Why we all should be concerned about how psychiatric drugs are researched, developed, and marketed
The research, development and marketing of psychiatric drugs has become a very large and lucrative industry. In 2015, the sales of psychiatric drugs in the United States alone generated revenues of over $70 billion. With so much profit at stake, there’s an obvious risk that the best science and most altruistic motives may not always be steering this industry.
This risk has been proven to be real and substantial, and concerns about conflicts of interest and bias in the research and practice of medicine and psychiatry have in the past two decades become increasingly prominent topics of public discussion.
One 2010 analysis found that over 60% of all medical studies in the U.S. were funded by drug companies. In practice, this usually means that the drug company maintains significant influence, and often extremely tight control, over all of the crucial decisions including designing the trial, setting it up and recruiting participants, conducting the trial, collecting, statistically analyzing and summarizing the data, selectively publishing the results in medical journals and presenting findings to health regulators, physicians or the media. And the results are unequivocal: Every formal study of the topic has shown that when researchers are being funded by a drug company, their studies are much more likely to come to conclusions that favor that company’s drug.
That’s not entirely surprising. While pharmaceutical companies tend to portray themselves to the public as pure engines of innovative scientific research, several independent analyses have concluded that the pharmaceutical industry is likely spending about twice as much on marketing and promotion as on research and development. As part of that, trying to ensure that their clinical drug trials produce favorable findings about their drugs has become a key part of most brand-name pharmaceutical companies’ advertising and marketing plans, just as maximizing profits for shareholders is part of their corporate mandates.
The resulting drop in trustworthiness of medical research has become so widely recognized and concerning that all of the world’s leading medical journals have in recent years made high-profile efforts to try to institute stronger conflict-of-interest policies. But the journals have struggled in these efforts – They themselves are often financially reliant on drug company purchases of advertising and article reprints, while the majority of expert medical and psychiatric researchers also accept gifts, meals, funding, payments for participation in events, and/or research grants from the pharmaceutical industry.
To make matters even more concerning, the pharmaceutical industry now provides more than half of the annual funding of the Food and Drug Administration (FDA)—the very government agency that is tasked with approving and regulating drugs in the United States. Some have argued that this has put our own public drug regulator in a conflict of interest, where many FDA employees see themselves as responsible for catering to companies’ needs. And not coincidentally, it has become common practice for senior pharmaceutical industry executives to actually gain employment at the FDA, and for senior officials to leave the FDA to work for pharmaceutical companies.
Consequently, in the same way that we need to be skeptical of glowing claims we may hear about consumer products like breakfast cereals, soft drinks or cars, we have to be skeptical of claims about psychiatric drugs. But it’s not always easy to critically appraise the claims of pharmaceutical companies, researchers and mental health practitioners; it’s vital to be able to understand the intersections of money, power, policy, research practices, regulation, industry, media, and non-profit organizations that steer the research and marketing of drugs. So in this essay, we’ll help you do just that, explaining how drugs are typically researched, approved by the FDA, brought to market, and promoted throughout society. Along the way we’ll highlight the many points in the process where manipulation, deception, and corruption occur far too commonly, and give real examples to elucidate these issues and help you empower yourself to think more critically about the safety, efficacy, and scientific evidence base of psychiatric drugs.
Related reading:
Dorsey, E. Ray, Jason de Roulet, Joel P. Thompson, Jason I. Reminick, Ashley Thai, Zachary White-Stellato, Christopher A. Beck, Benjamin P. George, and Hamilton Moses. “Funding of US Biomedical Research, 2003-2008.” JAMA 303, no. 2 (January 13, 2010): 137–43. doi:10.1001/jama.2009.1987.
Ferris, LE, and RH Fletcher. “Conflict of Interest in Peer-Reviewed Medical Journals: The World Association of Medical Editors Position on a Challenging Problem.” Journal of Young Pharmacists : JYP 2, no. 2 (2010): 113–15. doi:10.4103/0975-1483.63143.
Gagnon, Marc-André, and Joel Lexchin. “The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States.” PLOS Medicine 5, no. 1 (January 3, 2008): e1. doi:10.1371/journal.pmed.0050001.
Light, Donald W., Joel Lexchin, and Jonathan J. Darrow. “Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs.” SSRN Scholarly Paper. Rochester, NY: Social Science Research Network, June 1, 2013.
International Committee of Medical Journal Editors. “Sponsorship, Authorship, and Accountability.” (August 2007).
