioral disorders such as Tourette’s and irritability associated with autism. This popularity is despite the reality that antipsychotics have a high incidence of negative side effects—greater than antidepressants and anti-anxiety medications.

The problems with antipsychotics have been known for a few years. As far back as 2010, Robert Field wrote: “Antipsychotic Medications Are Spelling Legal Trouble for Drugmakers” for the journal Pharmacy and Therapeutics. In 2007, Bristol-Myers Squibb paid $515 million to settle charges of illegally marketing Abilify for children and the elderly, “In contravention of FDA-approved labeling.” But that hasn’t been the end of legal troubles regarding Abilify. On May 3, 2016, the FDA published a safety announcement warning that Abilify (aripiprazole) can trigger impulse-control problems such as “compulsive or uncontrollable urges to gamble, binge eat, shop, and have sex.” These urges reportedly stop when the drug is discontinued or the dose reduced.

These compulsive behaviors can affect anyone who is taking the medicine. As a result, we are adding new warnings about all of these compulsive behaviors to the drug labels and the patient Medication Guides for all aripiprazole products.

The mechanism of action for Abilify is not clearly understood, but researchers think it over-stimulates dopamine 3 (D3) reward receptors, which are mainly located in the limbic system. This in turn triggers the compulsive behaviors. Gaboriau et al. reviewed case reports in Addictive Behaviors and indicated that pathological gambling (PG) appeared as quickly as a few days after Abilify was started; sometimes after an increase in dosage with 7 of the 8 case reports. PG then decreased after Abilify treatment was stopped or decreased; again sometimes as soon as a few days afterwards.

Limitations on the Gaboriau et al. findings included that most of the patients were already gambling before starting with Abilify. Several patients also had a history of substance use disorders. However, the authors noted that the same D3 receptor was implicated in another study by J. E. Ahiskog of the dopamine agonist medications, pramipexole and ropinirole, which are commonly used to treat Parkinson’s disease.

This hyperstimulation would apparently be particularly enhanced in cases of a previous treatment by antipsychotics acting as a dopaminergic receptors antagonist, owing to the up-regulation and the dopaminergic receptor hypersensitivity processes. The partial agonist action of aripiprazole then causes stronger effects. Moreover, the intrinsic dopamine pharmacodynamic activity of aripiprazole imparts it less action agonist than a complete agonist, which could explain why the occurrence of PG is sometimes late or due to dosage increase.

The above concern with Abilify was also supported by the findings of a study by Moore, Glenmullen and Mattison reported in JAMA Internal Medicine. Adverse drug event reports received by the FDA from 2003 to 2012 were reviewed for the six dopamine receptor agonist drugs marketed in the U.S. The review identified 1580 reports of impulse control disorder events, including pathological gambling, hypersexuality, compulsive shopping and others. They also detected weaker signals for antidepressants and antipsychotics.

The Daily Beast reported on a massive tort lawsuit being filed against Otuska and Bristol-Myers Squibb charging that Abilify created a compulsion for sex and gambling. Moreover, the suit claims the drug makers knew of the serious side effects because of required changes in Canadian and European warning labels, but waited for years to warn U.S. consumers. Thomas Moore of the Institute for Safe Medication Practices explained the drug triggers an urge to gamble constantly, sometimes with people with no prior interest. “It might be people starting to spend $300 a week on lottery tickets, and in other cases people will gamble away tens of thousands of dollars.” Moore went on to say:

We live in a society whose rules and laws assume people are responsible for their actions, including running up a large gambling debt. . . But we have scientific evidence that sometimes a drug can trigger a pathological urge to gamble so severe it can ruin someone’s life.

A woman who began using Abilify to aid in treating her PTSD developed a compulsive gambling problem. She used up her unemployment checks, pawned her husband’s automotive tools, and lied about needing money for baby formula. “Nothing was off-limits when it came to getting the money I needed to keep up the ruse.” She’d stuff her bed at night in order to fool her husband into thinking she was asleep when she was actually at the casino playing the slot machines.

Another woman developed hypersexuality. She started with online chatting with men. She became obsessed with sexual fantasies and took sexualized pictures of herself and sent them to select ‘friends.’ “I just couldn’t stop with the pictures and fantasies.” She also went on shopping sprees. Then her husband caught her. “The drug has destroyed my life, my reputation, and the lives of those I love.”

The website RxISK has multiple reports on adverse events with Abilify. “Abilify from the Inside Out” described bouts of akathisia (a state of agitation, distress, and restlessness), unusual aggression or anger, first time episodes of psychosis, suicidality, at least three confirmed suicides, movement disorders such as tremors, and (of course) compulsive gambling. The author said the reports were hard for him to read. Since most of the patients were on several meds, some patients couldn’t be sure that Abilify alone caused the problem. Even stopping Abilify was related to adverse drug events.

The above noted 2007 lawsuit, where Bristol-Myers Squibb paid $525 million to settle charges of illegal marketing, unveiled some of the marketing records for Abilify. Remember, one of the concerns was that it was illegally marketed for use with the elderly. The sales reps for Abilify would invite nursing home staff to picture a new resident, hunched in their chair, staring off into space because of ‘depression.’ “’Who wants to see that when they come to visit Mom on a Saturday?’ the reps would ask. ‘Wouldn’t we like to see her up and about, looking lively?’” The sale pitch worked. One woman wrote the following to RxISK:

I have seen many commercials about how drugs like Abilify can perk people right up. . . So I was not only disappointed and frightened by the results, but felt once again tricked and exploited by the big promises that drug companies make but never seem to keep.

I wish the above concerns weren’t true. But I’ve known individuals whose experiences on Abilify are consistent with the above discussion of its adverse effects. Sadly, even when sanctions are in the millions of dollars, the profits are higher. And it seems the cards are stacked against pharmaceutical companies being held accountable financially. So consumers have to fight against this by refusing to use Abilify and telling others what you have read here. If you are interested in other articles on the problems with Abilify and the other antipsychotics, try: “Antipsychotic Big Bang” or “Abilify in Denial” on this website.

03/7/17

Between a Rock and a Hard Place

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Terry Lynch is an Irish physician and psychotherapist who challenged the commonly held view that psychiatric disorders are legitimate brain disorders. He did so in a brief video that had an interesting take on the issue. He showed where two of the organizations affiliated with the U.S. National Institute of Health (NIH) apparently have different opinions about whether several psychiatric disorders should be considered to be brain disorders.

In his video, “It’s official: Psychiatric diagnoses are NOT known brain disorders,” Lynch gave a screen capture from the “Brain Basics” educational resources page of the National Institute of Mental Health (NIMH). He highlighted the opening statement there, which says: “Welcome. Brain Basics provides information on how the brain works, how mental illnesses are disorders of the brain, and ongoing research that helps us better understand and treat disorders.”  Further down the page is the following: “Through research, we know that mental disorders are brain disorders.” These disorders were said to include depression, anxiety disorders, bipolar disorder, attention deficit hyperactivity disorder (ADHD) and many others.

He also called attention to a second NIH Institute, the National Institute of Neurological Disorders and Stroke (NINDS). The official mission statement of NINDS is “to seek fundamental knowledge about the brain and nervous system and to use that knowledge to reduce the burden of neurological disease.” On the NINDS homepage is search engine where you can search by disorder. Lynch proceeded to show that depression, bipolar and schizophrenia were not listed in the NINDS database as neurological disorders. ADHD does appear in the NINDS, database but was not mentioned by Lynch in his video. You can replicate what I’ve said here be searching the “Brain Basics” page on NIMH and the NINDS database here.

