08/3/18

Lies, Damn Lies and Autism Statistics

The Center for Disease Control and Prevention (CDC) recently published a study, “Prevalence of Autism Spectrum Disorder,” that said the overall prevalence rate for Autism Spectrum Disorder (ASD) in the US was 16.8 per 1,000 (one in 59) children who were 8 years old in 2014. Estimates of ASD increased from one in 150 children during 2000-2002 to one in 68 during 2010-2012. This means the prevalence of ASD doubled in the twelve years between 2000 and 2012; then it increased another 16% between 2012 and 2014. One autism expert said those rapid increases were not believable, and even “preposterous.”

Darold Treffert made the above comments in his article for Scientific American, “We Need to Stop Moving the Goalposts for Autism.” Dr. Treffert is an expert on savant syndrome and wrote two books on the topic. He was also a consultant for the movie Rain Man. He believes the reported increases in ASD were the result of moving the goalposts in diagnosis by diluting the condition and expanding the definition of ASD.

Problems he pointed to in the CDC study included the fact that figures included what he called “educational autism,” meaning a diagnosis made by teachers or educational specialists; and “medical autism,” a diagnosis based on review of available medical records. “There are no actual in-person evaluations.” Another issue he pointed out was the extremes of prevalence reported between states within the Autism and Developmental Disabilities Monitoring (ADDM) Network used for the CDC study. New Jersey, one of the eleven ADDM sites in the US, reported a prevalence of 2.93 percent for ASD, more than double that of Arkansas at 1.31 percent.

From my perspective as an observer of “autism” for over 60 years, I do believe there is an actual increase in the number of cases of autistic disorder, but it is not an epidemic. And it has not been an increase of 31 percent in two years here in Wisconsin, for example, or a more than 150 percent increase in the U.S. in the past decade. That is simply not believable. Instead much of that “epidemic” is a dilution of the rigor of the criteria for autism.

He noted some examples of misdiagnosis, and said the first step is to make a correct diagnosis. The broader and less precise the diagnosis becomes, the less chance of finding subgroups “among increasingly heterogeneous, diluted diagnostic groups.” He believes autism is a group of disorders, rather than a single disorder. In order to detect autism with precision Treffert said we need to start calling things by their right names. “The present method of assessing prevalence in the U.S. is not doing that well since we keep moving the goalposts.”

Treffert referred to another Scientific American article by Simon Baron-Cohen, “Is It Time to Give Up on a Single Diagnostic Label for Autism?” When reviewing the rationale for a single diagnostic label for ASD, Baron-Cohen said the term spectrum in ASD refers to the heterogeneity in autism. Although all autistic individuals share certain core features, “there are huge disparities in many areas.” This heterogeneity is part of the meaning of the term “spectrum.” He then pointed to other benefits of the ASD label:

It allows the clinician to describe the person without shoehorning them into a rigid subgroup. Its flexibility also allows for individuals who previously transitioned between different subgroups. And it reduced the risk that service providers might exclude a person because they didn’t meet the eligibility criteria based on a rigid subtype. So, the consensus among clinicians is that the addition of the word “spectrum” was helpful and long overdue. Most clinicians therefore find it useful to have the flexibility of the very broad single diagnostic label.

He then turned to the downside of a single diagnostic label. The American Psychiatric Association combined what had been Asperger Syndrome (AS) with classic autism in the DSM-5, believing the diagnosis of AS was unreliable. Hindsight suggests that wasn’t the problem. Rather, the contrast between AS and classic autism had value and “perhaps should have been retained.” He suggested using a typology of subtypes within ASD. “Under this approach, we could keep the single umbrella category called the autism spectrum and within this have type 1, type 2, etc.”

Treffert commented that the search for a reliable, consistent measure of autism prevalence occurred outside the U.S., as well. He referred to a different set of researchers in “Global Data on Autism Spectrum Disorders Prevalence” whose data for ASDs suggested the global rate was around 1.7 per 1,000 (one in 588), not the 16.8 per 1,000 (one in 59) reported by the CDC study. The authors noted in many developing countries the reported rates of ASD are significantly lower than in developed countries. “Whether this truly reflects an absolute low prevalence, deficits in diagnostic skills, maladaptation of diagnostic criteria as it relates to cultural differences in behaviour, or under sampling are issues that continue to be discussed.” Treffert added there is also an inconsistency between how the DSM-5 and the World Health Organization’s International Classification of Diseases (ICD) define ASD.