Ruff, Kathleen. “Scientific Journals and Conflict of Interest Disclosure: What Progress Has Been Made?” Environmental Health 14 (2015): 45. doi:10.1186/s12940-015-0035-6.
Schott, G; Pachl, H; Limbach, U; Gundert-Remy, U; Ludwig, W; Lieb, K. “The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 1. A Qualitative, Systematic Review of the Literature on Possible Influences on the Findings, Protocols, and Quality of Drug Trials.” Dtsch Arztebl Int, 2010; 107 (16): 279-85 DOI: 10.3238/arztebl.2010.0279
Wazana A. "Physicians and the pharmaceutical industry: is a gift ever just a gift?" JAMA. 2000;283:373–380. doi: 10.1001/jama.283.3.373.
World Association of Medical Editors. “Conflict of Interest in Peer-Reviewed Medical Journals.” (July 25, 2009)
How psychiatric drugs are discovered or developed
In the 1940s, medically-oriented psychiatrists relied primarily on interventions like doctor-induced insulin coma, electroshock, and lobotomies, and had at their disposal very few chemical substances to administer to psychiatric patients. This would start to change in the 1950s. A surgeon named Henri Laborit noticed that chlorpromazine, an antihistamine that was being used to treat nausea, allergies and other conditions, seemed to alter mental states and induce calm in his patients before surgery. Word spread, and chlorpromazine was soon being given to psychiatric patients in U.S. mental institutions under the brand name Thorazine. The drug became one of the most widely prescribed early neuroleptics or tranquilizers – which today are more commonly called antipsychotics.
Such accidental discoveries have been typical of the psychiatric drug industry. Unlike in certain areas of medicine where researchers are able to target a specific, biologically detectable pathology such as a bacterial infection, there are no biological markers of any kind for what are commonly called “mental disorders”. (Read more about this issue in ICI’s “How Mental Disorders are Diagnosed”.) Therefore, new psychiatric drug possibilities are not found by honing in on underlying biological abnormalities and working to eradicate or resolve them pharmacologically. New drugs are generally “stumbled upon” when researchers simply happen to observe a drug altering mental, emotional, or behavioral states in research subjects. Researchers sometimes subsequently develop a biological hypothesis about what the particular drug may be doing to help “treat” mental or emotional states and, if the drug becomes successful in the marketplace, other pharmaceutical companies may then develop chemically similar drugs and market them in similar ways.
For example, the idea that depressed feelings were caused by low levels of the neurotransmitter serotonin was developed after it was observed that selective serotonin reuptake inhibitors (SSRIs) – drugs that in part temporarily increase the levels of serotonin re-circulating in the brain – seemed to slightly alleviate depressed feelings in some people. This biochemical hypothesis about depression was almost immediately disproven by subsequent research but, due to intensive marketing and public relations efforts by the pharmaceutical industry, the idea that low serotonin levels are related to depression has endured to this day in the media, among mental health organizations, and even in the minds of many average physicians and psychiatrists as if it were long-established fact.
Similarly, when it was identified that many of the antipsychotic drugs in part disrupted dopamine activity in the brain, it was then that drug companies, the American Psychiatric Association, and many practicing psychiatrists began to promote the hypothesis that the experiences related to a diagnosis of schizophrenia or psychosis might be caused by a “chemical imbalance” of excessive dopamine. This hypothesis, too, has never been proven.
Related reading:
López-Muñoz, Francisco, Cecilio Alamo, Eduardo Cuenca, Winston W. Shen, Patrick Clervoy, and Gabriel Rubio. “History of the Discovery and Clinical Introduction of Chlorpromazine.” Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists 17, no. 3 (September 2005): 113–35.
Hirschfeld, R. M. “History and Evolution of the Monoamine Hypothesis of Depression.” The Journal of Clinical Psychiatry 61 Suppl 6 (2000): 4–6.
A brief snapshot of the drug approval process in the United States and the risks of off-label prescribing
Before any new pharmaceutical drug can be sold in the United States by prescription, it must be approved as relatively safe and effective for its intended use by the U.S. Food and Drug Administration (FDA).
