RECENTLY I received a call from a woman who was certain she was “bipolar.” At forty-two years old, Julie (not her real name) appeared to have everything – a stable marriage, four children she was raising with warmth and effectiveness, a thriving home business. But despite a life marked by academic and family success, she struggled with low self-esteem and episodes of sadness. At times she felt irritable and withdrawn, at others highly productive.
Julie felt a wave of hope after viewing a television ad for Abilify, an antipsychotic medication now frequently prescribed for bipolar disorder. Julie’s subsequent Google search on “bipolar disorder” led her to believe that she, too, had the disease. And despite the fact that thirty seconds of that one-minute Abilify advertisement discussed potential side effects, Julie was convinced she could benefit from the drug.
Julie’s call was not unique. Almost daily, it seems, I get a call from someone who has diagnosed him or herself as bipolar and asks me to prescribe Abilify or one of the other heavily advertised, newer, antipsychotic drugs. They’ve seen the ads, visited the websites, taken the quizzes and decided, “that’s me.” What’s more, they often sound pleased that they have identified what ails them – though it seems strange that someone would be pleased to have a disease that many consider one of the cruellest known. Bipolar disorder can destroy families and ruin lives. It causes people to do profoundly humiliating and self-destructive acts. Later, they recover and become fully cognisant of the things they have done, as well as the fact that another episode could strike at any time. Between 10 and 20 per cent of patients with bipolar disorder end up committing suicide; far more seriously consider it.
It is difficult to turn down a distressed patient’s request for help, particularly when they are convinced they have a medical problem whose solution may be found in a simple pill. People find comfort in an explanation for their pain, particularly if they feel that they share the pain with the likes of Virginia Woolf, Gustav Mahler and Carrie Fisher. Often they are crushed, or even angry, when I assure them that while their pain is real, their bipolar disorder is not. And, even if someone truly has bipolar disorder, in my view the scientific evidence shows that Abilify and many of the other wildly popular new medications should not generally be the treatment of choice. In fact, despite US$164 million worth of marketing in 2008 (which resulted in US$3 billion worth of sales), Abilify does not seem to me to be a particularly useful drug for bipolar disorder. As the ad that Julie saw concedes, the drug can cause severe side effects including akathisia, a condition marked by extreme restlessness; suicidal thoughts; diabetes; stroke; and seizures. The one long-term controlled study published on Abilify’s effectiveness as a maintenance drug for bipolar disorder is so biased it’s essentially meaningless. A hard look at the evidence, in fact, suggests that the drug is far less effective than older (and cheaper) drugs, and perhaps no more effective than a sugar pill.
Sixteen years ago, Peter Kramer’s breakthrough book Listening to Prozac described how a new generation of antidepressants was leading psychiatrists (and Americans in general) to change their way of perceiving – and treating – the ailing human psyche. With antidepressants becoming such powerful antidotes to psychological ills ranging from true depression to oversensitivity, low self-esteem and social inhibition, Kramer wrote of a nascent “biological materialism” that he perceived in the psychiatry profession, one that reduced human moods, temperaments and personalities to physiological flaws. “Though I had never taken psychotherapeutic medication,” he wrote of the glamour of Prozac, “I, too, seemed to be under its influence.” Since then America has plunged headlong into an era of “designer psychopharmacology,” one in which life’s troubles and one’s personality traits allegedly can be medicated away, a pill for every problem, just as plastic surgery allows us to get rid of undesirable physical features.
As the first “blockbuster” psychopharmacologic agent, Prozac ultimately achieved sales topping US$2 billion a year, producing more than 25 per cent of Eli Lilly’s total profits. Naturally, the pharmaceutical industry emulated the Prozac model in marketing its newer agents. Over the last few years, that marketing has had a powerful influence on the way psychiatrists practise – and the way Americans view their emotional lives. Unfortunately, this effect isn’t due to breakthroughs in our understanding of the nature, causes, or treatment of mental illness. Instead, it’s due to drug companies’ manipulation of the evidence about how well medications work, and psychiatrists’ collaboration in pushing Americans into using certain (always newer and more expensive) drugs. Indeed, the marketing of these new drugs has led to a corresponding increase in the diagnosis of the disorders that these medications are supposed to treat – and even, in some cases, to the invention of new disorders.
The pharmaceutical industry’s profit-oriented behaviour is hardly news. Fifty years ago Estes Kefauver, chairman of the US Senate’s Anti-Trust and Monopoly Subcommittee, harshly criticised the industry’s marketing-driven culture, a culture that resulted in prices inflated by marketing expenditures and new products no more effective than older ones on the market. David Healy has published a number of works, including The Creation of Psychopharmacology (Harvard, 2002), that chronicle the surprisingly weak science behind the development of psychiatric drugs. Recent years have witnessed a fresh wave of interest in the topic, including books like Dr Marcia Angell’s The Truth about the Drug Companies: How They Deceive Us and What to Do About It (Random House, 2004) and others by Katharine Greider and Shannon Brownlee, to mention a few. The media is also full of revelations of wrongdoing on the part of Big Pharma, including those generated by the work of Senator Charles Grassley, the ranking member of the Senate Finance Committee, which has been investigating the behaviour of the industry.