Allen Frances, the chair for the DSM-IV, added another perspective into the autism “epidemic” in his book, Saving Normal. He said before the DSM-IV, the diagnosis of autism was extremely rare. But the DSM-IV broadened the concept of autism by introducing Asperger’s disorder. And prevalence rates are extremely sensitive to any change in how a psychiatric disorder is defined. “The twentyfold increase in just twenty years occurred because diagnostic habits had changed radically, not because kids were suddenly becoming more autistic.”

As chair of the DSM-IV Task Force, I deserve blame for not having anticipated the rush to overdiagnose Asperger’s. It would have been useful in advance to predict the changes in diagnostic rates and to explain their causes. We should have proactively taken steps to educate the public and the media about what the labels mean and what they don’t mean—that kids hadn’t changed, just the way they were being diagnosed. It’s a lot easier to trigger a fad then end one.

The prevalence of autism surely came from improved surveillance and identification by doctors, teachers, families and patients. Some of the increase was also because of the introduction of Asperger’s disorder, “a new diagnosis that greatly broadened the concept of autism.” But Frances estimated that about half of the increase was due to the service opening provided—“children get the diagnosis incorrectly because it is the ticket to more attention in the school system and more intense mental health treatment.”

It would be better if school decisions were not so closely coupled to a psychiatric diagnosis that was developed originally only for clinical, not for educational, purposes. Many of the mislabeled kids do get special attention; they just don’t need the extra added stigma that comes with an incorrect diagnosis of autism.

Frances also pointed out another issue leading to the drastically high prevalence rate found by the CDC study: epidemiological miscount. He said every so often we hear about the climbing rates of some psychiatric disorder, which in this case is autism. These rates are generated by a psychiatric epidemiologist, “using a method that is inherently flawed and systematically biased in the direction of overreporting.” Epidemiological studies, like that conducted by the Autism and Developmental Disabilities Monitoring (ADDM) Network, rely on lay interviewers with no clinical experience and no ability to determine whether symptoms are clinically meaningful or not. “They make their diagnoses of psychiatric disorders based upon symptoms counts alone with no consideration of whether the symptoms are severe or enduring enough to really warrant diagnosis or treatment.”

The ADDM study, as Treffert pointed out, had no in-person interviews. The ADDM staff reviewed records and abstracted information from “comprehensive evaluations” that were completed in the local communities. A child was considered to meet the case definition for ASD,

If he or she displays behaviors, as described on one or more comprehensive evaluations completed by community-based professional providers, consistent with the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision (DSM-IV-TR) diagnostic criteria for autistic disorder; pervasive developmental disorder–not otherwise specified (PDD-NOS, including atypical autism); or Asperger disorder.

Allen Frances noted where this always results in greatly inflated rates. Psychiatric symptoms in mild form are widely distributed in the general population. From time to time almost everyone will experience isolated or mild symptoms of a psychiatric disorder. “But isolated or mild symptoms alone do not define psychiatric disorder—they must cohere over time in a specified way and also cause significant distress or impairment.” Epidemiological studies, Frances said, regularly disregard these factors. “They mistakenly diagnose as psychiatric disorder symptoms that are mild, transient, and lacking in clinical significance.”

Results generated in this rough-and-ready way are no more than an upper limit on the prevalence of any given mental disorder. They should never be taken at face value as a true reflection of the real extent of illness in the community. Unfortunately, the exaggerated rates are always reported without proper caveat and are accepted as if they are an accurate reflection of the real prevalence of psychiatric disorder. Disraeli exaggerated only a tad when he said: “There are three kinds of lies: lies, damned lies, and statistics.”