But there’s a very large, commonly used loophole allowing circumvention of this entire process: The drug doesn’t actually have to be approved as safe or effective for all of the uses for which doctors may end up prescribing it. Physicians can prescribe “off-label” – meaning they can prescribe drugs for indications that are not approved by the FDA and are not listed on the official drug label. Many psychiatric drugs, in fact, fall into this category. They were approved as relatively safe and effective for very specific uses – in certain cases simply for short-term, non-psychiatric uses such as controlling epileptic seizures – yet now are being widely prescribed by doctors and psychiatrists for a wide range of psychiatric uses and for long periods of time. This common practice presents unknown risks to patients.
However, even when a drug has been approved by the FDA for certain psychiatric uses, that doesn’t always mean it’s truly safe and effective for those uses, either. Let’s walk through the process of FDA approval to understand why that’s the case.
Though physicians can prescribe whatever drugs they deem to be in the best interests of their patients, for a pharmaceutical company to be legally allowed to market a drug to doctors and to the public as relatively safe and effective for a particular, specific use, the pharmaceutical company must get FDA approval to do that. FDA approval can often mean billions of dollars in additional profits for a drug company, not only because it can lead to exclusive marketing rights, but also because FDA approval often is, in the minds of physicians and the public, a “stamp of approval” of safety and effectiveness.
FDA approval involves a four-step process:
- During an initial trial (Phase 1), the drug company tests their drug – usually in animals – to see how well its active ingredient is tolerated and what if any adverse effects it causes.
- In Phase 2, the drug company tests its drug on healthy human subjects in order to determine optimal doses of the drug and further assess its safety. None of the trial participants at this stage are diagnosed with the disease or condition that the drug is ultimately intended to treat.
- Phase 3 is the most important phase. During it, the drug company runs larger clinical trials involving patients who have been diagnosed with the targeted disease or disorder. The drug company typically hires outside researchers to conduct one or more “randomized, placebo-controlled trials” (RCTs) where all of the patients are randomly assigned to taking either the drug or a placebo or a comparison drug that is already approved. (A placebo is a pill that looks like the drug being studied, but that typically has no medical effects.) Often these are “double-blinded” studies, where neither the researchers nor patients are supposed to know until the end of the trial who was taking a drug or placebo. There are two basic types of Phase 3 trials – those that focus mainly on measuring the effectiveness of the drug for treating the targeted disease or disorder, and those that focus more specifically on monitoring for adverse effects of the drug. Finally, the pharmaceutical company presents the findings from these trials to the FDA for review.
- The Phase 4 trials are post-market safety studies. If at the end of Phase 3 the FDA approves the drug for the new intended use, then the pharmaceutical company is expected to (but is often not forced to) collect reports of adverse events and notify the FDA of risks and harms that are becoming evident as the drug is being taken by many more people under real-world conditions.
On the surface, this drug approval process might seem straightforward and reliable. In reality, this is far from the case. There are many points throughout the FDA drug approval process that leave a lot of room for important information about a drug to be missed entirely and for misleading or biased results to emerge. Phase 4 real-world surveillance of adverse effects, for example, is often not enforced by the FDA and drug companies simply never do it or do it only spottily. But since Phase 3 is the most important phase, in the next section we’ll explore in detail how even the medical “gold standard” research method of double-blinded, randomized, placebo-controlled clinical trials can easily be made to produce misleading, biased results favoring a psychiatric drug.
How clinical trials can easily produce falsely favorable findings about drugs – And how often it happens
The double-blinded, randomized, placebo-controlled drug trial is widely used in medicine and psychiatry as a “gold standard’ method for removing bias from studies. Unfortunately, it is still very easy and common for such studies to be biased. And every study of this issue has shown that drug company funding of a clinical trial tends to lead to more favorable findings about the company’s own drug. But how does this happen?
A long-time editor of the British Medical Journal published an instructive list of “Examples of Methods for Pharmaceutical Companies to Get the Results They Want from Clinical Trials”. We’ve added examples from his list and from other sources to our own list below. After that, we’ll look at examples of these techniques being used in actual clinical trials for psychiatric drugs.
How Researchers Can Bias Clinical Trials to Make Psychiatric Drugs Seem Safer and More Effective than They Actually Are
- Keep the trial so short that there isn’t time for the effectiveness of your drug to wear off, or for the real, long-term harms of the drug to emerge.
- Do a pre-trial test of your drug and identify all of the people who respond well to it, and then keep only these good responders in the actual trial.
- Trial your drug against too high a dose of a competitor drug, so that your drug will appear less toxic.
- Use creative ways to categorize adverse events during the trial as symptoms of people’s diagnosed mental disorders, rather than as side effects of your drug.