Accompanying these revelations, and well described in a number of books including Howard Brody’s Hooked: Ethics, the Medical Profession, and the Pharmaceutical Industry (Rowman and Littlefield Publishers, 2007) and Jerome Kassirer’s On the Take: How Medicine’s Complicity with Big Business Can Endanger Your Health (Oxford University Press, 2005) is a growing recognition that members of the American medical profession have placed themselves in financial and professional conflicts of interest to become part of what is, in essence, a colossal marketing machine. Nowhere have the consequences of this culture of conflicts been as profound as in the field of psychiatry. Alison Bass’s book Side Effects: A Prosecutor, a Whistleblower and a Bestselling Antidepressant on Trial (Algonquin, 2008) focuses on the deception behind the testing and marketing of one antidepressant (Paxil). But far from being an aberration, the Paxil story is just one of dozens of examples of the way that Big Pharma and its physician collaborators market psychiatric drugs – stories in which the combination of human desperation and a dearth of hard facts about psychiatric illness leaves the field ripe for marketing exploitation.
THE URGE to ease human suffering is strong. The Bayh–Dole Act of 1980, which gave universities intellectual property control of the inventions, including drugs, that they discover or develop from federally funded research, was passed in an effort to hurry new medicines (and, it was hoped, relief) to the market. (Conspicuously absent from their PR campaigns is the fact that pharmaceutical companies rely largely on government-supported, university-based research to come up with truly new medications. For example, in 1998 the Boston Globe examined thirty-five of the most important and top-selling drugs the Food and Drug Administration had approved in the prior five years, and found that all but two of them had been developed, at least in part, with funds from the FDA itself or from the National Institutes of Health.) As a result of the Act, university–industry collaboration in clinical drug trials blossomed, and industry sponsorship of drug trials increased; in a random sample of 500 drug trials published between 1981 and 2000, the percentage that were industry-sponsored went from 26 per cent to 62 per cent – a 2.4-fold increase. But this influx of industry support also caused a wholesale shift from basic research to clinical trials, changing the focus of American medical research away from seeking to understand and cure diseases and towards the testing of drugs that could be rapidly moved to the marketplace, often little different from those already available. As Dr Angell calculates, only 14 per cent of the 415 new drugs that received FDA approval from 1998 to 2002 were truly innovative.
The arrangement seemed to work well – at first. The pharmaceutical industry relied on academic psychiatrists to design and run the studies; academics benefited from lucrative contracts that allowed funds to be skimmed off to support other research projects and support staff. But over time a clash of cultures developed. University research systems tend to be relatively slow and ponderous when compared to the business world. Yet, because new drugs have only twenty years of patent protection, expediency in the testing and approval process is crucial from a marketing perspective. The highly competitive pharmaceutical industry couldn’t waste time and money on scientific research that had no marketable product in the foreseeable future.
As a result, the pharmaceutical industry began to take a more aggressive role in university research, and to move clinical trials away from academic settings. Angell notes that while about 80 per cent of industry-sponsored trials were done at academic institutions in 1980, within a decade that share had dropped to less than 40 per cent. Instead, the pharma sponsors designed, controlled and analysed the studies. Academic physicians would lend their name and assistance to clinical trials, but a worrying number of the papers detailing the research were ghost-written by the pharmaceutical company (or an outside PR shop), and then published under the name of the prestigious university partners, known in the trade as “key opinion leaders,” or “KOLs.”
Unfortunately, despite the impressive names on the papers, industry sponsorship tended to skew the reporting of results. As one 2006 analysis found, in 90 per cent of published pharma-sponsored studies comparing antipsychotic drugs, the reported overall outcome was in favour of the sponsor’s drug. They found that the industry-sponsored studies contained multiple sources of bias, including improper dosing; biased selection of study subjects; biased statistics and methods; and inaccurate reporting of results and wording of findings. In other words, the stated study findings were frequently not in agreement with the study data. This last point is crucial since few physicians – or media reporters – take the time to review a study’s complicated methods and analyses critically, relying instead on the findings as reported in the study abstract. As Harry Loynd, president of Parke, Davis and Company in the 50s and 60s, once famously noted, “If we put horse manure in a capsule, we could sell it to 95 percent of these doctors.”
And sell they did, through all sorts of creative methods that were eagerly embraced by physicians. One of the most successful was the sponsorship of “continuing medical education,” or CME. In order to maintain their licences, physicians are required to obtain a certain number of CME credits per year – often by attending conferences, where, presumably, they’ll learn about new medical advances. Starting in the late 1990s, the pharmaceutical industry began exerting increasing influence on these CME events. Industry sponsorship of CME grew to more than US$1.2 billion in 2007, funds that were spent on things like paying KOLs to give talks (usually prepared by the company and often little more than thinly veiled advertisements for its products) at sumptuous dinners, lunchtime meetings and “symposia.” To make matters worse, the proceedings from the symposia would often be published in medical journals, as if they were a scientific meeting – and then they would show up in PubMed, the National Institutes of Health’s searchable library of scientific publications. Sales of the reprints became a major revenue source for medical journals, and are also used by pharmaceutical sales reps to convince physicians of the efficacy of a drug. Other free, industry sponsored, educational “opportunities” were showered on physicians; lectures on CDs and tapes, “throw-away” journals with CME credit available by completing a brief quiz, flashy medical websites, and even computer and PDA software that, while appearing to be educational material were, in reality, sophisticated infomercials.