05/31/16

To Be or Not to Be Bipolar

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

12/31/15

Medieval Alchemy

Three years after the publication of the fourth edition of the DSM in 1994, the US became the only country in the world to allow direct to the consumer advertising of pharmaceuticals. Now there’s New Zealand. Soon after the approval, pharmaceutical advertising was everywhere in the US. Over the next decade, from 1997 to 2007, drug companies tripled their spending on marketing. Everyday problems were being portrayed as unrecognized psychiatric disorders. The chair of the DSM-IV, Allen Frances, admitted they had failed to anticipate how easily their manual could be utilized to promote pharmaceutical sales. They were not able to stem the flood of “false demand” instigated by the marketing done by drug companies. “Within a few years, it was clear the drug companies had won and we had lost.”

We should have been far more active in educating the field and prospective patients about the risks of overdiagnosis. There should have been prominent cautions in DSM-IV warning about overdiagnosis and providing tips on how to avoid it. We should have organized professional and public conferences and educational campaigns to counteract drug company propaganda. None of this occurred to anyone at the time. No one dreamed that drug company advertising would explode three years after the publication of the DSM-IV or that there would be the huge epidemics of ADHD, autism, and bipolar disorder—and therefore no one felt any urgency to prevent them. . . . We missed the boat. (Allen Frances, Saving Normal, p. 74)

Frances said the evidence for this diagnostic inflation is clear. There has been a fortyfold increase in childhood bipolar disorder. Autism diagnoses have increased twentyfold. “Attention deficit/hyperactivity has tripled; and adult bipolar disorder doubled.” The result has been huge profits for the drug companies.

At the very top of the Pharma hit parade are the antipsychotics at a resounding $18 billion a year. Antidepressants produce a hardy $12 billion a year, despite the fact that many are now off patent and sold in cheaper generic versions. Fifteen years ago, stimulants were a rounding error in drug company sales at a measly $59 million a year. Now with direct-to-consumer advertising and heavy marketing to doctors, sales have been juiced up to a hefty $8 billion a year. And because primary care doctors love to prescribe them, antianxiety agents are eight in sales among drug classes—even though they probably do much more harm than good. (Saving Normal, p. 105)

Patients regularly misdiagnosed themselves and asked their doctor for “the magic pill that would correct their chemical imbalance,” just as the advertisements suggested. And as requested, doctors prescribed the medications. “Patients who requested a drug they had seen advertised were seventeen times more likely to walk out of the office with a prescription.” Primary care physicians (PCPs), such as general practitioners, obstetrician-gynecologists and pediatricians, now prescribe most of the psychiatric drugs in the US.

Using data from August 2006 to July 2007, Ryan DuBosar noted in “Psychotropic drug prescriptions by medical specialty” that 59% of the psychotropic prescriptions were written by PCPs. Breaking down the drug by class, PCPs prescribed 37% of the antipsychotics, 52% of the stimulants, 62% of the antidepressants and 65% of the anxiolytics (anti-anxiety meds). Frances said: “Too often, drugs are used promiscuously in a way that approximates the quackish practice of medieval alchemists.”

On November 17, 2015, the American Medical Association (AMA) adopted a new policy that calls for a ban on direct to the consumer advertising of prescription drugs. The new policy calls for a physician task force and launching an advocacy campaign to promote prescription drug affordability.

The AMA Board Chair-elect, Patrice Harris, said the vote reflects concerns among physicians about Pharma’s commercially-driven promotions and the impact of marketing costs in escalating drug prices. She said direct-to-consumer advertising also created a demand for new and more expensive drugs, even when these drugs may not be appropriate. “Patient care can be compromised and delayed when prescription drugs are unaffordable and subject to coverage limitations by the patient’s health plan. In a worst-case scenario, patients forego necessary treatments when drugs are too expensive.”

Reporting for Reuters, Susan Kelly noted that the AMA did not say how the ban could be overturned. There have been a series of court decisions determining that the ads are a form of commercial speech protected by the U.S. Constitution. PhRMA, the largest trade group for the pharmaceutical industry in the US, said the ads increase consumer awareness of available treatments for diseases. PhRMa spokesperson, Tine Stow said: “Providing scientifically accurate information to patients so that they are better informed about their health care and treatment options is the goal of direct-to-consumer pharmaceutical advertising about prescription medicines.” REALLY?

Allen Frances said that Big Pharma seems to feel it is above the law. “Almost all of the companies have absorbed huge fines and even criminal penalties as punishment for their illegal sales practices. He published a chart in Saving Normal that he referred to as the drug company hall of shame. It contained information on fines and settlements by Pharma for off-label promotion (which is illegal at this time) as well as shady marketing and fraudulent misbranding. The sum total of the fines between 2004 and 2012 was $12.06 billion.