- Unblind the trial “by accident”, so that researchers and patients can easily ascertain who is taking the drug and who is taking placebo.
- Use a combination of several different measures of effectiveness and definitions of effectiveness in the trial, and then only publish the results for the measures that showed your drug was effective.
- Do a trial that occurs at multiple different medical centers at the same time, and then only publish results from the medical centers where your drug appeared to be effective.
- Do multiple trials at the same time, and then only publish the results for the trials that favored your drug.
- Analyze “subgroups” of participants in the trial (e.g. selecting for a certain age, race, gender, economic background, previous treatment history, or subcategory of diagnosis, etc.) and then only publish the results for the subgroups for whom your drug appeared to be effective.
- Make the abstract and conclusions for the published study sound generally positive about your drug, and then bury less favorable details deep in the article or in supplemental tables where most people won’t go to read them.
- Report percentages, numbers and “statistical significance” in ways that are designed to sound more impressive or scarier than they really are. For example, if 1 out of 1,000,000 people taking your drug contracted a serious illness from it compared to 2 out of 1,000,000 people taking your competitor’s drug, freely admit to other researchers that people taking your drug only had a statistically insignificant 0.0001% lower chance of contracting a serious illness. But tell the news media and average physicians that people taking your drug had a 50% reduced risk of contracting a serious illness, while your competitor’s drug doubled the risk of serious illnesses.
- Make sure all of the participants in the trial have been taking your dependence-forming psychiatric drug for long enough to actually become physically dependent on it. Then, create a placebo comparison group by forcing half of those participants to abruptly withdraw from your dependence-forming drug. When people in the placebo group suddenly start suffering through intense physical, emotional and mental drug withdrawal symptoms, your drug will look much more effective and safe compared to placebo.
Unfortunately, the types of manipulations described above are not uncommon in psychiatric drug studies. Indeed, many meta-analyses of large numbers of studies of psychiatric drugs show that these kinds of practices are in fact more the rule than the exception. Some of the selected representative examples below include references to many other examples.
Some Typical Examples of Bias and Manipulation in Influential Psychiatric Drug Trials
During both trials submitted to the FDA for the approval of the anticonvulsant Lamictal (lamotrigine) for treating people diagnosed with bipolar disorder, the researchers changed their primary way of measuring the drug’s effectiveness many times, including once more after the trials were completed. The FDA medical review noted that the drug would have failed to beat placebo if not for the final, last-minute change in what the researchers were measuring.
Source: U.S. Food and Drug Administration. “Medical Review: Lamictal.” (June, 2003)
A 2014 study in BMJ Open reviewed 142 clinical trials of antipsychotic and antidepressant drugs where detailed trial information had been provided to government regulators by law, and then examined how forthright the study authors were when they published these same studies in medical journals for the scientific community and general public. The BMJ Open study found that half or more of the published versions of these studies omitted mentioning deaths or suicides that had occurred during the trials, omitted mentioning serious adverse drug effects that had been identified during the trials, and/or omitted mentioning the trials’ less positive longer-term findings.
Source: Hughes, Shannon, David Cohen, and Rachel Jaggi. “Differences in Reporting Serious Adverse Events in Industry Sponsored Clinical Trial Registries and Journal Articles on Antidepressant and Antipsychotic Drugs: A Cross-Sectional Study.” BMJ Open 4, no. 7 (July 9, 2014). doi:10.1136/bmjopen-2014-005535.
A 2006 study in the American Journal of Psychiatry found that, out of 33 studies and official medical reports comparing different antipsychotic drugs to each other, 90% of them concluded that the drug produced by the funder of the study or report was the best drug. The AJP researchers noted that this created “contradictory conclusions” when competing drug companies funded studies of each other’s drugs. The AJP researchers identified many instances of bias and manipulation in both the trials and the published studies, such as choosing trial participants in biased ways, using clearly inappropriate dosages, withholding data, making positive claims in abstracts that didn’t correspond to negative information provided deeper in the study, and using terms like “equally effective” very loosely.
Source: Heres, Stephan, John Davis, Katja Maino, Elisabeth Jetzinger, Werner Kissling, and Stefan Leucht. “Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation Antipsychotics.” American Journal of Psychiatry 163, no. 2 (February 1, 2006): 185–94. doi:10.1176/appi.ajp.163.2.185.