One response to the differences Lynch found would be to say that NINDS attends to neurological disease, while NIMH addresses a different kind of brain dysfunction, namely mental or psychiatric disorders. But that response doesn’t resolve the dilemma. Because the next question becomes what is the difference between neurological disease and mental/psychiatric disorder? Attempting to articulate the difference may have placed psychiatry in a sort of catch-22 situation.

Lynch addressed this dilemma in an essay he wrote, “Psychiatry: Between a Rock and a Hard Place.” His opening statement there was that contrary to their repeated claims of doing so, “psychiatrists do not treat known organic illnesses.” They do not treat known organic brain disorders, which are under the care of neurology and neurosurgery. He said emotional and psychological distress typically comes under the care of counseling or psychology. So where, then, does psychiatry fit in?

Psychiatry is caught between a rock and a hard place—somewhere between the medical specialties treating known brain diseases (neurology and neurosurgery) and the talk therapies of counseling and psychology. Psychiatrists, according to Lynch, invented terms such as “mental illness” or “mental disorder,” and made themselves the experts who would diagnose and treat said illness/disorder. “They have fed the public with unsubstantiated ideas about neurotransmitters, chemical imbalances and brain disorders, ideas which the public have generally believed wholeheartedly.”

The challenge for psychiatry has been to carve out its own distinct identity. Claims that depression and other psychiatric diagnoses are biological illnesses are crucial to psychiatry’s identity and its unmerited position at the top of the mental health pyramid. These assertions separate psychiatry from the talk therapies and ensure that psychiatry has first claim to these “diseases” and the people they diagnose as having them.

He said psychiatry wants to be more closely aligned with the respected medical standing of neurology than to psychology or counseling. But it has to be seen as distinct from neurology to maintain a separate identity. “Specializing in ‘mental illnesses’ and ‘mental disorders’ provides the needed distinction.” Towards that end, Lynch said psychiatry has convinced the general public (and perhaps themselves) that psychiatric disorders are biological illnesses. In the process, they have side stepped “the fact that there is no reliable corroborative scientific evidence for this.”

For over a century, psychiatry has reassured the public that both the necessary understanding and more effective solutions lie just around the corner. “Bear with us, we are almost there,” psychiatry’s catchphrase for the past 100 years and more, buys them more time, every time.

Lynch thought psychiatry would confront a nightmare of their own making if it ever connected brain abnormalities to psychiatric diagnoses. If structural or functional brain abnormalities were ever found to be associated with psychiatric diagnoses, care of those individuals would likely be transferred away from psychiatry to neurology—“a specialty that deals with known brain abnormalities.” He said precedent within medicine would dictate that responsibility for those patients would be transferred to neurology or some other relevant specialty.

Given this, Lynch thinks the best position for psychiatry is to stay exactly where it is. As long as there are no reliable biological abnormalities identified, there is no threat to their position. By claiming that mental disorders are rooted in biology, psychiatry has set itself apart from talk therapies. “As long as no biological abnormalities are reliably identified, there is no threat that their bread and butter will be removed from them to other medical specialties.” Maintaining the myth that biological solutions are imminent, satisfies the public and preserves it’s position.

“If biology isn’t seen as central to the experiences and behaviours that have become repackaged as so-called “mental illnesses,” what special expertise can mainstream psychiatrists claim to possess?” So when psychiatrists defend their pronouncements on depression or any other psychiatric label, they are not just defending a diagnosis. “They are defending themselves, their ideology, their modus operandi and ultimately, their status and role in society as the perceived prime experts in mental health.”

Lynch is not alone in his views of psychiatry and diagnosis. There are clear echoes of the thought of Thomas Szasz in what he says. Peter Breggin, Joanna Moncrieff, Robert Whitaker, Peter Gøtzsche, David Healey, Sami Timimi and others would agree with parts, if not all, of what he asserts. Here, for example, is a blog article by Chuck Ruby for the International Society for Ethical Psychology & Psychiatry (ISEPP), “Blue Illness.” Reflecting on an article that affirmed depression was a mental illness, Ruby noted that for decades, attempts have been made to demonstrate the brain-pathology basis of depression.

Despite the billions of public dollars invested in this research, no such evidence of brain pathology has been discovered. The only thing this research has shown is that our experiences and behaviors are mirrored by changes in the brain. This is something we already knew. Yet, instead of giving up the search and redirecting those monies to more worthy research of real diseases, the mental health industry repeats the worn out pronouncement that discovery is just around the corner! Ironically, if such a discovery came, wouldn’t depression then fall within the medical specialty of neurology, the real medical specialty that studies real brain illnesses?

In the concluding paragraphs of their book, Psychiatry Under the Influence, Robert Whitaker and Lisa Cosgrove wrote that from a scientific standpoint, psychiatry is facing a legitimacy crisis. “The chemical imbalance theory is collapsing now in the public domain.” The former director of the NIMH, Thomas Insel, has written of how second generation psychiatric drug are no better than the first, “which belies any claim that psychiatry is progressing in its somatic treatment of psychiatric disease.”

The disease model paradigm embraced by psychiatry in 1980 has clearly failed, which presents society with a challenge: what should we do next?

Terry Lynch is right. Psychiatry is between a rock and a hard place. But save your sympathy for the patients who are there with it.

02/24/17

Misdiagnosing Substance Use

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Allen Frances doesn’t like the DSM-5 and you can hear him say so here.  He said our mental health system was in a mess. And he is afraid that with DSM-5, it will get even worse. “People who are essentially normal are being diagnosed with mental disorders they don’t have.” Small changes in the diagnostic system can result in tens of millions of normal people qualifying for a diagnosis. He used himself as an example, stating how he would qualify for several of the DSM-5 disorders. Typical symptoms of grief over his wife’s death, lasting beyond two weeks, would have signified him as having a Major Depressive Disorder.

Anther mistake was combining what had been two different diagnoses of substance use in the DSM-IV—Substance Abuse and Substance Dependence—into one: Substance Use Disorder. Substance Abuse was when someone had recurrent, but intermittent, trouble from recreational binges. Substance Dependence was a continuous and compulsive pattern of use, often with tolerance and withdrawal. The majority of substance abusers “never become addicted in any meaningful sense.”

The two DSM IV diagnoses have radically different implications for treatment planning and for prognosis. Artificially lumping them together in DSM-5 forces inaccurate diagnosis, loses critical clinical information, and stigmatizes as addicts, people whose substance problem is often temporary and influenced by contextual and developmental factors.

Hasin et al., “DSM-5 Criteria for Substance Use Disorders: Recommendations and Rationale,” presents the rationale used by the DSM-5 workgroup for substance use disorders for its changes, particularly combining abuse and dependence into one disorder. They recommended the combination as well as dropping one diagnostic criteria (legal problems) and adding one (craving). Two criteria are required to diagnose a Substance Use Disorder. The number of criteria met will indicate mild (2 to 3 criteria), moderate (4 to 5), and severe disorders (6 or more). The following chart, taken from the article, illustrates the changes from DSM-IV to DSM-5.