Yet a Pharma company has been in court attempting to assert that it has “a constitutional right to share certain information about its products with doctors.” The drug companies have been increasing their pressure on the FDA to relax its guidelines around off-label marketing. See “Pharma Goes to Court” for more on this issue.

Frances said it is our fault that we allowed drug companies to prey on our weakness. “Diagnostic questions should be decided by what is best for the patient, not what is best for the doctor or the APA [American Psychiatric Association] or Pharma or the consumer group.” All this could be reversed if we had the political will to do so. He proposed fourteen ways to tame Pharma. The top six were:

No more direct-to-consumer advertising on TV, in magazines, or on the internet.
No more drug company-sponsored junkets, dinners, promotional gifts, or continuing medical education for doctors or medical students.
No more financial support for medical professional organizations.
No more beautiful salespeople congregating in the doctors’ waiting room.
No more free samples.
No more off-label marketing.

These changes strike at the heart of Pharma’s marketing strategy, so it won’t be easy to get Congress to approve the changes. Pharma outspends all other industries in its lobbying efforts. Since 1998, the pharmaceutical industry has spent $3,716,474,293 lobbying Congress. In 2017 Pharma has spent $209,395,967. Annually they outspend all other industries. See OpenSecrets.org for more information on this issue. The OpenSecrets data was updated to reflect spending since this article was originally published in 2015.

07/29/15

Pharma Goes to Court

Okay, stay with me on this one. I want to talk about some jousting going on in the court system between Pharma and regulatory agencies, like the FDA. Amarin Corporation is suing the FDA, saying that the FDA violated its first amendment rights to free speech. The company argued that it has “a constitutional right to share certain information about its products with doctors.” Lawyers for the company believed this was the first time a manufacturer has sued the agency before the FDA ruled against them. The future “blockbuster” at the center of this fight is an omega-3 fatty acid product derived from fish called Vascepa. That’s right prescription strength fish oil.

As a matter of fact, according to Katie Thomas of The New York Times, Vascepa is the only existing product for Amarin. The FDA approved Vascepa for patients with extremely high levels of triglycerides, which are linked to heart disease. When the company sought to expand the drug’s approved reach to individuals with severe levels of triglycerides, the FDA denied its request. Lawyers for the company claim the company is not trying to market Vascepa to a wider population of patients than it was approved for, which is illegal. Amarin merely wants to make statements about its product that manufacturers of fish-oil supplements make—namely that there is “supportive but not conclusive research” that shows fish oil products like Vascepa may reduce the risk of coronary hear disease.

A lawyer for Amarin pointed out where doctors are already prescribing Vascepa off-label, which is legal for doctors to do once the FDA approves a drug for any purpose. “Those doctors who are already prescribing off-label need more information, not less, about what their treatment options are.” John Sullivan said on Drug and Device Law, that the content of Amarin’s supporting brief was convincing. In addition to the “truthful, non-misleading statements it wants to provide to healthcare workers, it wants to provide the results of its ANCHOR clinical trial and other peer-reviewed articles on the connection between the active ingredient in Vascepa and coronary risk.

But is all this legal dancing around just about the right of a relatively small biopharmaceutical company to make the same claims about its prescription drug that dietary supplement companies can make about their fish oil products?

Toni Clarke, writing for Reuters, noted where drug companies have been increasing their efforts to pressure the FDA to relax its guidelines since a 2012 decision (2-1) from the Second Court of Appeals overturned the conviction of a sales representative for Orphan Medical, who was caught talking to physicians about off-label uses for the narcolepsy drug, Xyrem. The court said truthful and non-misleading off-label “speech” was protected by the First Amendment. “Pharmaceutical companies are citing the Caronia and similar rulings to pressure the FDA to let them talk more freely about off-label use.”