A 2015 study in JAMA Psychiatry examined clinical trials for nine different antidepressants that that had been submitted to the FDA by drug companies seeking approvals for treating people diagnosed with anxiety disorders. Over a quarter of the studies did not show even slightly positive findings about the drugs; nevertheless, these negative studies were usually either never published or, when they were published in psychiatry journals they were made to sound more positive about the drug than they actually were.
Source: Roest AM, de Jonge P, Williams CD, de Vries Y, Schoevers RA, Turner EH. “Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses.” JAMA Psychiatry. Published online March 25, 2015.
There were only three trials submitted to the FDA to prove the effectiveness of the ADHD drug Concerta – one trial was just four weeks in length and two trials were only one week in length. All three trials involved many young children who were already taking Ritalin, a drug with the same active ingredient as Concerta, methylphenidate. For the trials, the main drug group simply switched from Ritalin to Concerta. But to create the placebo group, the researchers forced a large number of the children to abruptly stop taking their Ritalin. Since methylphenidate is known to cause physical dependence, many children in the placebo group would likely have been suffering acute physical and mental drug withdrawal effects, thereby making Concerta look both safer and more effective compared to placebo than it actually was.
Source: U.S. Food and Drug Administration. Concerta Drug Approval Package: Medical Review. (2000)
Studies published in the British Medical Journal in 2008 and 2012 found that when medical researchers – including those of psychiatric studies – knew for certain which patients were taking the drugs and which patients were taking placebo, those researchers tended to significantly inflate and exaggerate positive effects of the drugs.
Sources:
Gøtzsche, Peter C. “Unblinding in SSRI Trials due to Side Effects Is an Important Source of Bias.” The British Journal of Psychiatry, December 7, 2016.
Wood, Lesley, Matthias Egger, Lise Lotte Gluud, Kenneth F. Schulz, Peter Jüni, Douglas G. Altman, Christian Gluud, Richard M. Martin, Anthony J. G. Wood, and Jonathan A. C. Sterne. “Empirical Evidence of Bias in Treatment Effect Estimates in Controlled Trials with Different Interventions and Outcomes: Meta-Epidemiological Study.” BMJ 336, no. 7644 (March 13, 2008): 601–5. doi:10.1136/bmj.39465.451748.AD.
Hróbjartsson Asbjørn, Thomsen Ann Sofia Skou, Emanuelsson Frida, Tendal Britta, Hilden Jørgen, Boutron Isabelle et al. “Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.” BMJ 2012; 344 :e1119
A 2015 study in the Journal of Clinical Epidemiology reviewed 185 meta-analyses of clinical trials of antidepressants for treating people diagnosed with depression. (Meta-analyses are often cited as the best summaries of all the available clinical evidence.) This JCE study found that 79% of the meta-analyses involved authors with one or more significant conflicts of interest, and 29% of these meta-analyses had authors who were actually employees of pharmaceutical companies assessing their own company’s antidepressants. The meta-analyses were 22 times less likely to include negative statements about a drug in the abstract’s conclusions if the research team included even just one co-author who was employed by the manufacturer of one of the drugs being evaluated.
Source: Ebrahim, Shanil, Sheena Bance, Abha Athale, Cindy Malachowski, and John P. A. Ioannidis. “Meta-Analyses with Industry Involvement Are Massively Published and Report No Caveats for Antidepressants.” Journal of Clinical Epidemiology 70 (February 1, 2016): 155–63. doi:10.1016/j.jclinepi.2015.08.021.
In 2001, the Journal of the American Academy of Child and Adolescent Psychiatry published an extremely influential study (“Study 329"), authored by some of the most reputable and high-profile child psychiatrists in the U.S. and Canada, that determined that the antidepressent Paxil (paroxetine) was safe and effective for children and adolescents. But during a coincidental U.S. Department of Justice fraud investigation into the drug company, internal company documents provided a rare glimpse behind the scenes of a major pharmaceutical company’s drug trials. As was stated in the 2012 legal settlement, and affirmed in an independent re-analysis that was published in the British Medical Journal in 2015, the data in the Study 329 Paxil trial clearly showed the exact opposite of what the original researchers had written: The drug was not any better than placebo, and it caused suicidal thoughts in some children and increased the rates of many other harms. However, the Study 329 researchers and/or the drug company co-authors had repeatedly changed the measures of effectiveness they were using until they found ones that favored the drug, suppressed key data about adverse drug effects, coded serious adverse drug effects in ways that reduced their significance, and coded some adverse events that were likely caused by the drug as being caused by depression, among other manipulations. Despite these findings, Study 329 has never been retracted.
