It was a simple experiment in healing the bereaved: Twenty-two patients who had recently lost a spouse were given a widely used antidepressant.
The drug, marketed as Wellbutrin, improved “major depressive symptoms occurring shortly after the loss of a loved one,” the report in the Journal of Clinical Psychiatry concluded.
When, though, should the bereaved be medicated? For years, the official handbook of psychiatry, issued by the American Psychiatric Association, advised against diagnosing major depression when the distress is “better accounted for by bereavement.” Such grief, experts said, was better left to nature.
But that may be changing.
In what some prominent critics have called a bonanza for the drug companies, the American Psychiatric Association this month voted to drop the old warning against diagnosing depression in the bereaved, opening the way for more of them to be diagnosed with major depression — and thus, treated with antidepressants.
The change in the handbook, which could have significant financial implications for the $10 billion U.S. antidepressant market, was developed in large part by people affiliated with the pharmaceutical industry, an examination of financial disclosures shows.
The association itself depends in part on industry funding, and the majority of experts on the committee that drafted the new diagnostic guideline have either received research grants from the drug companies, held stock in them, or served them as speakers or consultants.
Drug companies have shown an interest in treating patients who have recently lost a loved one, having sponsored and published the results of at least three trials in which the bereaved were treated with antidepressants, including the Wellbutrin study.
The financial ties between the creators of the APA handbook and the industry far exceed limits recommended in 2009 by the Institute of Medicine, a branch of the National Academy of Sciences.
The IOM limits reflect the fear that patient health could be compromised when diagnostic and treatment guidelines, which are widely used by doctors, are written largely by industry-hired experts and issued by medical societies that depend on industry funding.
While no evidence has come to light showing that committee members broadened the diagnosis to aid the drug companies, the process of developing the handbook was fraught with financial links to the industry:
■ Eight of 11 members of the APA committee that spearheaded the change reported financial connections to pharmaceutical companies — either receiving speaking fees, consultant pay, research grants or holding stock, according to the disclosures filed with the association. Six of the 11 panelists reported financial ties during the time that the committee met, and two more reported financial ties in the five years leading up to the committee assignment, according to APA records.
■ A key adviser to the committee — he wrote the scientific justification for the change — was the lead author of the 2001 study on Wellbutrin, sponsored by GlaxoWellcome, showing that its antidepressant Wellbutrin could be used to treat bereavement.
■ In 2010, another APA panel developed guidelines on how to treat patients once they have been diagnosed with major depression, including advice on medication. Six of the seven panelists had received consultant pay, lecture fees or research support from pharmaceutical companies, according to their disclosures. The association also appointed an oversight panel that declared that the recommendations had been free of bias, but most of the members of the “independent review panel” had previous financial ties to the industry.
In an interview, APA chief executive James H. Scully Jr. noted that in preparing the new handbook the organization had taken steps to reduce conflicts of interest. Two years before the Institute of Medicine published its restrictions, the APA required that panel members regularly file disclosures and placed limits on their financial connections to drug companies.
Each work group member was allowed to receive as much as $10,000 a year in income from pharmaceutical companies and hold as much as $50,000 in stock. Members could also receive unlimited amounts of money from pharmaceutical companies to conduct research.
Scully said that if no financial ties were permitted, many knowledgeable psychiatrists would be excluded because so many university studies are funded by pharmaceutical companies.
“We think we are on the right track,” Scully said in an interview. “If we need to make more changes, we’ll make them.”
But critics of such relationships, including officials at the Institute of Medicine, argue that such ties could put public health at risk and note that problems have appeared in other guidelines issued by medical groups relying on industry money and expertise.
“It’s not that this is a Machiavellian plot by the pharmaceutical industry,” said Lisa Cosgrove, a research fellow at the Edmond J. Safra Center for Ethics at Harvard University and a psychology professor at the University of Massachusetts Boston. “But when you have so many of these industry relationships on a committee, it creates a pro-industry bias that compromises their ability to be objective.”
Some drug companies have long shown an interest in treating depression in people mourning the loss of a loved one.
The 2001 trial of Wellbutrin, for example, was sponsored by GlaxoWellcome. In publishing the results, its authors challenged the old limits on treating the bereaved.
“The results of this study challenge prevailing clinical wisdom that . . . bereavement [as then defined] should not be treated,” it said.
Similarly, a 2009 paper published in the Journal of Affective Disorders found that the antidepressant Lexapro “improved depressive, anxiety, and grief symptoms in individuals experiencing a major depressive episode related to the loss of a loved one.”
The study was paid for by the Forest Research Institute, a subsidiary of drugmaker Forest Laboratories.
What is “normal” grief after a death? How does it differ from major depression? When should such distress be treated?
Throughout the world of medicine, when doctors are faced with difficult or unfamiliar questions, they turn to guidelines developed by medical associations and societies.
These diagnostic and practice guidelines, which number in the thousands, specify medications, doses and treatments. They offer advice on everything from the right drugs to give a cancer patient to how to treat Lyme disease. Insurance companies consult them in determining coverage. The guidelines are supposed to represent “best practices,” and to be based on unbiased expert opinion and, whenever possible, pure evidence.