A coalition of pharmaceutical companies known as the Medical Information Working Group has petitioned the FDA to “’adequately justify and appropriately tailor its regulatory regime in light of Caronia and similar rulings.” This coalition includes Pfizer, Sanofi, Novartis AG, Johnson & Johnson, Eli Lily and Co., GlaxoSmithKline, Purdue Pharma, and Bayer Healthcare Pharaceuticals. What’s at stake is the right of manufacturers to attempt to persuade physicians to use their products for unapproved uses. This would be a potentially serious weakening of the FDA’s regulatory authority. Oh, and it could mean billions of dollars in potential sales for Pharma.

The FDA sent a letter to Amarin, essentially saying that it did not have concerns with most of the information Amarin proposed to communicate to doctors. The FDA pointed to existing guidance documents that indicated Amarin could distribute the results of its ANCHOR clinical trial results through peer-reviewed articles. Further, it said Amarin could communicate summaries of those trail results, but not in marketing materials or through sales reps.

Then on June 23, 2015, the FDA filed its brief in response to Amarin’s Motion for Preliminary Injunction. The brief called the lawsuit a frontal assault on the framework for new drug approval, rather than a narrower as-applied constitutional challenge. Lisa Baird, writing for ReedSmith, further noted where the FDA felt that if successful, the Amarin litigation “has the potential to establish precedent that would return the country to the pre-1962 era when companies were not required to prove that their drugs were safe and effective for each of their intended uses.”

At the heart of the matter is the distinction made by the FDA between drugs and dietary supplements. The FDA brief noted that Amarin ignored “the critical reality that drugs present markedly different considerations from dietary supplements.” After citing several legal rulings in support of this claim, the FDA said that Amarin wanted to market Vascepa as a drug intended to treat patients who are already being treated with statins, but continue to be at risk for cardiovascular disease. “Yet, FDA has found on multiple occasions that the heart disease claim did not meet the statutory standard of significant scientific agreement as the claim is based on ‘less persuasive studies.’” The potential harm posed by drugs is presumably much greater than that posed by dietary supplements.

These considerations amply justify a more cautious approach to drug approval and promotion, and the applicable statutory scheme recognizes this necessity. Unlike drugs, there is no statutory requirement of premarket approval for dietary supplements to be distributed. See 21 U.S.C. § 301 et seq. In addition, as a result of Pearson, claims about dietary supplements are held to a much lower standard (credible evidence) than the robust evidentiary requirement for drugs (substantial evidence) or the intermediate standard that FDA applies to reprints. See 21 U.S.C. § 355(d) & (e); Woodcock Decl. ¶¶ 31-32. Unlike for drug claims, qualified health claims “can be made [for dietary supplements and foods] under some circumstances even when the weight of the scientific evidence is against the claim, provided there is some credible evidence supporting it.” Woodcock D ecl. ¶ 33. Indeed, the June 5 Letter advised Amarin that if it “were to repackage and re-label [its] product as a dietary supplement” and ensure that other relevant conditions were met, “FDA would not object to your inclusion on that dietary supplement of the” heart disease claim. June 5 Letter at 10. Plaintiffs thus conflate two separate regulatory regimes and seek to make Amarin subject only to the aspects of each regime that it finds convenient—an approach that is unsupported by law and contrary to logic and sound public health policy.

This is an important and potentially a serious game changer in FDA attempts to protect the public from the growing evidence of the harmful marketing tactics of Pharma. This jousting between Amarin and the FDA is taking place in the context of the recent approval of “The 21st Century Cures Act,” which was unanimously approved by the House Energy and Commerce Committee on May 21, 2015. Toni Clarke reported that language in the bill adds pressure on the FDA to relax its guidelines.

Allen Frances, in his book Saving Normal, published a chart that he called the drug company “hall of shame.” Prepared by Melissa Raven, PhD, it listed the fines and settlements by Pharma companies for off-label promotion, marketing and fraudulent misbranding of 20 well know pharmaceuticals. Most of the companies noted above who are part of the Medical information Working Group were listed there. Here are the companies and their total fines and settlements between 2004 and 2012 recorded in the table in Saving Normal. The fines and settlements combine both civil and criminal cases. Johnson & Johnson ($1.44 billion); GlaxoSmithKline ($3 billion); Abbott ($1.5 billion); Novartis ($422.5 million); Forrest ($313 million); AstraZeneca ($520 million); Pfizer ($2.3 billion); Eli Lily ($1.415 billion); Bristol-Myers Squibb ($515 million); Purdue (almost $635 million). I think it’s clear why Pharma is going after the FDA. The sum total in fines and settlements from the chart was $12.06 billion between 2004 and 2012.