Frances is not alone in seeing value with two distinct types of substance use disorder. Carleton Erickson in The Science of Addiction noted how the distinction allowed for the differentiation between individuals with drug-related problems who could stop using when they wished (substance abusers), and others who had the disease of chemical dependence. Chemically dependent people have a dysregulation of the mesolimbic dopamine system and generally cannot stop using drugs without intensive intervention into their drug use problems. “According to these criteria, drug abuse in intentional, ‘conscious,’ or voluntary. Drug dependence is pathological and unintended.”

In his article, “DSM-5 Made a Mistake Eliminating Substance Abuse,” Allen Frances indicated the DSM-5 workgroup for substance use disorders based its rationale for dropping Substance Abuse on studies suggesting the distinction was hard to make. He said the results of the studies were not definitive. Moreover, their interpretation was flawed by what he said was a basic DSM-5 misunderstanding of the nature of psychiatric diagnosis. “All DSM disorder overlap with other DSM disorders and also frequently with normality.” Fuzzy boundaries among near diagnostic neighbors are common and not a sufficient excuse to collapse clinically valuable distinctions.

Carleton Erickson’s discussion of the degrees of severity with drug problems helps to illustrate this misunderstanding. He indicated there were mild, moderate and severe forms of both drug abuse and drug dependence. Most people don’t think in terms of severity with substance use problems. You either have a problem or you don’t; you either abuse drugs or you don’t. He then illustrated their relationship to drug-seeking behavior as follows.

Drug Abuse

Drug Dependence

Drug-Seeking

Mild

Little/None

Moderate

Some

Severe

Mild

A Lot

Moderate

Even more

Severe

All the Time

The overlap referred to by Frances occurs between severe drug abuse and mild drug dependence. The inability of psychiatric diagnosis to make a clear distinction here seems to have led to the decision to collapse the abuse and dependence diagnoses into one category in the DSM-5.

I think another overlap between drug abuse and drug dependence happens with regards to self-control. A distinction is necessary between self-control of thoughts, feelings and behavior when drinking and control of the drug intake itself. Any substance use can lead to a loss of self-control over an individual’s thoughts, feelings and behavior. When that loss of control results in recurrent, intermittent trouble, there is a drug abuse problem. The severity of this type of loss of self-control and the related intermittent trouble varies.

Not everyone who abuses a drug experiences the classic sense of losing of control over how much of the drug they use. A loss of control over drug intake—a continuous and compulsive pattern of use—is only evident within drug dependence. And again, the severity of this loss of control over drug intake varies. So I’d adopt Erickson’s degrees of severity with drug abuse and dependence problems as seen below.

Loss of Self-Control in Abuse

Loss of Control over Drug Intake in Dependence

Mild

Moderate

Severe

Mild

Moderate

Severe

A substance abuse problem with severe trouble related to loss of self-control may be indistinguishable from a substance dependence problem with mild loss of control over drug intake. Both people would look at their severe “trouble” and attribute it to drinking or drugging too much. Given an equal motivation to avoid further “trouble,” the substance abuser would likely have an easier time maintaining abstinence. Carleton Erickson said chemical dependence is not a “too much, too often, withdrawal” disease; it’s a “I can’t stop without help disease.” There is a pathological, compulsive pattern to substance use.

There does seem to be a “fuzzy boundary” between Substance Abuse and Substance Dependence. Nevertheless, the distinction still carries some clinical and diagnostic value. I agree with what Allen Frances said: “The change was radical, creates obvious harms, and provides no apparent benefit.” What should clinicians do? Frances suggested they simply ignore the DSM-5 change. He said it was appropriate and clinically preferable to continue making the distinction.

There is nothing sacred or official about the DSM-5 choices — I know because I made the choices for DSM-IV. The ICD coding system is official; the DSM codes are just one groups’ fallible adaptation of them. It is of great significance that the official coding in ICD-10-CM does not follow the DSM-5 decision to eliminate Substance Abuse. Instead, ICD-10-CM retains the DSM-IV terminology and continues to provide separate Substance Abuse and Substance Dependence codes for each of the major classes of substances.

The ICD-11 workgroup, currently in the final stage of development before field tests, will continue to separate Substance Dependence and Harmful Substance Use. The guidelines for dependence are revised and simplified into three diagnostic features: impaired control over substance use; increasing priority in life and physiological features. Severity qualifiers were suggested only for alcohol intoxication. They also introduced a new diagnostic category, with no equivalents in ICD-10 or DSM-5: single episode of harmful use. Frances commented:

The DSM-5 mistake thus places it out of line with ICD-10, ICD-11, previous DSM’s, and well established clinical practice. Clinicians remain truer both to clinical reality and to ICD coding when they ignore the new DSM-5 lumping of substance use disorders and instead continue to distinguish Substance Abuse from Substance Dependence. DSM’s are explicitly meant to be used only as guides, not worshiped as bibles. Clinicians are free to ignore DSM whenever it makes mistakes that go against clinical common sense and the International coding system.

02/14/17

Psychedelic Depression

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You are lying in a comfortable reclining chair in a private room with low lights. You are dressed in your street clothes, but you are also connected to monitors for blood pressure, pulse and oxygen saturation. A medical practitioner locates a vein on your arm and uses a tiny needle to insert a thin, flexible tube into your vein. You barely feel the needle inserted because it doesn’t hit any muscle. The tube is connected to a bag of fluid raised a couple of feet above your head and it delivers a carefully measured dose of ketamine directly into your bloodstream to treat your depression.

The above description is for a procedure called ketamine infusion, as it was described on the Ketamine Advocacy Network website. Further reading suggests you will have an almost ethereal experience. It could include a dissociative effect, an out-of-body sensation. You will appear to be asleep, but in reality your mind is very active. “In a state of deep relaxation, you may find that you’re able to reflect on past traumas or current anxieties in a very calm, matter-of-fact way – with zero emotional pain.” Many patients prefer to let their thoughts wander. They suggest doing whatever maximizes your sense of calm and relaxation, as long as your doctor agrees.

Although most patients find the experience relaxing and pleasant, some can have brief moments of fright. Patients who begin the infusion in a state of high anxiety seem most susceptible to this. Many are desperately pinning all their hopes on ketamine to relieve their suffering, which is totally understandable but can amp up their anxiety. Some patients get very tense at the thought of not being in total control of their thoughts or body. Try your best to relax before the infusion begins.

What’s not to like about the above-described treatment for depression? First, remember that it is not an FDA-approved treatment. Second, ketamine used in higher doses than in an infusion is the club drug favorite, Special K. Third, the antidepressant effect from ketamine is limited and of an unknown origin.

Ketamine is a Schedule III controlled substance, approved as a general anesthetic. As Peter Simons reported, it is not approved by the FDA as a treatment for depression and other mental health concerns because of a lack of clear benefit and limited knowledge of its risks. There is some truth to the fact that as a generic drug, it is not attractive for pharmaceutical companies to develop it as a therapeutic agent; they won’t make billions of dollars with it. But the research for its efficacy in treating depression is mixed. Simons referred to a new study by Voort et al. in the Journal of Affective Disorders that extended the duration of depressive symptom remission, but did not fully remit the depression.  He said:

Only one of the twelve patients experienced remission of depression. The pattern shown by previous studies is similar. Within hours after treatment, patients experience a euphoric release of depression, but depressive symptoms return within a day or two. For some patients, they return worse than before. Additional treatments every day or every week have the same effect, but the effect is not cumulative. Once weaned off the continual weekly ketamine treatments, around 90% of patients relapse. As evidenced by this current study, even with continuous treatment, only a small number of patients experience any benefit.