Over time, academic psychiatrists, and their departments, came to depend on these contracts with the pharmaceutical industry, even as that dependence led to a blurring of the line between commercial and medical interests. Even speakers who talk about their own research are subject to censoring. I recall a lecture given a few years ago by a visiting researcher who admitted, with some embarrassment, that he had been required to submit his slides for review to the talk’s sponsor and ordered to make changes. Other cases appear to be far more egregious. According to a congressional inquiry, Dr Joseph Biederman, a prominent Harvard child psychiatrist and a KOL for Johnson & Johnson, which manufactures Risperdal (risperidone – an antipsychotic drug advocated for use in pediatric bipolar patients), asked the company for hundreds of thousands of dollars for a “Johnson & Johnson Center for the study of pediatric psychopathology.” One of his stated goals for the centre was to “move forward the commercial goals of J. & J.” In another case, according to federal investigators, Forest Laboratories paid Dr Jeffrey Bostic, the director of “School Psychiatry” at Massachusetts General Hospital $750,000 over seven years to give 350 presentations promoting pediatric use of the anti-depressants Celexa and Lexapro – despite the fact that the FDA hadn’t yet approved the drugs for children. And under pressure, and a total of $2.8 billion in settlements for promoting its drugs for “off label” use and failing to disclose known adverse effects of its drugs, Eli Lilly now discloses payments to physicians in its “faculty registry.” Despite an individual limit of $75,000, Lilly’s payments to physicians for the first quarter of 2009 totalled $22 million.
Another piece of legislation intended to hasten the availability of new and better drugs also had unintended consequences. The Prescription Drug User Fee Act, enacted in 1992 by Congress, was designed to accelerate the FDA’s drug approval process. It permitted the FDA to collect fees from drug manufacturers when they submitted a “New Drug Application,” and mandated strict deadlines for approval decisions. These fees now cover approximately half of the budget of the FDA’s new application review division. What emerged is a relationship similar to that of the accounting firm Arthur Andersen to Enron, in which an auditing or regulatory agency relies on the financial support of the entity it is charged to monitor. This conflicted relationship, along with the FDA’s system of approval – which requires only that a new drug be shown to be more effective than placebo, not as good or better than other available agents – has contributed to an avalanche of new psychiatric medications gaining initial FDA approval, or approval for new indications, over the past fifteen years.
With new drugs rapidly appearing on the market, and the publication of drug trials becoming increasingly controlled by the drug industry, a well-intended movement in medicine caught on: “evidence-based medicine,” or EBM. While medicine, when properly practised, has always depended on evidence, EBM seeks to base the evaluation and treatment of illness on reproducible scientific evidence. Psychiatry especially, after years of focusing on psychoanalytically based treatments, had been criticised for fuzzy guidelines, the overuse of case studies, and a lack of objective verification of effectiveness. As such, doctors (as well as patients and insurers) wanted to know what treatments actually worked. EBM uses carefully structured experiments and analyses to help understand diseases and their treatment, including randomly controlled trials and meta-analyses. But randomly controlled trials are complicated and the process can break down (or be broken) in myriad ways, yielding false or misleading results. For example, psychiatric illness and its severity can be difficult to define or measure objectively. Likewise, the response to treatment can be measured many different ways.
The end result is that Big Pharma (and its collaborating physicians) are able to create studies that look – at first blush – to be scientifically controlled and valid, but when examined more objectively are skewed so severely that they serve more as marketing instruments than scientific data. Meta-analyses use statistical methods to combine a number of studies into one large one, increasing the effective size and thereby increasing the ability to tease out subtle trends. But the medical literature is skewed by a phenomenon called “publication bias.” Producing a paper for publication requires a tremendous amount of work; researchers and medical journals are far more motivated and likely to publish experiments that show positive results. And industry is under no obligation to publish negative data. As recent court cases have discovered, in some instances studies that looked unfavourable to the sponsor have been hidden completely. This means that meta-analyses, particularly those comparing new treatments to older ones or placebo, and most especially those that use industry-sponsored trials, can start with cherry-picked data – making the analysis’s findings a foregone conclusion. As Glen Spielmans and Peter Parry suggest, “while evidence-based medicine is a noble ideal, marketing-based medicine is the current reality.”
All of these developments are evident in the way that psychiatric drugs have been marketed for a range of psychiatric illnesses – including depression, schizophrenia and ADHD, resulting in a sea change in the psychiatric medications that are prescribed in the United States. Prozac and a raft of imitators including Paxil, Zoloft and Lexapro have almost completely replaced the previous generation of antidepressants, despite evidence that the older drugs may be more effective, at least for severe depression. A similar shift has taken place in the treatment of schizophrenia. As a recent commentary in the Lancet, pointedly titled “The spurious advance of antipsychotic drug therapy” laments, the “additional benefits and fewer adverse effects” of the newer drugs are “now, and only now, seen as a chimera that has passed spectacularly before our eyes before disappearing and leaving puzzlement and many questions in [their] wake.” To date, four major pharmaceutical companies have settled charges related to illegal marketing of their newer antipsychotic drugs (Eli Lilly: Zyprexa US$1.4 billion; Bristol-Myers Squibb: Abilify US$515 million; Pfizer: Geodon US$301 million; AstraZeneca: Seroquel US$520 million) .
BUT NOWHERE is the pattern more evident than in the rush to market drugs for bipolar disorder. For fifty years lithium was the treatment of choice for bipolar disorder. A naturally occurring element, lithium was readily available, cheap and relatively effective in tempering both the highs and lows that characterise what was then called “manic depression.” But lithium has significant side effects, including frequent urination, tremor and a feeling of one’s mind being slowed. And it can be very dangerous in overdose. In response to these problems, Abbott Laboratories mounted a massive promotional campaign to replace lithium with Depakote (divalproex) in the 1980s and 90s. This new drug was effective (although probably not as effective as lithium); it also carried a higher suicide risk. But it had fewer other side effects. Through aggressive promotion Depakote all but replaced lithium in the maintenance treatment of bipolar disorder.