The FDA announced that it plans to hold a public meeting this summer to address drug company concerns with restrictions on what they can say about off-label use of drugs. But as of the beginning of July, I could find no indication of a set date and time for the public meeting. Perhaps the FDA decided to delay scheduling the meeting until there was an indication what would happen with the 21st Century Cures Act. They may also want to see further reaction to its June 23, 2015 brief filed in response to Amarin’s Motion for Preliminary Injunction.

If I wanted to build case law precedents to justify my constitutional right to share certain information about my pharmaceutical products with doctors, I think I’d first try to have the courts rule in favor of a product like pharmaceutical grade fish oil. It’s already sold as a dietary supplement and there are hardly any known side effects. If successful, I’d build on it and the Caronia case by filing additional litigation in an attempt to cut off the FDA regulations against off-label promotion and marketing of pharmaceuticals at the knees.

01/12/15

Can Addicts Stop Using Without Help?

Maia Szalavitz wrote on Substance.com that she stopped shooting coke and heroin when she was 23. “I quit at around the age when, according to large epidemiological studies, most people who have diagnosable addiction problems do so —without treatment.” Although she personally got treatment help, her article was about people who stop without treatment or assistance from self-help, 12-Step programs. It was provocatively titled: “Most People with Addiction Simply Grow Out of It: Why Is This Widely Denied?” She’s currently finishing her sixth book, Unbroken Brain, “which examines why seeing addiction as a developmental or learning disorder can help us better understand, prevent and treat it.”

Szalavitz referenced an epidemiological study, which suggested that a significant proportion of individuals achieve remission from addiction at some point in their lifetime. This study by Lopez-Quintero et al. found that “half of the cases of nicotine, alcohol, cannabis and cocaine dependence remitted approximately 26, 14, 6 and 5 years after dependence onset, respectively.” An article by Gene H. Heyman reviewed four studies, including the Lopez-Quintero one, and suggested that: “most addicts were no longer using drugs at clinically significant (emphasis added) levels by the age of 30.” According to Heyman:

The idea that addiction is a disease characterized by compulsive (involuntary) drug use goes hand in hand with the belief that addicts require lifelong treatment and that treatment is necessary for recovery. However, the epidemiological results indicate that most addicts do not take advantage of treatment; nevertheless, most quit. The logical inference is that remission from drug dependence does not require treatment.

The implications of Heyman’s and Szalavitz’s interpretation of the research studies they cited has far reaching consequences, particularly for the addiction treatment industry. So I want to take a look at these epidemiological studies that led them to conclude that most addicts quit drug or alcohol use (or enter remission) on their own. Heyman’s review article looked at four national epidemiological surveys of the prevalence of psychiatric disorders. Szalavitz seems to cite references to these same four studies or other articles by Heyman. So my interaction will be with the discussion in Heyman’s article: “Quitting Drugs: Quantitative and Qualitative Features.”

Hyman presented data from four large national epidemiological studies that reported high remission rates of diagnosed substance-related disorders. The studies and their remission rates were as follows: 76% for NCS, the National Comorbidity Survey; 83% for the NCS-R, the National Comorbidity Survey Replication; and 81% for the NESARC, the National Epidemiological Survey on Alcohol and Related Studies. Another study, the Epidemiological Catchment Area (ECA) survey reported a lower remission rate of 57%, but had combined the criteria for substance abuse and substance dependence into one category. He concluded: “The results do not support the often heard claim that addiction is a chronic, relapsing disease.”

Now I also have problems with defining addiction in pure medical/disease model terms and would be happy to see a more socially and cognitively nuanced definition of addiction become mainstream. But those self-generated remission rates seemed awfully high. How was this remission quantified?

First, let’s look at a critique of epidemiological miscounts by Allen Frances. Frances was the chair appointed by the American Psychiatric Association for the fourth edition of the DSM, the Diagnostic and Statistical Manual of Mental Disorders used by the epidemiological researchers to quantify their definition of “remission.” He initially pointed to an article by Regier et al., “Limitations of Diagnostic Criteria and Assessment Instruments for Mental Disorders” published in the journal, Archives of General Psychiatry in 1998. The Regier et al. article abstract raised concerns with “significant differences in mental disorder rates from 2 large community surveys”—the ECA and the NCS, two of the studies cited and discussed by Heyman.