Adverse effects can include increased symptoms of depression, anxiety, and suicidality. Only seven of twelve participants reported any therapeutic effect, and only one patient experienced remission by the end of the trial. One person died by suicide and another was hospitalized for suicidality. “These results confirm suspicions that ketamine is a dangerous experimental treatment with limited benefits and serious risks.” These seem to be further reasons why the FDA has yet to approve ketamine as a treatment for depression.

The addictive potential with ketamine is a real concern. The fast-action and rapid fading effect of the drug seems to potentiate its psychological dependency. Ketamine is also widely misused in East and South-East Asia. In Ketamine: Dreams and Realities, Karl Jensen, a British psychiatrist and a leading authority on ketamine said it was far more likely to create periods of dependence than other psychedelic drugs. “The risk is certainly very high in comparison with drugs such as LSD, DMT, and psilocybian mushrooms, but it is not more than half of those who like it.”

Tolerance is rapid and marked; and the ability to remember the experience fades. Some users, he said, will continue to take ketamine for its cocaine-like effects, its calming effects or its potential to relieve anxiety or depression. However, the fading effect can lead to using higher doses in order to resume its dissociation experience. Jensen then gave an extended quote from The Essential Psychedelic Guide, by D.M. Turner, who died from a ketamine-related incident. The Erowid report on Turner said that in 1996 Turner drew a hot bath, injected an unknown amount of ketamine “and settled in for the last trip of his life.” He lost consciousness at some point and drowned. Turner wrote:

A major concern regarding safe use of Ketamine is its very high potential for psychological addiction. A fairly large percentage of those who try Ketamine will consume it non-stop until their supply is exhausted. I’ve seen this in friends I’ve known for many years who are regular psychedelic users and have never before had problems controlling their drug consumption. And I’ve seen the lives of several people who developed an addiction to Ketamine take downward turns. After about two years of once-per-week Ketamine use I even found that I had developed an addiction…Amongst those I know who use Ketamine, I’ve seen very few who can use it in a balanced manner if they have access to it…One of the most remarkable things I experienced in becoming aware of and breaking my Ketamine addiction was the intervention of…[psilocybian mushrooms and DMT]. The DMT provided insights into the negative effects Ketamine was having on my life: a reduction in ambition; a reduction in healthy mortal fears, such as the fear of death; as well as a reluctance to confront fears or difficult tasks and situations directly. Frequent use of Ketamine can lure one as an escape since a blissful and fantastic state of fearless, disembodied consciousness is so easily available.

For more discussion of ketamine and its use as a treatment for depression, see: “Ketamine Desperation,” “Family Likeness in Depression Drugs?”, “Ketamine to the Rescue?”, “Falling Down the K-Hole.”

Although ketamine is a generic drug, esketamine (C13H18CINO) is a patented knock-off of ketamine (C13H16CINO) by Janssen Pharmaceuticals, a division of Johnson & Johnson. In August of 2016 esketamine was granted its second designation by the FDA as a Breakthrough Therapy for treating major depression with an imminent risk of suicide. A Breakthrough Therapy Designation expedites the development process of a drug when it demonstrates the potential for substantial improvement over existing therapies of if it for life-threatening conditions.

Esketamine is an intranasal product, not administered by infusion. Like ketamine, it is a general anaesthetic and a dissociative. It acts primarily as an antagonist with the NMDA receptor, but is also a dopamine reuptake inhibitor. It is more potent and is eliminated more quickly from the body than ketamine. There is also some evidence that it has a more dissociative (hallucinogenic) effect than ketamine.

A study published in Biological Psychiatry by Singh et al. reported the efficacy and safety data from one of the completed FDA trials for esketamine. Science Daily quoted Murray Stein, a deputy editor for Biological Psychiatry, as saying the study showed benefits of the drug over placebo and suggested that the lower of the two doses could be equally effective and also safer. “Though the mechanism of ketamine (and esketamine) antidepressant effects remains unclear, this study clearly demonstrates a benefit, at least in the short term, of this drug for treatment-resistant depression.” Additional clinical trials are testing a wide range of doses to determine the optimal dosing, assessing other possible side effects, and seeking to establish the safety of esketamine in the longer term. Unfortunately, clinical trials don’t last long enough for most drugs to clearly establish an adverse effect like addiction.

There are now two separate drugs in development as fast-acting antidepressants, esketamine and ALKS-5461, whose active ingredients can be reasonably inferred to lead to addiction. As was already mentioned, ketamine is currently classified as a Schedule III controlled substance by the DEA, as is buprenorphine, the active ingredient in ALKS-5461. I hope the FDA will acknowledge the very real risk of addiction with these new molecular entities. The seductive allure of a fast-acting antidepressant could override this concern and lead to their approval as antidepressants without this needed warning. If they are approved, they should at least be classified as Schedule III Controlled Substances.

02/3/17

“Political” Science?

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A 2014 study by a well known researcher from Columbia University indicated that “Sexual minorities living in communities with high levels of anti-gay prejudice experienced a higher hazard of mortality than those living in low-prejudice communities.” The press release for the study said it was the first study to look at the consequences of anti-gay prejudice for mortality. The study’s lead author, Mark Hatzenbuehler, said: “The results of this study suggest a broadening of the consequences of prejudice to include premature death.” The authors thought their study’s results highlighted the importance of examining structural forms of stigma and prejudice as social determinants of health and longevity among minority populations. A significant and potentially important finding—except it may not be true.

The original study, “Structural Stigma and All-Cause Mortality in Sexual Minority Populations” by Hatzenbuehler et al. was published in the February 2014 issue of Social Science & Medicine. Another researcher, Mark Regnerus, set out to replicate the Hatzenbuehler et al. study, but was not able to do so. Regenerus included a more refined imputation strategy in his replication, but still failed to find any significant results. “No data imputation approach yielded parameters that supported the original study’s conclusions.” Regenerus said:

Ten different approaches to multiple imputation of missing data yielded none in which the effect of structural stigma on the mortality of sexual minorities was statistically significant. Minimally, the original study’s structural stigma variable (and hence its key result) is so sensitive to subjective measurement decisions as to be rendered unreliable.

Writing for the National Review, Maggie Gallagher said that Regenerus’s failure to replicate the Hatzenbuehler et al. study amounted to a repudiation of that study. She also thought the study was faked. “When social justice displaces truth as the core value of academics, bad things happen to science.” She implied Hatzenbuehler might have slipped a bogus study into a major social-science journal, “confident that nobody would want to review and contest its findings, which so please the overwhelmingly liberal academy.”

Gallagher then referred to Mark Regenerus as an emerging scientific hero; a “modern-day Galileo standing up to the new theology of the Left.” But I think she misses the point. Both Hatzenbuehler and Regenerus are doing exactly what they are supposed to do in science: publishing their results and attempting to replicate the research of others. Henry Bauer, a professor of Chemistry & Scientific Studies at Virginia Polytechnic Institute and State University, describes how the “knowledge filter” in science can help uncover the real failures and confirm the true successes.