Sources:
Restoring Study 329: Scientific Integrity Though Data Based Medicine.
U.S. Department of Justice. “Press Release: GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data.” (July 2, 2012)
Keller, Martin B., Neal D. Ryan, Michael Strober, Rachel G. Klein, Stan P. Kutcher, Boris Birmaher, Owen R. Hagino, et al. “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial.” Journal of the American Academy of Child & Adolescent Psychiatry 40, no. 7 (July 1, 2001): 762–72. doi:10.1097/00004583-200107000-00010.
In conclusion, just because many clinical trials may claim to show that a psychiatric drug is safe and effective and the FDA has approved the drug, it does not necessarily mean that the drug actually is safe and effective. Indeed, without delving deeply into the study details oneself, it is impossible to know what the terms “safe” and “effective” were even referring to during any particular study. (To learn more about the ways in which “safe” and “effective” have been used in drug trials submitted to the FDA for each class of psychiatric drug, explore ICI’s “Interventions” section.)
How prescribers learn about drugs, and why we should be concerned about it
After completing their basic medical education, doctors and psychiatrists continue to get information about new drugs in a variety of ways. Most of these blur the boundaries between education and advertising in ways that even the most knowledgeable experts can sometimes not easily unravel.
The pharmaceutical industry has been estimated to spend on average up to $61,000 per year per U.S. practicing physician and psychiatrist in providing free sample drugs, visits from company representatives, gifts, meals, trips, etc. This also includes seminars, workshops, Continuing Medical Education (CME) and other professional development activities for doctors, the vast majority of which are funded and run by pharmaceutical companies or by their contracted third-party communications and public relations firms. In many cases, drug companies not only pay for physician or psychiatrist “key opinion leaders” to lead these sessions, but they pay for the time and expenses of average family physicians and general-practice psychiatrists to attend.
Surveys have shown that the majority of practicing physicians accept and participate in these kinds of relationships with the pharmaceutical industry. ProPublica provides a free (though far from comprehensive) “Dollars for Docs” online app to search financial disclosures about pharmaceutical company payments to specific physicians. Numerous studies have shown that physicians tend to believe that they are not being unduly or improperly influenced or manipulated in such situations, while they usually in fact are. Even small gifts like pens or free lunches, or personal visits from pharmaceutical company sales representatives, have been shown to significantly alter physicians’ prescribing habits even against best practices. It’s unclear why this is, but it’s possibly because it’s not so much about the gifts as about the friendly, trusting relationships that get built between the pharmaceutical company representatives and the physicians and psychiatrists.
Furthermore, the educational programs and ‘Best Practices’ guidelines of many professional associations and societies for physicians and psychiatrists are often directly or indirectly funded by drug companies. For example, some 68% of the Task Force members for the American Psychiatric Association’s latest edition of the Diagnostic and Statistical Manual of Mental Disorders reported having financial ties to pharmaceutical companies, and at least 56% of those who posted disclosure statements admitted having industry ties such as holding stock in pharmaceutical companies or serving on the boards of pharmaceutical companies.
Those physicians and psychiatrists who are concerned about all of these conflicts of interest will seek out more independent sources of information about new drugs, but those are often less readily available because there is not much funding for such organizations.
Another common way that average physicians and psychiatrists learn about drugs is through illegal off-label promotion. While physicians and psychiatrists are free to prescribe drugs off-label in their own practices, there are laws in the U.S. that forbid pharmaceutical companies from marketing their drugs for off-label purposes or otherwise attempting to actively persuade doctors to prescribe off-label—that is, for uses that are not approved by the FDA and listed on the drug product label. But despite federal laws to prevent these practices, they are widespread. For example, numerous U.S. Department of Justice investigations have revealed drug companies illegally promoting antipsychotics for use in dementia patients and even paying kickbacks to doctors for doing so. Antipsychotics are not approved for tranquilizing and controlling the behavior of elderly people with dementia – and in fact the labels specifically warn against the practice because the drugs have been shown to increase mortality among the elderly – yet in the wake of illegal promotional efforts by pharmaceutical companies antipsychotics have in recent years become one of the most commonly prescribed drugs in nursing homes.