Frances also presented his critique of epidemiological studies that use DSM diagnoses in Saving Normal. There he pointed to the “inherent limitations” of defining clinical cases in epidemiological studies. They used lay interviewers who make “diagnoses” by symptom counts, with “no consideration of whether the symptoms are severe or enduring enough to warrant diagnosis or treatment.” As a consequence, the judgment of a clinician is missing. “This results in rates that are always greatly inflated.” Symptoms “that are mild, transient and lacking in clinical significance” are mistakenly diagnosed as symptoms of psychiatric disorder.

They should never be taken at face value as a true reflection of the real extent of illness in the community. Unfortunately, the exaggerated rates are always reported without proper caveat and are accepted as if they are an accurate reflection of the real prevalence of psychiatric disorder. (Saving Normal, p. 86)

Another problem with these studies was how they defined “remission.” Remission was simply not reporting the required number of symptoms to meet the diagnosis over the previous year. Remission had a broader meaning than just “quitting” or abstinence.

The diagnostic criteria for substance abuse and dependence found in the DSM-IV were used by all the studies reported in Heyman. The ECA study, as noted above, included individuals who were “substance abusers” and “substance dependent.” The other studies only looked at those who were “substance dependent.” Remission for the ECA study was defined as no reported symptoms, while in the others, it was defined as two or less. This was based upon the separate criteria needed for each diagnosis—only one from the list for substance abuse, but three for substance dependence.

In Mad Science, Kirk, Gomory and Cohen noted how the DSM’s diagnostic criteria are the de facto definitions of mental disorder in the U.S. However, they said that describing a set of behaviors and labeling them as symptoms or diagnostic criteria does not establish the presence or absence of an illness or disorder.

Descriptive diagnosis is a tautology that distracts observers from recognizing that DSM offers no indicators that establish the validity of any psychiatric illness, although they may typically point to distresses, worries or misbehaviors (Mad Science, p. 166).

So the importance of clinical judgment, pointed to by Frances, in making a diagnosis of the existence or remission of substance dependence or substance abuse is essential. Following the critique of Frances and Regier et al. and their concerns with inconsistencies and limitations of using diagnostic criteria in epidemiological studies, the reported incidence rates of both substance dependence AND remission are likely to be greatly inflated in the studies reviewed by Heyman.

The conclusion that large populations of individuals with diagnosable addiction problems (substance dependence, according to Heyman) can stop or remit without help in such high percentages is suspect. In addition, the “diagnosis” of individuals as substance dependent in these studies is probably inaccurate for many of them. It is likely that many of those labeled as substance dependent in the studies were only substance abusers. According to Carlton Erickson in The Science of Addiction, substance abusers are more likely to make changes in their substance use because of “significant impairment or distress in their life as a consequence of their use.” They may quit on their own, without treatment. They may even go back to moderate or controlled drinking or mature out of the habit.

12/3/14

To Use or Not Use Antidepressants

I ran across a report from the National Center for Health Statistics when reading Saving Normal by Allen Frances that had some incredible facts about antidepressant use in the United States. The report said that 11% of Americans 12 years and over take antidepressant medication. Women were 2.5 times as likely to take antidepressants as men. Individuals 40 and over are more likely to take antidepressants than those younger than 40. “Twenty-three percent of women aged 40-59 take antidepressants, more than any other age-sex group.”

When the severity of depressive symptoms was considered, use of antidepressant medication rose as the severity of symptoms increases. This seems logical; the worse your depression is, the more likely you are to try medication. But look at the other end of symptom severity—7.6% of those taking antidepressants have NO REPORTED symptoms of depression. The Data Brief pointed out that this group could include people taking antidepressants for reasons other than depression and those who are being “successfully” treated with antidepressants, and just don’t have any symptoms currently. See the table below.