Bauer asks what would happen if most scientists rounded off or fudged their findings. What if they thought more about who wanted results and less about what an experiment actually showed? “To understand why science may be reliable or unreliable, you have to recognize that science is done by human beings, and that how they interact with one another is absolutely crucial.” He then went on to describe how frontier science leads to publication in the primary literature.

If those [findings] seem interesting enough to others, they’ll be used and thereby tested and perhaps modified or extended – or found to be untrue. Whatever survives as useful knowledge gets cited in other articles and eventually in review articles and monographs, the secondary literature, which is considerably more consensual and reliable than the primary literature.

Regenerus’s findings themselves have to be replicated; by more than one additional study before Gallagher’s assessment that Regenerus repudiated Hatzenbuehler et al. is confirmed. Concluding the study was faked or bogus based just upon his findings is irresponsible and goes beyond what Regenerus himself said.

Regenerus said the findings of the Hatzenbuehler et al. study seemed to be very sensitive to subjective decisions made about the imputation of missing data, “decisions to which readers are not privy.” He also thought the structural stigma variable itself was questionable, “Hence the original study’s claims that such stigma stably accounts for 12 years of diminished life span among sexual minorities seems unfounded, since it is entirely mitigated in multiple attempts to replicate the imputed stigma variable.” He thought his study highlighted the importance of cooperation and transparency in science.

The unavailability of the original study’s syntax and the insufficient description of multiple imputation procedures leave unclear the reasons for the failed replication. It does, however, suggest that the results are far more contingent and tenuous than the original authors conveyed. This should not be read as a commentary on missing data or on the broader field of the study of social stigma on physical and emotional health outcomes, but rather as a call to greater transparency in science (Ioannidis, 2005). While the original study is not unique in its lack of details about multiple imputation procedures, future efforts ought to include supplementary material (online) enabling scholars elsewhere to evaluate and replicate studies’ central findings (Rezvan et al., 2015). This would enhance the educational content of studies as well as improve disciplinary rigor across research domains.

Regenerus is not a scientific hero and Hatzenbuehler is not a research villain. But two other individuals identified by Gallagher in her article may fit within those categories.

Michael LaCour co-authored a paper along with Donald Green that was published in the prestigious journal Science in December of 2014. The original article abstract said: “LaCour and Green demonstrate that simply a 20-minute conversation with a gay canvasser produced a large and sustained shift in attitudes toward same-sex marriage for Los Angeles County residents.” Green is a highly respected political science professor now at Columbia. LaCour was a political science grad student at UCLA.

Back in September of 2013, Michael LaCour met with David Broockman at the annual meeting of the American Political Science Association and showed him some of the early results of his study. Writing for NYMag.com, Jesse Singal noted how Broockman was “blown away” by some of the results LaCour shared with him. LaCour also told him he was looking to get Donald Green as a coauthor on the paper. Coincidentally, Green happened to be Broockman’s undergraduate advisor when they were both at Yale.

Singal pointed out that LaCour’s results were so noteworthy because they contradicted every established belief about political persuasion. “The sheer magnitude of effect LaCour had found in his study simply doesn’t happen — piles of previous research had shown that.” In early 2015, Broockman decided to replicate LaCour’s findings. The first clue there was something wrong was when he realized the estimated cost for a replication would be a cool million dollars. Where would a grad student like LaCour get the money or funding for a study like that? That first anomaly eventually led to: “Irregularities in LaCour (2014),” a 27 page report he coauthored with Josh Kalla and Yale University political scientist, Peter Arnow.

“Irregularities” is diplomatic phrasing; what the trio found was that there’s no evidence LaCour ever actually collaborated with uSamp, the survey firm he claimed to have worked with to produce his data, and that he most likely didn’t commission any surveys whatsoever. Instead, he took a preexisting dataset, pawned it off as his own, and faked the persuasion “effects” of the canvassing. It’s the sort of brazen data fraud you just don’t see that often, especially in a journal like Science.

Green quickly emailed the journal and asked for a retraction, which he received. When contacted about comments that he had failed in his supervisory role for the study, Green said that assessment was entirely fair: “I am deeply embarrassed that I did not suspect and discover the fabrication of the survey data and grateful to the team of researchers who brought it to my attention.”

LaCour had a job offer as an incoming assistant professor at Princeton rescinded. He also reportedly lied about several items on his curriculum vitae, including grants and a teaching award. You can review a post mortem of the LaCour controversy by Neuroskeptic for Discover Magazine here. Neuroskeptic thought LaCour’s objections to Broockman et al. were weak. He also thought Lacour’s objections to the findings of Broockman et al. failed to refute their central criticism.

Cases of seeming scientific fraud, like that of LaCour, draw attention to themselves when they are discovered. Writing for STAT News, Ivan Orlansky and Adam Marcus described a survey by researchers in the Netherlands of working scientists. They were asked to score 60 research misbehaviors according to their impressions of how often the misbehaviors occur, their preventability, the impact on truth (validity), and the impact of trust between scientists.  The respondents were more concerned with sloppy science than scientific fraud. Fraud, when it occurred, has a significant impact on truth and public trust. But those cases are rare; and detected cases are even rarer. They concluded:

Our ranking results seem to suggest that selective reporting, selective citing, and flaws in quality assurance and mentoring are the major evils of modern research. A picture emerges not of concern about wholesale fraud but of profound concerns that many scientists may be cutting corners and engage in sloppy science, possibly with a view to get more positive and more spectacular results that will be easier to publish in a high-impact journal and will attract many citations. In the fostering of responsible conduct of research, we recommend to develop interventions that actively discourage the high-ranking misbehaviors from our study.

So it would seem that problems with the Hatzenbuehler et al. study are not fraud, but could be due to smaller more pervasive issues in its research, such as a shoddy methodology. The LaCour case catches more attention and generates mistrust because of its apparent fraud. Orlansky and Marcus are right. Although not as flashy as fraudulent research, the smaller, less outrageous research sins are a greater threat to scientific credibility. Gallagher may have let her own ideology influence how she emphasized these two cases, but she was unquestionably right in her concluding remarks:  “Science is not right-wing or left-wing. But to work, it needs scientists fearlessly committed to truth over their preferred outcomes.”

01/24/17

Herding Pharma “Cats”

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The Chinese government released a report in September of 2016 by the State Food and Drug Administration (SFDA) that found fraudulent clinical trial practices on a massive scale. The SFDA concluded that over 80% of clinical trial data was fabricated. The scandal was the result of a “breach of duty by supervision departments and malpractice by pharmaceutical companies, intermediary agents and medical staff.” More than 80% of the applications for the mass production of new medications have been cancelled, with warnings by the SFDA that further evidence of malpractice might still emerge.

Radio Free Asia also reported the SFDA indicated much of the clinical trail data was incomplete at best. But it also failed to meet basic analysis requirements or was untraceable. “Some companies were suspected of deliberately hiding or deleting records of adverse effects, and tampering with data that did not meet expectations.” Apparently, this came as no surprise to industry insiders. “Clinical data fabrication was an open secret even before the inspection.”