Abbott’s success in this area blazed a trail for other manufacturers to market a new generation of bipolar drugs, the so-called “second generation antipsychotics,” or SGAs. Originally they were developed as treatments for schizophrenia, but Big Pharma realised that the market for those drugs was relatively limited, since the disease occurs in only 1 per cent of the population, and those with the illness tend to be poor and often uninsured. Eli Lilly, anticipating that Prozac would lose its patent protection in 2001, was already working on “LifePlan” – a strategic plan for marketing its new SGA Zyprexa (olanzapine) – by 1994. According to internal documents leaked recently, LifePlan outlined how “The Company is betting the farm on Zyprexa.” Their product summary from 1997 suggested that Zyprexa sales would increase fourfold if Zyprexa could be viewed as a “Depakote-like… MOOD STABILIZER” rather than a “Risperdal-like… Antipsychotic,” despite the fact that the company did not have data to support this goal.
Yet as early as 1995, Lilly knew that Zyprexa had serious side effects, including severe weight gain. Those of us with experience in using Zyprexa have seen occasional cases of patients gaining thirty pounds or more. And soon data emerged linking the drug to diabetes, heart disease and even death in patients with dementia. Despite this, the sales team mapped out a specific timeline for promoting Zyprexa, as well as an elaborate and carefully scripted coaching program to make primary care doctors (referred to as “the last major untapped segment” of the market for Zyprexa) comfortable treating bipolar disorder with the drug – including how to deflect their questions about weight gain. This last step was crucial since the majority of psychiatric medications in the United States are prescribed by family doctors, not psychiatrists.
Not content to stop there, Lilly went on to enlist the help of NAMI (the National Alliance for the Mentally Ill, now renamed National Alliance on Mental Illness), which was originally established as a grassroots, non-profit advocacy organisation for the mentally ill and their families. Between 1999 and 2001, NAMI was actually run by Gerald Radke, Eli Lilly’s marketing manager, whom Lilly loaned to NAMI, complete with salary. Lilly also donated more than US$2.5 million to the organisation during that period. As a result, in part, of the Lilly–NAMI bond (which helped convince legislators and insurance companies that antipsychotics were appropriate for treating bipolar disorder and should be included on formularies), by 2000 Zyprexa was the leading antipsychotic in the world, and by 2003 annual sales topped US$4 billion. Lilly ended up paying $1.4 billion to the federal government to settle civil and criminal charges, making separate settlements with thirty-six states, and settling product liability claims with 28,500 patients. Still, it’s clear the company profited greatly through Zyprexa’s marketing success. Not wanting to be left out, other pharmaceutical companies jumped on the NAMI bandwagon. As uncovered recently by Senator Grassley, almost 75 per cent of NAMI’s funding for the years 2006–08 – $23 million – came from Big Pharma.
Seeing Lilly’s massive success in moving Zyprexa into the far more lucrative bipolar arena, Bristol-Myers Squibb and its affiliate Otsuka employed the same tactic with their SGA Abilify (aripiprazole), also originally developed for schizophrenia. But the scientific evidence purporting to show that the drug could be used as a mood stabiliser in the maintenance treatment for bipolar disorder is shockingly sparse and seriously biased. In truth, the medical literature contains only one randomised controlled trial examining the use of Abilify for maintenance of bipolar disorder and in my view, if you tease out the details of this study, the drug’s approval for and use to treat bipolar disorder defies logic.
The study was published as three separate papers between 2003 and 2007. The first paper claims to demonstrate that the drug is more effective than placebo in treating acute mania. This is not surprising since the first-generation antipsychotics, which act in a similar manner on the brain, have been used for years to treat acute mania, but not as mood stabilisers.
The next phase of the study, published in 2006, claims that Abilify “was superior to placebo in maintaining efficacy in patients with bipolar I disorder…” A closer look at the study reveals at least three major flaws. First, only subjects who had responded to Abilify in the first phase were included (that is, two-thirds of the subjects – all those who had not responded to Abilify – were excluded). Second, the subjects who were switched to placebo in the second phase were abruptly taken off medication, which has been shown frequently to cause a relapse in bipolar disorder. Thus it would be expected that a greater number of those switched to placebo would suffer a withdrawal relapse. Third, the removal of any medication that suppresses acute symptoms, as does Abilify, will cause some subjects – especially those not yet fully recovered – to appear more symptomatic.
The final phase of the study, the true maintenance portion of the trial, followed the remaining subjects over the subsequent seventy-four weeks. Published in 2007, it concluded: “Over a 100-week treatment period, aripiprazole monotherapy was effective for relapse prevention in patients who were initially stabilised on aripiprazole for six consecutive weeks, and it maintained a good safety and tolerability profile.” Like the previous paper this last one had “editorial support” from a ghostwriter (this time from a company that brags: “a brand assigned to Ogilvy Healthworld will be a success – no matter if it is a major new launch or a product that requires special attention”). Indeed, it appears Abilify needed “special attention” to create its life as a mood stabiliser. Over the maintenance phase, only seven subjects (18 per cent) on Abilify completed the trial. Those on placebo fared slightly better, with 19 per cent completing the final seventy-four weeks. A look at the raw numbers is even more telling. Of the 567 subjects who began treatment with Abilify, minus the eighty-three who were switched to placebo, ultimately only seven completed the 100-week trial, for a completion rate of less than 1.5 per cent. How a medication that successfully maintained less than 1.5 per cent of subjects, fewer on a percentage basis than placebo, can be called “effective for relapse prevention” strains credibility. But as of November 2009 these papers were cited (cumulatively) in over 315 other scientific journal articles, thus cementing the study’s claims as fact. As one former Zyprexa rep quips, “Statistics are like prisoners, torture them long enough and they’ll tell you what you want to hear.”