Depressive symptoms	Percent
Total
None	7.6
Mild	19.2
Moderate	28.4
Severe	33.9
Males
None	4.4
Mild	11.5
Moderate	18.6
Severe	21.0
Females
None	10.9
Mild	24.6
Moderate	34.5
Severe	39.9

Allen Frances suggested that part of the problem was that drug companies capitalized on the placebo effect, that is: “people getting better because of positive expectations independent of any specific healing effect of the treatment.” Treating the “worried well” expanded the customer pool and guaranteed a pool of satisfied customers. “Placebo responders often become long-term loyalists to medication use even when the medication is perfectly useless.”

The best way to get great results with a pill is to treat people who don’t really need it—the highest placebo response rates occur in those who would get better naturally and on their own.

What’s at stake? The Statistics Portal indicated that the top ten selling antidepressants in 2011-2012 grossed 8.5 billion dollars. Considering that most of the antidepressants are off patent and not as profitable to the drug companies, this is an incredible haul. Another indication of the pervasiveness of antidepressant use in the U.S. is to look at the number of prescriptions written. The top antidepressant drugs in the U.S. based upon the number of dispensed prescriptions in 2011-2012 are given in the following chart, again from The Statistics Portal.

Antidepressants	Prescriptions
Celexa (citalopram hydrobromide)	39,087,000
Zoloft (sertaline hydrochloride)	37,893,000
Prozac (fluoxetine hydrochloride)	24,961,000
Trazadone (trazadone hydrochloride)	23,449,000
Cymbalta	18,468,000
Lexapro	16,367,000
Paxil (paroxetine hydrochloride)	13,834,000
Effexor (venlafaxine hydrochloride ER)	13,679,000
Wellbutrin (bupropion hydrochloride XL)	13,365,000
Elavil (amitriptyline hydrochloride)	12,880,000

Returning to the NCHS Data Brief, once people start taking antidepressants, they tend to continue taking them. Sixty-one percent of Americans taking an antidepressant have been taking it longer than 2 years; 13.6% have been taking them ten or more years. The problem is that the widespread use of antidepressants and their long-term use may be actually causing depression.

Robert Whitaker commented in Anatomy of an Epidemic that prior to the appearance of antidepressant drugs, depression was seen as a rare problem with typically good outcomes over time. Now the NIMH says that an episode of major depression “can occur only once in a person’s lifetime, but more often, a person has several episodes.” In 2012, an estimated 16 million adults and 2.2 million adolescents had at least one depressive episode in the past year.

Whitaker noted how Italian psychiatrist, Giovanni Fava began in 1994 to look at the changing face of depression. In that article, Fava raised the possibility that “long-term use of antidepressant drugs may also increase the biochemical vulnerability to depression and decrease its likelihood of subsequent response to pharmacological treatment.” In a 2003 article, Fava suggested that antidepressants may, in some cases, actually cause depression. “Whether one treats a depressed patient for 3 months or 3 years, it does not matter when one stops the drugs. A statistical trend suggested that the longer the drug treatment, the higher the likelihood of relapse.”

In a 2014 article, “Rational Use of Antidepressant Drugs,” Fava said that rational use of antidepressant drugs should consider all the potential benefits and harms. They should only be used with the most severe and persistent cases of depression. They should be used for the shortest possible duration. Using antidepressants to treat anxiety disorders should be reduced, unless a major depressive disorder is present or other treatments have been ineffective.

These suggestions may seem to be radically different from current guidelines such as those of the American Psychiatric Association, but they reflect the weighing of risk, responsiveness and vulnerability that should be applied to the use of AD [antidepressant drugs] in each individual case.

To use or not to use antidepressants, that is the question. There is serious potential harm that may occur with their use. And sometimes they can literally save a life. What seems to be clear is that current guidelines for their use can, in the long run, worsen the problem they were originally supposed to “treat.” Along with the above suggestions for the rational use of antidepressants given by Fava, I think there needs to be a change in how we think about psychiatric drugs. The current disease-centered model of drug action needs to be replaced by a drug-centered model of drug action. You can find more on this distinction in the writings of Joanna Moncrieff, such as The Myth of the Chemical Cure and my article, “A Drug is a Drug is a Drug.” Also see two longer articles on antidepressants available in the Counseling Issues section under the “Resources” link of this site.

Faith Seeking Understanding

Charles Sigler, D.Phil.

Tag: Saving Normal