Many of the new drugs were combinations of existing ones. Clinical trial outcomes were written beforehand, and their data presented so it agreed with the fabricated outcomes. A doctor at a top Chinese hospital said the problem lay with the failure to implement regulations governing clinical trial data. “Guangdong-based rights activist Mai Ke said there is an all-pervasive culture of fakery across all products made in the country.” Reporting for Pharmafile, Ben Hargreaves said:

The root of the issue is then not regulation, with regulation for clinical trials running on similar lines to Western practises, but in the lack of adherence to them. China’s generic drug industry has struggled with quality problems and therefore there is a temptation for companies to manipulate data to meet standards. The report found that many of the new drugs were found to be a combination of existing drugs, with clinical trials outcomes written beforehand and the data tweaked to fit in with the desire outcomes.

Sadly, clinical trial problems are not unique to China. An editorial published in the British journal The Lancet Psychiatry described multiple issues beginning with how subjects are recruited, moving on to determining what the control group should be, and ultimately defining meaningful outcome measures. Sometimes, trial recruits receive “care” they didn’t agree to. “Researchers and ethics review boards need to examine the ethical arguments and practical procedures from other areas of medicine where consent is problematic.” If such trials are done, regular and rigorous monitoring is essential. Patient safety and autonomy needs to be a priority.

In his discussion of the editorial, Justin Carter elaborated on one of the problems with recruiting subjects. An individual was recruited into a study on three antipsychotics while under a forced commitment order from a judge. “The psychiatrist who recruited him was in charge of the study and was his treatment provider and was also empowered to report on the patient’s progress to the judge.” The individual died by suicide during the drug trial.

The work of Irving Kirsch and others has shown the problem with inert placebos (sugar pills). The side effects from medication make it easy for participants to guess which study group they are in.

And when the trial is over and the data in, do the outcome measures really provide something meaningful for people’s lives? If the ultimate goal is for people to fell better and resume their prior level of functioning, should outcome measures by primarily patient self-reports, clinical assessment, or differences shown by imaging or the as-yet-to-be-clearly-identified biomarkers?

Given the problems running and interpreting psychiatry trials, it is essential to learn how even the most successfully tested interventions work in real clinics with the broad patient population. Implementation, uptake, and effectiveness in real-life settings must be analysed, and delivery of new innovations modified accordingly. Future research should be thought of not as a plain linear process from innovation to trial to implementation, but as a virtuous circle where research feeds into the clinic and vice versa.

Another issue pointed to by Carter was the validity and reliability of the diagnosis or classification system used to determine who to include and who to exclude from the trials. The DSM system, now in its fifth edition (DSM-5), is the current “bible” for assessing and diagnosing problems the psychiatric medications in clinical trials are supposed to “treat” in the U.S. Yet there have been questions about the reliability and validity of the DSM dating from an argument raised by Robert Spitzer and others in the 1970s that ushered in changes still embedded in the DSM-5. Rachel Cooper gave a brief history of the reliability questions with the DSM in “How Reliable is the DSM-5?” You can also refer to “Psychiatry Has No Clothes,” “Where There’s Smoke …”, and  “The Quest for Psychiatric Dragons,” Parts 1 and 2.

A few weeks before the release of the DSM-5, Thomas Insel, then the NIMH Director, announced the NIMH would be “reorienting” its research away from DSM categories. The agency’s new approach is called the Research Domain Criteria (RDoC) project. For now, RDoC is a research framework and not a clinical tool. But NIMH has high hopes for it: “RDoC is nothing less than a plan to transform clinical practice by bringing a new generation of research to inform how we diagnose and treat mental disorders.” While Tom Insel has moved on to work for Alphabet (Google), RDoC is alive and well within NIMH. You can keep up with news about RDoC on the “Science News About RDoC.”

The Science Update for February 16, 2106 noted the March 2016 issue of the journal Psychophysiology would be devoted to the RDoC initiative. Dr. Bruce Cuthbert said the special issue was a unique opportunity for researchers to engage with one another and reflect on work being done in various laboratories throughout the country. He thought it was encouraging to see many investigators already engaged in the kind of work RDoC advocates. “What this shows is that while the RDoC acronym may be new, the principles behind RDoC are certainly not new to psychiatric research.”

If the principles behind RDoC are not new to psychiatric research, how can it bring “a new generation of research to inform how we diagnose and treat mental disorders” in order to transform clinical practice? It sounds a lot like using the same deck of cards to just play a new card game. RDoC may not be the transformative framework it’s touted to become.

Added to these issues is the failure of pharmaceutical companies to publically report the results of clinical trials, as they are required by law to do. New reporting rules will take effect on January 18, 2017. But advocates for transparency in clinical research have cautioned the success of the new rules will depend upon the willingness and vigor of government enforcement of those rules. The failure to enforce the existing rules, which went into effect in 2008, led to widespread noncompliance with reporting requirements. If the FDA had fined the violators, they could have collected an estimated $25 billion.

Reporting for STAT News, Charles Piller said studies have indicated only a small fraction of trials will comply with the law. Yet there are no current plans to increase enforcement staffing at the FDA and NIH. That’s a big problem, according to Ben Goldacre, an advocate for full disclosure in clinical research. Francis Collins, the NIH director said they are serious about this and will withhold funds, if needed. “It’s hard to herd cats, but you can move their food, or take their food away.”

The legislation that created ClinicalTrials.gov emerged from numerous cases of drug manufacturers withholding negative trial results, making drugs look more effective and less harmful. Efforts to market the antidepressant Paxil for teenagers more than a decade ago stimulated the push for better reporting. A recent analysis in the journal BMJ found that GlaxoSmithKline, Paxil’s manufacturer, failed to disclose 2001 data showing the drug to be no more effective than a placebo, and was linked to increased suicide attempts by teens.

Writing for Time, Alexandra Sifferlin reported on a new study that suggested many of the medical reviewers for the FDA go to work for the drug companies they oversaw while working for the government. One of the study’s authors said: “I don’t think there is overt collusion going on, but if you know in the back of your mind that a major career opportunity after the FDA is going to work on the other side of the table, I worry it can make you less likely to put your foot down.”

Returning to the Francis Collins metaphor, it seems that the willingness to try and herd Pharma cats is dependent on whether or not you are afraid they will scratch you in the attempt.

01/13/17

Iatrogenic Gun Violence

© StephanieFrey | stockfresh.comfresh eggs. Araucanas are also known as the Easter Chicken for the blue or greenish colored eggs they lay.

Whenever I read about horrific violence like the incident in the Fort Lauderdale airport, I wonder what role psychiatric medications played. I wonder if the violent behavior was iatrogenic—was it caused by psychiatric medications? This question will sound counter intuitive for many people. Surely the reverse is true. Psychiatric medication and proper diagnosis should have prevented it. Let’s see if it is.

Esteban Santiago was deployed to Iraq from April 2010 to February 2011 with the 130th Engineer Battalion, the 1013th Engineer Company of the Puerto Rico National Guard. After flying from Alaska to Fort Lauderdale Florida, he retrieved his baggage, which incidentally contained a semi-automatic handgun. Santiago had followed proper protocol, checking the weapon with TSA. He went into the men’s bathroom, loaded his weapon and opened fire in Terminal 2 of the airport, killing five people and wounding six others. A witness said he was just randomly shooting people, with no rhyme or reason to it.