A KEY EVENT that influenced my questioning of the doctor–pharma relationship occurred just over a decade ago, when I was invited to be a consultant on a special panel of psychiatrists meeting to discuss our impressions of the newly released Zyprexa. Having considerable experience in the use of Clozapine, Lilly’s earlier atypical antipsychotic on which Zyprexa was modelled, I was offered an attractive sum of money to fly to a fancy resort in Florida to discuss my experience with the newer drug.
Alas, the “conference” rapidly devolved into a hard-sell marketing show. Meaningful discussion about the drug was discouraged, mindless praise encouraged. During the wrap-up meeting the speaker, a psychiatrist, tried to whip up excitement in the audience like an auctioneer, exhorting the crowd to yell out ways Zyprexa could be used. We could have been at a circus sideshow, with a charlatan hawking his patent medicine of 100 years ago. They clearly were not interested in hearing our impressions about the drug (good or bad), but only in getting us on board to spread the word: prescribe. I felt that I had been lured to the meeting on false pretences; it seemed clear to me their intent was to exploit the reputation and influence of my colleagues and me.
Big Pharma uses professional representatives – the aforementioned KOLs – for one reason, because they work – and, yes, data is monitored to show how well they work. Although it is not widely known, pharmacies in the United States sell data on the medications they dispense, including who receives them and who wrote the prescriptions. Companies like IMS Health and Verispan mine and collate the data and sell it to the pharmaceutical companies. They then monitor how the prescribing habits of attendees change after a CME conference, providing direct evidence of the effectiveness (or lack thereof) of KOLs and CME programs.
Of course, the arrangement also serves to line the pockets of the KOLs themselves. As a profession psychiatrists take more money from the pharmaceutical industry than any other medical specialty. A 2007 article in the New York Times found that in Vermont, one of the few states with a “sunshine law” that tracks drug company payments to physicians, payments to psychiatrists averaged $45,692 in 2005. Equally shocking, that same article reported that “psychiatrists who took the most money from makers of antipsychotic drugs tended to prescribe the drugs to children most often,” despite the fact the drugs are especially risky for children and, in many cases, had not yet been approved for use in kids.
Most who collaborate with industry, from accepting a free lunch or CME dinner, to participating in industry-sponsored research, to being a KOL, no doubt do so with the best of intentions. Treating serious mental illness can be a frustrating and heart-wrenching experience, but as Senator Grassley’s investigations reveal, some appear to have overreached. Alan Schatzberg, chairman of Stanford University’s psychiatry department and recent president of the American Psychiatric Association, who served as a KOL for Zyprexa, among others, and also served as principal investigator of an National Institutes of Health–sponsored study of mifepristone (better known as RU-486) for the treatment of psychotic depression. Yet he was found to have a US$6 million stake in Corcept Therapeutics, the company developing mifepristone.
Meanwhile, Charles Nemeroff, chairman of the department of psychiatry at the University of Miami, formerly the chair at Emory University, received over US$960,000 from GlaxoSmithKline (for personal use), all while conducting research projects on their drugs, and declaring only US$35,000 of this to the university. He typically made at least US$3500 per talk, speaking about GSK’s products. During this time he was also receiving money from Janssen, Lilly, Merck and others.
Other KOLs used their influence for other than financial gain. Wayne MacFadden, AstraZeneca’s former US medical director for Seroquel (quetiapine), confessed to having sex with at least two (and perhaps as many as four) female Seroquel research collaborators in hotel rooms paid for by AstraZeneca, as well as offering Vicodin to one and suggesting kinky-sounding punishment to another for looking at research that was unfavourable for Seroquel.
Another tactic to increase sales is to expand the pool of patients who, potentially, could take the new drugs. A particularly egregious example of this is the push by Big Pharma and a number of their psychiatrist allies to create a whole new disease called “Pediatric Bipolar Disorder,” or PBD. Although bipolar disorder has been described for 2000 years, it had always been regarded as an illness that generally hits (at least in its manic phase) in adolescence or later. In fact, a recent study tracked 207 children at high risk of bipolar disorder prospectively for up to fifteen years. Of these 207, sixty-seven went on to develop a major mood disorder. Corroborating earlier studies, the researchers “did not find evidence of pre-pubertal mania.” Nevertheless, aided by popular books and a few eager child psychiatrists, PBD has become a popular diagnosis for children (even babies) who exhibit signs of impulsivity, irritability and hyperactivity. What muddles the picture, of course, is the fact that these symptoms commonly occur in children with ADHD, as well as perfectly normal children and adolescents.
Last year an investigation by Senator Grassley found that three prominent advocates of PBD from Massachusetts General Hospital had collectively received over US$4 million from the drug industry and neglected to report the majority of this income to authorities. Also uncovered was the slide used by one of them, Joseph Biederman, to solicit further funding from Johnson & Johnson executives by offering to run a trial of their drug Risperdal that “will support the safety and effectiveness of risperidone in this age group.” The age group he was referring to was preschoolers; the favorable results he promised were for an experiment that had not been done.
