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It was a simple experiment in healing the bereaved: Twenty-two patients who recently had lost a spouse were given an antidepressant.
The drug, Wellbutrin, improved "major depressive symptoms occurring shortly after the loss of a loved one," as reported in the Journal of Clinical Psychiatry.
But when should the bereaved be medicated? For years, the official handbook of psychiatry, issued by the American Psychiatric Association - the Diagnostic and Statistical Manual of Mental Disorders - advised against diagnosing depression when the distress is "better accounted for by bereavement." Such grief, experts said, was better left to nature.
But that opinion may be changing.
In what some prominent critics have called a bonanza for the drug companies, the APA this month voted to drop the old warning against diagnosing the bereaved, opening the way for them to be treated with antidepressants.
The change, which could have significant financial implications for the nation's $10 billion antidepressant market, was made 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 guideline have either received grants from drugmakers, held stock in them, or served them as speakers or consultants.
The ties between the APA handbook creators and the industry far exceed limits recommended in 2009 by the Institute of Medicine, a branch of the National Academy of Sciences. The IOM warned that patient health could be compromised when guidelines, which are widely used by doctors, are written by industry-hired experts and issued by groups that depend on industry funding.
While there is no evidence has that committee members broadened the diagnosis to aid the drug companies, the financial links between those who developed the handbook and the industry are clear:
Eight of the 11 members of the APA committee that spearheaded the change reported financial connections to drug companies - speaking fees, consultant pay or research grants, or holding stock, according to the disclosures filed with the association. Six of the 11 reported financial ties during the time that the committee met, and two more reported ties in the five years leading up to the committee assignment, according to APA records.
The key adviser who wrote the scientific justification for the change also was the lead author of the 2001 Wellbutrin study, sponsored by GlaxoWellcome.
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 those seven panelists had received consultant pay, lecture fees or research support from pharmaceutical companies, according to their disclosures. The APA appointed an oversight panel that declared the recommendations had been free of bias, but most of that panel's members also had ties to the industry.
In an interview, APA chief executive James Scully Jr. noted that in preparing the new handbook, the organization had taken steps to reduce conflicts of interest. 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 also could receive unlimited amounts of money from drug companies to conduct research.
Scully said that if no financial ties were permitted, many knowledgeable psychiatrists would be excluded. But critics, including officials at the Institute of Medicine, argue that such ties could put public health at risk.
"It's not that this is a Machiavellian plot by the pharmaceutical industry," said Lisa Cosgrove, a research fellow at the Edmond 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 for a loved one.
The 2001 trial of Wellbutrin, for example, was sponsored by GlaxoWellcome. In publishing the results, its authors questioned the old warning against treating the bereaved.
"The results of this study challenge prevailing clinical wisdom that ... bereavement - as then defined - should not be treated," it said.
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 it be treated?
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 pure evidence.
But the groups that develop these guidelines quite often 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 dosages of the company's drug. That higher dosing is now considered unsafe. Eleven of the 16 members of the panel that developed the guidelines have financial connections to the affected drugmakers, according to a published paper by Daniel Coyne of 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.
• An international conference on early breast cancer that was issuing guidelines endorsed a group of expensive drugs that appear to be no better than others in terms of patient survival. Twenty-four of 43 members on the panel, including both chairmen, had ties to the drugmakers, according to report by the Finnish Medical Journal.
In its 2009 report, the Institute of Medicine called for excluding 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 is "over the line," Roger Herdman of the Institute of Medicine said.
But Scully of the APA said his group sought balance.
"Our dilemma is: Do we not have the world's experts, or do we have limits and disclosures of their financial ties," he said.
But a survey of academic researchers showed that 36 percent of full professors at medical schools report no financial connections to drugmakers 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."
DSM a critical tool
Through the publication of its Diagnostic and Statistical Manual of Mental Disorders, the so-called DSM, the American Psychiatric Association plays a critical role in how psychiatry is practiced.
The DSM, a compendium of mental illnesses and their definitions, is one of the most important books in medicine, affecting treatment, insurance and court decisions.
The association runs on a budget of about $50 million a year, and pharmaceutical industry funding has been critical to its operations for years. Today, about 14 percent of its budget comes from drug companies, mainly in the form of advertising at annual meetings and in publications.
Revising the DSM is a multiyear, $25 million process. Panels of psychiatrists and other specialists - unpaid, and typically expert in their fields - handle the various aspects. Among the most important is how to handle major depression, which affects nearly 15 million American adults each 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 prescriptions for antidepressants are written by primary-care physicians and others, not psychiatrists, which makes the APA handbook a critical tool. Faced with a patient complaining of depression-like symptoms, a doctor is likely to rely on the DSM.
To draft the new depression guidelines, the APA formed the Mood Disorders Work Group, an 11-member panel. They chose as chairman Jan Fawcett, a University of New Mexico professor and an expert in suicide, mood disorders and psychopharmacology.
Fawcett, in turn, nominated the other members.
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 restrictions to "a financial colonoscopy."
Some DSM panel members had to give up "significant" income, he said, adding that he was skeptical of efforts to reduce ties to industry.
"It has gotten to be a witch hunt," he said.
In one of his own disclosures in 2007, when the committee's work began, Fawcett repored 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 panel members have numerous ties to drug companies, too. 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.
"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."
Panel members on such groups are often asked to make difficult decisions, sometimes based on sparse or ambiguous evidence. Their beliefs matter. In this case, what is the "normal" course of mourning?
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. In the current handbook - the revised version will be published in the spring - the "bereavement exclusion" recommends against diagnosing major depression in the bereaved when the symptoms are milder and of less than two months' duration. (If the signs are severe - thoughts of suicide, for example - major depression is supposed to be diagnosed.)
Proponents removing the bereavement exclusion say this allows for treatment of those who are suffering.
"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, the key adviser, said. "We are doing that person a disservice if we say they're not really depressed."
"The consequences of missing a major depression can be profound," he said.
A note in the new handbook is meant to warn doctors against confusing normal grief with a mental disorder, but some say its far too little.
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. 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, he said.
If a diagnosis "can be made into a fad, it will be made into a fad," Frances said. "If something can be twisted because a buck can be made from it, it will be twisted."
New York University professor Jerome Wakefield, who has studied the distinctions between "normal" grief and mental disorders, said the APA's new stance is "narrowing the range of acceptable emotion."
"Once you classify these forms of grief as disorders, the symptoms become a target for drug development."