But the associations and medical societies that develop these guidelines are subject to economic pressures, and quite often they receive money from pharmaceutical companies, often through advertising at conferences and sometimes through outright grants for developing the guidelines.
In recent years, those relationships have come under sharp criticism:
■ Guidelines written by the National Kidney Foundation and sponsored by the drugmaker Amgen effectively raised the recommended doses of the company’s drug. Those higher dosing targets are now considered unsafe. Eleven of the 16 members of the panel that approved the guidelines were found to have financial connections from the affected drug makers — they reported receiving consultant pay, speaker fees or research funds, according to a published paper by Daniel Coyne, a professor of medicine at Washington University.
■ An analysis last year of 17 guidelines used in cardiology indicated that 56 percent of members of work groups reported a conflict of interest, according to an investigation published in the Archives of Internal Medicine. A related study showed that about half of the treatment guidelines in cardiology were based on doctors’ opinions rather than more substantial evidence.
■ An international conference on early breast cancer that was issuing guidelines expressed a preference for a group of expensive proprietary drugs that appear to be no better than others in terms of patient survival. Twenty-four of 43 members on the panel, including both chairs, had financial ties to the makers of the proprietary drugs, according to a published account by Päivi Hietanen, the medical editor of the Finnish Medical Journal.
“Financial relationships with companies affected by clinical practice guidelines are common,” the 2009 Institute of Medicine report said.
While the IOM said that collaboration between pharmaceutical companies and doctors can be fruitful, it said that the risk of undue industry influence on clinical practice guidelines is “significant.”
“Having experts who are obligated in any way to industry doesn’t look good and on occasion might not be good. Why would we risk that?” said Roger Herdman of the Institute of Medicine.
In the 2009 report, the group called for trying to exclude individuals with conflicts of interest from panels drafting guidelines, limiting them to a “distinct minority.” The chairperson should have no conflict of interest, it said, and warned that even “small” ties to industry should disqualify candidates because even “small gifts may help to create and sustain relationships.” Physicians receiving them may not even be conscious of their influence, the group said.
At the APA, by contrast, most of the work group that handled the revised definition of major depression had financial conflicts, including the chairman, according to their disclosures.
Allowing panel members to receive $10,000 a year from the industry and other exceptions are “over the line,” Herdman said. “I think our committee would have said, ‘What?’ ”
But Scully said the APA sought to have a balance.
“Our dilemma is: Do we not have the world’s experts, or do we have limits and disclosures [of their financial ties].” Scully said. “We decided to have some balance here. You could say absolutism should prevail, but then where are you going to get your experts?”
It’s hardly impossible to find medical experts without financial ties to industry, however, according to research.
A survey of academic researchers, for example, showed that 36 percent of full professors at medical schools report no financial connections to the industry in the previous year.
The idea “that every expert in the field has industry relationships is not supported by the data,” said Eric Campbell, a medical professor at Harvard University, who conducted the surveys. Instead, he said, such claims are rather “propagandist in nature.”
Through the publication of its Diagnostic and Statistical Manual of Mental Disorders, or DSM, the American Psychiatric Association plays a critical role in how psychiatry is practiced.
Basically a compendium of mental illnesses and their definitions, the DSM is one of the most important books in medicine, affecting treatment, insurance coverage and court decisions.
The association itself runs on a budget of about $50 million a year, and for years industry funding has been critical to its operations. Today, about 14 percent of the association’s budget comes from pharmaceutical companies, mainly in the form of advertising at annual meetings and publications.
The portion of the APA budget that came from the industry had been as high as 34 percent in 2006, but has dropped, partly because of the recession and partly because in 2008 the association banned industry support for its education programs.
Revising the DSM is a multiyear, $25 million process. Several committees of psychiatrists and other specialists — unpaid, and typically expert in their fields — handle various aspects of mental health.
Among the most important aspects of the DSM is how it handles major depression, which affects nearly 15 million American adults in any given year, according to figures from the National Institute of Mental Health. In 2011, consumers spent more than $10 billion on antidepressants, according to figures from IMS Health, a health-care technology and information company.
About 80 percent of the prescriptions for antidepressants are written by primary-care physicians and others, not psychiatrists, a fact that makes the APA handbook particularly important. Faced with a patient complaining of depression-like symptoms, a general practitioner may be likely to rely on the association’s handbook for advice.
To draft the new guidelines on major depression, the APA leadership formed the Mood Disorders Work Group, which would become an 11-member panel. They chose as chairman Jan Fawcett, a professor of psychiatry at the University of New Mexico and an expert in suicide, mood disorders and psychopharmacology.
Fawcett, in turn, nominated the other members of the panel.
“In choosing people, I wanted some people who see patients, not just academics,” Fawcett said. “I wanted some people who were visionary and some people who are conservative and data-driven.”
Their financial ties to the industry were not a consideration, he said.
“I wanted them for their quality,” he said. “I knew whether they had integrity or not.”
Long ago, when he was serving his residency as a doctor, he recalls being a “rebel” for believing in medications — at the time, counseling was more in vogue. But then came the revolution in psychopharmacology, which made clear to him that there was a place for drugs as well as psychotherapy.