This newfound interest in PBD, by the way, is not shared by my colleagues outside the United States. A survey of child and adolescent psychiatrists in Australia and New Zealand found that 83 per cent felt pre-pubertal PBD was rare, very rare, or “not diagnosable,” 90 per cent felt it was over-diagnosed in the United States, 3 per cent felt it was appropriately diagnosed, and 1 per cent that it was underdiagnosed. Yet PBD is now the most common psychiatric diagnosis used for hospitalised children and adolescents in the United States; and from 1994 to 2003 the number of outpatient visits for children with a diagnosis of bipolar disorder increased forty-fold (4000 per cent).
WHEN I FIRST entered the field of psychiatry, I believed, perhaps somewhat naively, that it was on the verge of major breakthroughs and I wanted to be part of this. Instead, the field has veered from seeking to understand and develop novel treatments for mental illnesses (and perhaps even prevent or cure them) to the pushing of a series of me-too drugs, no more effective than the ones they replace – but far more costly. For example, SGAs such as Abilify, Zyprexa, Seroquel, and Ziprasidone, have all but replaced the earlier agents, even though their cost – up to US$1000 per month as opposed to around US$50 per month for the older drugs – is devastating to most patients and has virtually bankrupted many community mental health systems. Certainly, some patients have benefited from these new drugs, but far more are being prescribed the newer drugs, and would be better served by being on older, better-tested medication. Recent studies, not sponsored by the drug makers, show that the earlier drugs are at least as effective as most of the SGAs, and although the SGAs are claimed to have fewer side effects, this may be a trade-off for far more serious consequences in the long run, such as diabetes, heart attacks and stroke. When I point out the data showing this to students and doctors I teach, they often look crushed, or simply express disbelief. They want to believe the flashy presentations and famous KOLs; they too wish to believe that they are part of a new generation of healers with powerful new tools to ease suffering like never before possible.
Even psychiatry’s “bible,” the DSM (Diagnostic and Statistical Manual) produced by the American Psychiatric Association, which is the standard guide used for making psychiatric diagnoses and – perhaps most important – for billing was, like most psychiatric practice guidelines, written largely by industry KOLs. In fact, in its current iteration, DSM-IV, 100 per cent of the members on the panels for “Mood Disorders” and “Schizophrenia and Other Psychotic Disorders” had financial ties to drug companies. The recently released draft update, DSM-V, has been met with blistering criticism. Since no major advances have been made in our understanding of the causes of psychiatric illness, their diagnosis, or their treatment since DSM-IV, one must question why a new manual is needed. Still, DSM-V and its copyrighted offspring are likely to produce great income for the American Psychiatric Association.
One really can’t blame the pharmaceutical industry. They are simply following an effective business model. According to the annual report of PhRMA (Pharmaceutical Research and Manufacturers of America, the industry’s largest trade group), the large companies spend only 15 to 17 per cent of their income on research and development of new drugs – but two to three times this much on promotion. Is this how the industry wants to allocate its money? I doubt it. Corporations have a legal responsibility to put shareholders’ interests above all others. Profits must be maximised, and any seemingly altruistic actions must be justifiable in the long run on a financial basis. They do it because they have to and they do it because it works. In the current drug development and marketing paradigm, the medical profession is, in essence, blackmailing the pharmaceutical industry. From free pens to free CME to lucrative speaking arrangements, the industry must pay to play. And this money comes out of society’s pocket via inflated drug prices, diverted away from truly innovative research.
One might ask why there hasn’t been more oversight of the cosy relationship between psychiatry (and medicine in general) and the pharmaceutical industry? The simple answer is that an even cosier one exists between the industry and government. Last year, according to the Center for Responsive Politics,the pharmaceutical and health products industry spent US$236 million on lobbying, more than any other industry in the United States. With 1228 registered lobbyists it has 2.3 for every member of Congress, more than a third of whom are former federal officials. Former President George H.W. Bush was a member of the Eli Lilly board of directors, as was the former CEO of Enron, Ken Lay. Mitch Daniels, a former Lilly senior vice-president, and Sidney Taurel, president and CEO of Eli Lilly served as members of the National Security Council and the Homeland Security Council. They, along with former secretary of defense Donald Rumsfeld – who was CEO, president and chairman of Searle Pharmaceuticals, which through mergers ultimately became Pfizer – helped craft the Homeland Security Act, hastily passed in the wake of 9/11. The Act contains a rider protecting Eli Lilly from any legal action related to its product thimerosal. Exactly how this provision was intended to help protect us from Osama bin Laden is still not entirely clear.
The list goes on. Alex Azar, who as deputy secretary of Health and Human Services under George W. Bush, oversaw such agencies as the Food and Drug Administration, the National Institutes of Health, the Centers for Disease Control and Prevention, and the Centers for Medicare and Medicaid Services, in May 2007 became senior vice-president of corporate affairs and communication for Eli Lilly. Former Republican congressman Billy Tauzin, who in his role as chairman of the House Energy and Commerce Committee had authority over the pharmaceutical industry, spearheaded the passage of the infamous Medicare drug benefit overhaul, widely viewed as a giveaway to the industry. It prohibited the federal government from negotiating lower prices for medicine and continued the ban on importation of identical lower-cost drugs from Canada. After leaving office Tauzin assumed the role of head lobbyist for PhRMA, with a reported US$2 million annual salary.