Family members reported that he was a changed man when he returned from Iraq. His aunt said his mind was not right. At times he seemed normal, but other times he seemed lost. In Iraq, his unit cleared roads of improvised explosive devices and maintained bridges. Two people in his unit died while he was in Iraq. His aunt said: “He talked about all the destruction and the killing of children. He had visions all the time.” He had changed.

His brother Bryan confirmed that recently Esteban was hallucinating, but said he was receiving psychological treatment. Bryan said he believes the shooting rampage resulted from mental issues that surfaced after the Iraq tour. When Esteban’s tour ended, he was hospitalized for mental problems. Upon his release, he went to Puerto Rico where his father was ill and eventually died. While in Puerto Rico, he received mental health therapy. Esteban eventually moved to Alaska, where he joined the Alaska National Guard in November 2014. He was discharged in August of 2016.

Over the course of 2016, Santiago was repeatedly reported to Anchorage police for physical disturbances. In January of 2016 he was arrested and charged with assault and criminal mischief after an argument with his girlfriend. He allegedly yelled at her while she was in the bathroom and broke down the bathroom door. She told investigators that he tried to strangle her and struck her on the side of the head.

Santiago pleaded no contest to criminal mischief and assault charges. Under a deferred prosecution agreement, his charges would have been dismissed if he complied with the conditions. He was due back in court on March 28th, 2017 to assess his progress.

While living in Alaska, Esteban continued to receive psychological treatment, according to his brother. Although his girlfriend alerted the family to the situation in Alaska, Bryan said he did not know what mental health problem Esteban was being treated for; they never spoke about it by phone.

His son was born in September of 2016. In November of 2016, Esteban walked into an FBI office in Anchorage to report that his mind was being controlled by a U.S. intelligence agency. He told officials he had a firearm in his car, along with his newborn son. Santiago was checked into a mental health facility; his firearm was logged as evidence for safe keeping. The infant’s mother came for their child. FBI special agent Marlin Ritzman said:

During the interview, Mr. Santiago appeared agitated, incoherent and made disjointed statements. Although he stated he did not wish to harm anyone, as a result of his erratic behavior our agents contacted local authorities, who took custody of Mr. Santiago and transported him to the local medical facility for evaluation.

After conducting database reviews, interagency checks and interviews with his family members, the FBI closed its assessment of Santiago. Agents found no ties to terrorism during their investigation. A CNN senior law enforcement analyst and former FBI assistant director said Santiago hadn’t been adjudicated a felon and he hadn’t been adjudicated as mentally ill. So they couldn’t keep his weapon. The Walther 9-millimeter pistol was returned to him in the beginning of December. Authorities told CNN it was the pistol he used in the shooting incident in Fort Lauderdale.

Typically, Esteban was considered to be a calm young man who was never violent. Recently he began selling his possessions, including his car. Friends and associates noticed more erratic behavior. He bought a one-way ticket to Fort Lauderdale and packed his pistol and two magazines. His carryon bag with the pistol was his only luggage. He flew from Anchorage to Minneapolis to Fort Lauderdale. He retrieved his bag from the baggage claim area and went into a men’s room stall to load his pistol.

He shot the first people he saw, going up and down the carousels of the baggage claim, shooting through luggage to get at people that were hiding. He thinks he fired 15 bullets, aiming at his victim’s heads. A witness said Esteban showed no remorse. He didn’t say anything. “No emotion, no nothing. About as straight-faced as you get.” Afterwards, he just lay face down, spread eagle, waiting for the deputies to come and get him.

The above report was pieced together from information contained in the following reports by The New York Times here,  NJ.com here, CNN here, and NPR here.

There was no explicit mention of Santiago’s repeated involvement in “psychological treatment” involving psychiatric medications, but it highly probable he was taking psychiatric medication of some sort. The lack of any mention of his being prescribed medication may simply be due to confidentiality regulations. Or this silence could be due to the chicken-and-egg argument often applied to incidents involving violence and individuals with known psychiatric problems. Their mental illness, not the drugs to treat it, caused their horrific behavior.

Several psychiatrists have voiced concerns with psychiatry, its over reliance upon medication and denial of serious adverse effects from medication, like violence and suicide. Joanna Moncrieff said she’s sad her profession has not taken the harms drug treatments can do more seriously. She said it has a long history of ignoring the adverse effects of drugs, or attributing them to the underlying disease—of blaming the patient instead of the drug. “Too many psychiatrists have just accepted that drug treatments are good, and have not wanted to contemplate that actually these treatments could be harmful.”

First and foremost, she said, psychiatry needs to adopt a drug-centered model for understanding its drug treatments and what they do to people. Psychiatrists need more information, knowledge and training on what the drugs do—what effects they produce in people; “how they change the way that people think and feel and what sort of impact those changes have on people’s lives.” Watch two brief videos of her expressing her concerns here. You can read more about her “drug-centered model” here on this website: “A Drug is a Drug is a Drug.”

Peter Breggin has raised concerns with the association of violence and antidepressants since the early days of Prozac. In his 1991 book, Toxic Psychiatry, Dr. Breggin related newspaper and scientific reports pointing to an association between Prozac and “compulsive, self-destructive and murderous activities.” He said then he was personally familiar with several cases of compulsive suicidal or violent feelings that developed after taking Prozac. Over the years, his familiarity grew.

In “Psychiatry Has No Answer to Gun Massacres,” Breggin described how the Columbine High School shooter, Eric Harris had a “therapeutic” level of Luvox (fluvoxamine) in his body at the time of the murders.  He had a dose increase in his medication 2 ½ months before the assault and showed signs of drug toxicity five weeks before the event. James Holmes, the Aurora Colorado theater shooter, was in psychiatric treatment with the medical director of student health services, who was considered an expert on campus violence. She was concerned enough about Holmes to report him to the campus police and the campus threat assessment team a few weeks before the assault. When the assessment team suggested putting him on a 72-hour involuntary hold, she rejected the idea. “When Holmes quit school, the school washed its hands of all responsibility for him.”

In a 2010 journal article, “Antidepressant-Induced Suicide, Violence, and Mania: Risks for Military Personnel,” Dr. Breggin related how the adverse effects described in the 2009 edition of the Physicians’ Desk Reference for Zoloft (sertaline) resembled the most frequent psychiatric disorder associated with combat—PTSD—with its hyperalert overstimulated symptoms. He said identical or nearly identical warnings can be found in all antidepressant labels. “All these potentially dangerous symptoms are also commonly seen in PTSD in military personnel, posing the risk of worsening this common military disorder.”

Looking at the revised 2016 medication guide for Zoloft, we see that nothing much has changed with regard to adverse effect warnings. It said Zoloft and other antidepressant medications could increase suicidal thoughts or actions. Symptoms needing immediate attention included: acting aggressively or violent, feeling agitated, restless angry or irritable, an increase in activity or talking more than what is normal, acting on dangerous impulses, trouble sleeping, new or worse anxiety or panic attacks, trouble sleeping, other unusual changes in behavior or mood.

A condition known as “serotonin syndrome” has symptoms such as: agitation, hallucinations, coma and other changes in mental status. Symptoms of potential manic episodes included: greatly increased energy, racing thoughts, unusually grand ideas, severe trouble sleeping’s, reckless behavior, excessive happiness, talking more or faster.