“I’m still working at 78 because I love to watch patients who have been depressed for years come to life again,” Fawcett said. “You need those medicines to do that.”
In recruiting panelists, Fawcett said he had to inform candidates that they would have to disclose their industry ties and give up any industry income over $10,000 a year. He likened the financial restrictions to “a financial colonoscopy.”
Some DSM panel members had to give up “significant” income in order to serve, he said.
Fawcett, for example, who testifies on behalf of pharmaceutical companies in suicide lawsuits, had to give up three cases, he said.
He was skeptical of efforts to reduce the financial ties to industry.
“It has gotten to be a witch hunt,” he said.
“Most academics have taken money from pharma if they’re successful,” he explained, noting the limits on government research funding. “If you want to get any studies funded, where are you going to go? How are you going to do it?”
For example, in one of his disclosures filed with the courts in 2007, when the committee’s work was beginning, Fawcett indicated that he had served as an investigator for Bristol Myers, Eli Lilly and Abbott Laboratories. His 2011 disclosure with the APA indicated that he was working for Merck on its diagnosis manual.
Other members of the committee have numerous ties to drug companies, too, and not simply conducting research, according to disclosures from last year. One was holding stock in GlaxoSmithKline; one was a consultant to Servier and another a consultant to Pfizer; one had a grant from Astra Zeneca and another a grant from Pfizer and AstraZeneca.
Sidney Zisook, the key committee adviser who developed the scientific report justifying the change on bereavement, has had close ties, too. He has served as a speaker for AstraZeneca and Forest and as a consultant to Glaxo, though that work preceded his work for the committee by at least two years, he said.
He was also the lead author of the Glaxo study showing that Wellbutrin can be used to treat the bereaved.
“I don’t think these connections create any bias at all,” Fawcett said. “People can say we were biased. But it assumes we have no intelligence of our own.
“There has to be some cooperation between academia and pharma if you want to make any progress. People need to realize that.”
One of the reasons that the selection of panel members on such groups is so important is that the choices they make are difficult and the evidence sometimes sparse or ambiguous. Their beliefs on basic philosophical questions matter.
In this case, what is the “normal” course of mourning?
Generally, when a person has five of nine depressive symptoms — fatigue, insomnia, sadness, or others — for two weeks or more, the DSM called for a diagnosis of major depression.
The dispute arose over what to do about diagnosing depression in patients who are recently bereaved.
The current handbook — the revised version will be published in the spring — recommended against diagnosing major depression in the bereaved when the symptoms are milder and of less than two months’ duration. This is known as the “bereavement exclusion.” (If the signs of depression are severe — the patient has thoughts of suicide, for example — major depression is supposed to be diagnosed.)
The new handbook removes the bereavement exclusion. The proponents of the revision say this allows for a person who is grieving and suffering from major depression to be treated.
“We thought the evidence was overwhelming that if depression occurs in someone who is bereaved that it should be taken as seriously as any other major depression,” Zisook said. “We are doing that person a disservice if we say they’re not really depressed.”
Fawcett, the chairman of the group, and Zisook, a key group adviser, have specialized in suicide and say they see a danger in withholding diagnosis. Zisook is co-directing a suicide prevention program at the University of California San Diego.
“The consequences of missing a major depression can be profound,” he said.
A note in the new handbook is supposed to warn physicians against confusing normal grief and a mental disorder, but some prominent critics say that’s far too little to prevent drug companies from pushing pills on the bereaved.
Allen Frances, an emeritus professor from Duke University who headed the previous revision of the DSM, has called the change a “bonanza” for drug companies.
The new book “legalizes the marketing of grief as depression,” he said. “They’re acting as if the footnote will change the world — but only academics would think the footnote would matter.”
Guided by the new handbook, a primary-care doctor, “who sees their average patient for seven minutes,” will be far more likely to diagnose depression in people who are suffering normal grief, Frances said, particularly under pressure from drug salespeople.
In putting together the previous DSM book, Frances said he learned that if a diagnosis “can be made into a fad, it will be made into a fad. If something can be twisted because a buck can be made from it, it will be twisted.”
Mario Maj, one of the panel members who has declared no financial ties to the industry, declined to be interviewed for this article, saying the panel’s deliberations were supposed to be confidential.
But in a February editorial in the journal World Psychiatry, he appeared to embrace the logic of the old diagnostic manual.
“A major depressive syndrome is indeed an ‘expectable response’ to the death of a loved one,” he wrote.
Some prominent critics of the new DSM also say much of the fear of suicides in the bereaved is unsupported.
Jerome C. Wakefield, professor at New York University who has studied the distinctions between “normal” grief and mental disorders, said that in a major national survey, none of the bereaved who now could be subject to a diagnosis of depression had attempted suicide. Other data sets, he said, showed similar results — indeed, such individuals are less likely to attempt suicide than someone in the general population.
The APA’s new stance on bereavement is “narrowing the range of acceptable emotion,” Wakefield said. While he doesn’t think the experts on the committee acted out of “explicit venality or self interest,” he added: “Once you classify these forms of grief as disorders, the symptoms become a target for drug development.”