Few realise just how high the financial stakes are. In 2002 the combined profits for the ten drug companies listed in the Fortune 500 was US$35.9 billion, exceeding the total profits of the other 490 companies put together (US$33.7 billion). But I do see some hope for change. The emergence of passionate bloggers like Philip Dawdy at Furious Seasons, Dr Daniel Carlat at the Carlat Psychiatry Blog, Ed Silverman at Pharmalot, Jim Edwards at Bnet, and John Mack at Pharma Marketing Blog have brought news of Big Pharma’s behaviour, and psychiatry’s collusion, to ever greater numbers of people. Senator Grassley’s work has also revealed the sordid underbelly of my profession and has used shame (or in some cases force) to persuade companies and individuals to begin to change. Organisations like NoFreeLunch.org, Healthy Skepticism and National Physicians Alliance are working to realign doctors’ priorities. Some medical schools are asking their faculty to stop doing talks for drug companies. A number of medical journals are banning ghost-written journal articles. The American Psychiatric Association, which until recently received one-third of its revenue from industry is taking steps in the right direction, such as phasing out industry-sponsored symposia at their annual meeting. Carlat himself – an associate clinical professor at Tufts University – recently refused the US$170,000 that Schering-Plough offered him to peddle good news about its recently approved SGA Saphris. (Carlat went on to publish portions of the invitation letter from Schering-Plough on his blog, including the line that paid presenters “must present the Schering-Plough approved materials provided to you.”) Many American journals now require that drug studies be registered with ClinicalTrials.gov, the US government’s repository for trial data, which should decrease the likelihood that unfavourable data is hidden (although two recent publications show poor compliance with the registry). And a recent survey showed that pharma sponsorship levels for CME are dropping: CME providers reported receiving US$1 billion in educational grants from drug and device companies in 2008, down from US$1.2 billion in 2007.
Does society truly wish for physicians to claim CME credit for presentations sponsored by the pharmaceutical industry? Just as lawyers have to pay for their own continuing education, so too should physicians pay for theirs. The Accreditation Council for Continuing Medical Education, the organisation that monitors and approves CME, reports that over half of the funds for CME in this country come from industry. Of the US$1 billion industry spent last year on CME, US$225 million went to universities and US$202 million to professional societies, which – in essence – launder this money through what are euphemistically called “unrestricted educational grants.” And this is only for accredited CME; it does not include the avalanche of non-accredited information heaped on physicians.
If physicians choose to work for industry, that is certainly their prerogative, but they are assuming a very different professional role than a clinician or educator, and should no longer claim to serve as an unbiased doctor or teacher. There is a growing awareness of this problem; students at Harvard Medical School, for instance, protested in October 2009 against the conflicts of interest held by many of their professors. (Eerily, an employee of Pfizer was seen photographing the students during the protest.) As Louis Brandeis said in 1913, sunlight is the best of disinfectants.
In that vein, expanding the “sunshine laws” already enacted by several states – which require public disclosure of physicians who take kickbacks from industry – will be beneficial, and is part of the recently passed healthcare overhaul legislation. But concern remains about how this will be monitored. Payments can be hidden in many ways. It would also be beneficial if academic institutions and medical societies start taking a more aggressive stance in relation to faculty and members who commit academic fraud, such as claiming responsibility for studies they did not design and authorship for papers they did not write. Studies performed by a company marketing a product should be viewed for what they are: marketing. Moreover, relying on drug companies to police themselves and to provide accurate information about their products’ performance and problems is not realistic, nor is expecting the FDA to monitor them while at the same time depending on their financial support.
Finally, beyond the financial, political, and ethical considerations of these conflicts, we must consider the human suffering. Psychiatric patients are among the most vulnerable in our society, the very nature of their illnesses impairing their ability to advocate for themselves. There is a tongue-in-cheek saying in psychiatry: hurry up and use a new drug while it still works. This is because so many new drugs have turned out to be such huge disappointments. Breakthroughs have been few and far between. The last Nobel Prize awarded for a psychiatric treatment was in 1949, and that went to António Egas Moniz for developing the lobotomy. The last breakthrough psychiatric medication, one that might actually work significantly better than those it hoped to replace – rather than a marketing coup like Prozac and the SGAs – was Clozapine, which was discovered in 1959 and released for sale in Europe in 1971. Ultimately, its advantages have proven to be relatively modest for most patients, and offset by serious – sometimes fatal – side effects. Psychiatry’s overreliance on newer, less effective and less well-tested drugs is needlessly putting patients at risk. When the next breakthrough in psychiatry occurs it will not be popularised via an industry-sponsored infomercial, or come out in a ghost-written meta-analysis showing a statistical but not clinically significant effect. It will make headlines. And psychiatric diagnoses are generally not best made while watching a TV commercial. Since the underlying biological mechanisms of psychiatric illnesses remain unknown, and there are no useful diagnostic scans or blood tests, their diagnosis is made with a careful and thoughtful examination and history taking. Impartiality is crucial to this process. What it boils down to in the end is that most of us want our doctor to listen to us, not to profits. •
Nicholas Z. Rosenlicht is Clinical Professor of Health Science in the School of Medicine at the University of California, San Francisco. The views expressed in this article are those of the author and do not necessarily represent the views of, and should not be attributed to, the University of California, San Francisco.
This article and the commentary below are published in association with Healthy Scepticism.
And Australia?