Dr. Breggin concluded his article with the following cautions and recommendations. He said there was a strong possibility the increased suicide rates among active-duty soldiers were in part caused or made worse by the widespread prescription of antidepressant medication. Alone, they can cause a stimulant-like series of adverse effects. “These symptoms of activation can combine adversely with similar PTSD symptoms found so commonly in soldiers during and after combat.” He recommended the military study the relationship between psychiatric drug treatment and suicide as well as random or personal violence. He also suggested that antidepressants should be avoided in the treatment of military personnel.

Another emerging concern of an association between antidepressants and violence is in the research done by Yolande Lucire. She suggested that mutations in CYP450-encoding genes contributed to problems metabolizing psychiatric drugs, and thus were contributing factors in three cases of antidepressant-induced akathisia-induced homicide. The cytochrome P450 family of enzymes is responsible for metabolizing most of the drugs used in psychiatry. You can read her article here. You can also find another article: “Psych Drugs and Violence” on this web site. Within that article you will find a link to another article by Lucire on antidepressant-induced akathisia-related homicide and the CYP450 genes.

Hasn’t there been enough evidence associating suicide and violence with psychiatric medications, especially antidepressants, for open dialogue and more comprehensive scientific research into this public health issue? How many more Columbines, Auroras and Fort Lauderdales need to happen before we begin to address the association of psychiatric drugs and violence?

01/3/17

Like Footprints in the Sand

© koca777 | stockfresh.com

An amazing letter was sent to the president of the American Psychiatric Association (APA) on August 1, 2016 by no less than sixteen well known medical and psychological professionals from around the globe. They are attempting to have an article published in a 2004 issue of the American Journal of Psychiatry retracted. Their concern was that a recent analysis of that study found “gross misrepresentations” made in the article with regard to use of citalopram (Celexa) in treating child and adolescent depression. As of the beginning of December of 2016, the original journal article is still available; nor does there seem to have been any response to the letter requesting the retraction. Perhaps the APA hopes that if they simply ignore the issue, it will just go away.

The article was ghostwritten by agents of the manufacturer and seriously misrepresented both the effectiveness and the safety of citalopram in treating child and adolescent depression.

The letter was addressed to Dr. Maria Oquendo, the 2016 President of the APA. The coauthors of the letter expressed concerns with the “gross misrepresentations” made within the 2004 article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents.”

Since the publication of the analysis alleging the problems with the 2004 Celexa article, there were three different attempts to have it retracted. In response to a May 9, 2016 letter, the current editor for the American Journal of Psychiatry refused to retract the original study. Two other attempts, one to the former editor of the American Journal of Psychiatry who accepted the article, received no response. Given the failure of the American Journal of Psychiatry to retract the article, the letter’s authors are concerned that children and adolescents are put at risk of unnecessary harm because well-intentioned physicians who continue to prescribe citalopram to children and adolescents are being misled.

The 2004 citalopram study said it provided evidence that “citalopram produces a statistically and clinically significant reduction in depressive symptoms in children and adolescents.” It was said to be superior to placebo and the adverse events were mild.

In conclusion, citalopram treatment significantly improved depressive symptoms compared with placebo within 1 week in this population of children and adolescents. No serious adverse events were reported, and the rate of discontinuation due to adverse events among citalopram-treated patients was comparable to that of placebo. These findings further support the use of citalopram in children and adolescents suffering from major depression.

Yet there have been a series of lawsuits against Forest Laboratories, the manufacturer of Celexa, because of its serious side effects; and for Forrest’s failure to warn about the risks when using Celexa and other SSRIs. Drugwatch noted that Celexa is the best-selling antidepressant in 13 countries. Yet it has been linked to several congenital birth defects as well as autism. FindLaw noted evidence that Celexa and other antidepressants have been linked to an increased risk of suicidal behavior in patients under the age of 25.

Forest Laboratories also pleaded guilty in a 2010 criminal case for misbranding Celexa for a use not approved by the FDA. “According to the Department of Justice, Forest Pharmaceuticals had illegally promoted Celexa for the treatment of depression in children and adolescents. The company also pleaded guilty to obstructing justice and distributing an unapproved drug.” Forest Pharmaceuticals was fined $150 million.

A class action law suit, Celexa and Lexapro Marketing and Sales Practice Litigation, was brought by plaintiffs who alleged that Forest Laboratories misrepresented the safety and efficacy of Celexa and Lexapro when marketing the drugs for off-label pediatric use. Over 63,000 documents from Forest were deposited in a database maintained by the plaintiff’s attorneys. Jureidini, Amsterdam and McHenry reviewed 750 internal documents from this database in their 2016 article for the International Journal of Risk & Safety in Medicine.

They found that the published article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” contained efficacy and safety data that was inconsistent with the protocol criteria. Although the published article concluded citalopram was safe and significantly more efficacious than placebo for children and adolescents, the outcome measures “showed no statistically significant differences between citalopram and placebo.”

Unreported procedural deviations contributed to the claimed statistical significance of the primary outcome and negative secondary outcomes were not reported. Moreover, post hoc measures were introduced; and adverse events were misleadingly analyzed. The Wagner et al. citalopram study failed to mention five citalopram-treated subjects who discontinued treatment due to hypomania, agitation, or akathisia. “None of these potentially dangerous states of over-arousal occurred with placebo.” There were also many more adverse gastrointestinal events for citalopram than placebo. Yet the final report grouped the data in a way that masked the evidence for potential gastrointestinal intolerance.

In conclusion, corporate mischaracterisation of clinical trial results is of concern in psychiatry where outcome measures are more subjective and easily manipulated. Because few industry-sponsored studies gain public scrutiny and even fewer are ever formally retracted, it is important to make these articles transparent to correct the scientific record. It is furthermore imperative to inform the medical community of mischaracterized data that could lead to potential harm to children and adolescents who are vulnerable to the effects of medication on the growing brain and may increase suicidal thinking and behaviour.

STAT News reported the retraction request comes after years of controversy over the extent to which some drug makers massaged clinical studies to broaden their medicines’ market. Four years ago, GlaxoSmithKline paid $3 billion to settle civil and criminal charges of “preparing, publishing, and distributing a misleading journal article” about the use Paxil with children and adolescents. “The pill had not been approved for that use and the study cited by federal authorities had been ghostwritten.” David Healy, John Nardo, and Jon Jureidini, three of the sixteen individuals who submitted the letter to the APA requesting that the 2004 citalopram study be retracted, have been actively involved in critiquing the misrepresentation of Study 329 and attempting to get it retracted as well. See a series of articles Healy has written on this issue here, in the Mad in America archives.

After a running a gauntlet of reviews, Le Noury et al. were able to successfully publish a reanalysis of Study 329 in the British Medical Journal. But getting there wasn’t easy, see: “Restoring Study 329: Letter to BMJ” and “The Troubled Life of Study 329: Consequences of Failure to Retract.” However, the original article, “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression, A Randomized Controlled Trial,” was never retracted by Journal of the American Academy of Child and Adolescent Psychiatry (JAACAP).

Hmmm. Perhaps my opening comment that the APA is hoping the request to withdraw the 2004 citlopram article, “A Randomized, Placebo-Controlled Trial of Citalopram for the Treatment of Major Depression in Children and Adolescents,” wasn’t all that smarmy. They could be hoping that it will just fade away like footprints in the sand.