Child and adolescent psychiatrist Peter Parry responds to Nicholas Rosenlicht’s article
PSYCHIATRY is prone to pendulum swings. The extremes of the pendulum’s arc – “brainless psychiatry” and “mindless psychiatry” – were best encapsulated in Zbigniew J. Lipowski’s 1988 presidential address to the Canadian Psychiatric Association. Lipowski noted that the mid-twentieth-century hegemony of Freudian psychoanalysis led at worst to a “brainless” under-treatment of the biological aspects of serious mental disorders. But his immediate concern was a future, post-DSM-III (the 1980 third edition of the American Psychiatric Association’s diagnostic manual) world of “mindless psychiatry” driven by the increasing influence of pharmaceutical companies in research and medical education.
In the United States the pendulum is now at full swing, with the “pill for every ill” approach apparently widespread. The United States has an epidemic of “paediatric bipolar disorder” in preschoolers, typified by the tragic death from medication of four-year-old Rebecca Riley, who was diagnosed at twenty-eight months. And it’s spreading: a recent article in New Scientist, “How the US exports its mental illnesses,” detailed how pharmaceutical giant Glaxo Smith Kline had to promote a new vision of depression to the Japanese – who saw non-melancholic depression as a painful but character-building state rather than an illness – before marketing its antidepressant paroxetine.
So how applicable is this to Australia?
In 1990, my first year of psychiatry training, I read “Biologism in Psychiatry” in the journal of the Royal Australian and New Zealand College of Psychiatry, or RANZCP. The author, Derrick Silove, a professor from Sydney, had returned from the United States concerned by the “paradigm shift” of which Lipowski warned. “A recent study visit to North America impressed on me the seriousness with which Australian psychiatry should consider the recent ideological shift in the USA to an extreme biological model of mental disorders.…” he wrote. “We would be well advised not to underestimate the potency of North American cultural and intellectual hegemony on our ways of construing all aspects of the modem world.”
Silove was nonetheless hopeful that Australasian psychiatry, with the RANZCP’s emphasis on the biopsychosocial model and rigorous clinical training, would resist the American pendulum swing. Twenty years later it is fair to say his hopes have been partially realised. Psychiatry training in Australia and New Zealand is long and rigorous and still steeped in the biopsychosocial approach. While the American DSM-IV is the “bible” of diagnostic terminology, it generally still remains balanced here by an individual “case formulation” approach to a patient’s real human history and situation. You shouldn’t pass the RANZCP exams if you can’t show this holistic biopsychosocial approach.
But the overburdening of public mental health in the last two decades has seen an erosion of psychosocial therapies, rushed ward rounds and less time for due consideration of the unique contexts of individual patients’ problems. Into these fissures can seep biologism, with its siren call of easy presumptive diagnoses and overly simplistic medication fixes.
Continuing medical education in Australia, as in the rest of the world, is too heavily dependent on pharmaceutical industry sponsorship. The psychiatric literature is global and Rosenlicht’s argument applies equally here. This literature, and accompanying pharmaceutical advertising, affects general practice, general medicine and paediatrics – fields without the RANZCP level of training.
Australasian psychiatry cannot fully escape the global biomedical zeitgeist. Philip Boyce, president of the RANZCP in 2005, noted in his presidential address: “The tragedy is that as our knowledge grows, our approaches to treatment seem to become simplistic, with psychiatric practice sadly becoming dumbed down (at least in some sectors in both countries), with a tendency to adopt a cookbook approach to our treatments and a lack of sophistication in the way we understand patient problems. The current paradigm seems to be that if a patient suffers from a specific DSM disorder, then there is a specific medication for this. If that medication does not work, try some other medication or add something to it.
“There are a number of trends that have contributed to this: increased service demand, the deification of DSM, the influence of the pharmaceutical industry, a misunderstanding of evidence-based medicine (EBM), managerialism and the influence of consumerism.”
(Nicholas Rosenlicht quotes a paper about the pharmaceutical industry’s influence on evidence-based medicine that I co-authored with Glen Spielmans. I provided a more lay-accessible version here, for Crikey’s health blog, Croakey.)
The “influence of consumerism” feeds into the desire for quick fixes and to avoid painful introspection about personal or family dynamics. The Australian public may have more innate common sense and scepticism than many in the United States, but is not immune. Television advertisements for antipsychotic drugs, like the one “Julie” watched, are prohibited in most nations including Australia. But the world is now a small, interwired place. Having read American websites, Australian parents are presenting to child mental health services wondering if their child has “paediatric bipolar disorder.” Australians buying Newsweek in March 2008 would have read the cover story of a ten-year-old American boy “Max” diagnosed bipolar at age two and having had thirty-eight psychiatric drugs in his short life.
Finally, compared to the United States, Australia has a more solid protective factor than its national sceptical character – universal Medicare, which allows generous access (by global standards) to psychotherapy and family therapy. Despite some cases of over-servicing, this access is vitally worthwhile.
When I attended the American Academy of Child & Adolescent Psychiatry conference in Hawaii last year I presented a paper reporting on a survey of child psychiatrists in Australia and New Zealand showing 90.5 per cent believed bipolar over-diagnosed in US children, 6 per cent unsure and 3.5 per cent thinking the Americans had the diagnostic rates correct or under-diagnosed. That drew some interest. What several US colleagues told me was that if they give some insurance companies a diagnosis of “parent–child relational problem” (which is actually in the DSM) they won’t get paid, if they say the child has “adjustment disorder” they might get some minimal funding, and if they say “bipolar disorder” then they get better funding, though it may be mainly for medication – a clear case of “diagnostic upcoding” in action. Australia’s comparatively rational health system is some protection in this increasingly wanting-to-be-mad world. •
Peter Parry is a child and adolescent psychiatrist at Flinders University