When drug companies market illegally in this way and are caught, the companies can be fined and face other sanctions. The fines are often small, though, compared to how much money the companies can make by doing this promoting, which is likely the reason this illegal practice has not abated over many years. (Public Citizen has compiled a list of the many fraud penalties paid by pharmaceutical companies over the past several decades.) For example, in 2012 the drug company GlaxoSmithKline (GSK) was fined $3 billion primarily for marketing its antidepressants Paxil and Wellbutrin for unapproved uses and withholding safety data on their diabetes drug Avandia, the biggest such fine in U.S. history. For perspective, GSK’s profits that year alone were three times that amount, over $9 billion.
Related reading:
Almashat, Sammy et al. “Twenty-Five Years of Pharmaceutical Industry Criminal and Civil Penalties: 1991 Through 2015 (Chart Book).” Public Citizen. (March 31, 2016)
Cosgrove, L., Bursztajn, H. J., & Krimsky, S. (2009). Developing unbiased diagnostic and treatment guidelines in psychiatry [Letter to the Editor]. The New England Journal of Medicine, 360, 2035-2036.
Gagnon, Marc-André, and Joel Lexchin. “The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States.” PLOS Medicine 5, no. 1 (January 3, 2008): e1. doi:10.1371/journal.pmed.0050001.
Mintzes, Barbara, Joel Lexchin, Jason M. Sutherland, Marie-Dominique Beaulieu, Michael S. Wilkes, Geneviève Durrieu, and Ellen Reynolds. “Pharmaceutical Sales Representatives and Patient Safety: A Comparative Prospective Study of Information Quality in Canada, France and the United States.” Journal of General Internal Medicine 28, no. 10 (October 2013): 1368–75. doi:10.1007/s11606-013-2411-7.
Norris P, Herxheimer A, Lexchin J, Mansfield P. Drug Promotion: What We Know What We Have Yet to Learn. World Health Organisation and Health Action International. Geneva: 2005.
U.S. Department of Justice. “Press Release: Johnson & Johnson to Pay More Than $2.2 Billion to Resolve Criminal and Civil Investigations.” (November 4, 2013)
Wazana A. "Physicians and the pharmaceutical industry: is a gift ever just a gift?" JAMA. 2000;283:373–380. doi: 10.1001/jama.283.3.373.
How psychiatric drugs are marketed through the news media
The United States is one of the only countries in the world that allows ‘direct-to-consumer’ advertising of pharmaceutical drugs. As a result, Americans are exposed to billions of dollars worth of prescription drug advertising in the media every year. But these ads aren’t the only channel through which drug companies influence us about their products. More subtle and arguably even more effective advertising for drugs comes through the regular programming and news stories of these same major media outlets. While it’s obvious that an advertisement will be biased and promotional in nature, many who hear about a particular illness or a drug’s safety and effectiveness on a TV program, read about it in a magazine or newspaper, or learn about it at a website like WebMD are more likely to regard the source as independent and trustworthy. News or media coverage of illnesses and drugs is, in effect, “free advertising” at its best for drug companies, because news stories come with a stamp of approval from an apparently independent source. Knowing this, the pharmaceutical industry cultivates relationships with news media, often by contracting third-party communications and media relations firms and working in collaboration with reputable researchers, universities and other institutions that they fund.
How does it work? You can peer into the process yourself by looking at a widely used source of mental health-related news releases, the “Mind and Brain” section of the website ScienceDaily.
First, a study is published that puts a positive light on the company’s drug or highlights the dangers of a disease, disorder or condition which the company’s drug treats, and then a news release highlighting the most dramatic or compelling aspects of the study’s findings are distributed. Professional reporters can usually obtain a more confidential “early view” of the news release and of the study itself. Typically the news release doesn’t look like it came from a pharmaceutical company or media relations firm but instead from a reputable university or research institute that was involved in the study. These news releases usually provide quotes, contact information for sources, and relevant background. Sometimes a quick call to the primary source listed also leads to contact information for celebrities or ordinary people who’ve been diagnosed with the condition or who’ve claimed to benefit from the drug. Notably, many medical journals now have policies asking authors to disclose their sources of funding and conflicts of interest, but if you follow health news, you have likely noticed that it is extremely rare for news reports to include any such disclosures from authors, experts, celebrities or any of the sources involved in the story.
All of this helps busy health reporters produce quick and compelling stories that often serve to promote drug treatments, unless an individual reporter takes the time to actually read the entire study, dig more deeply, and contact independent expert sources and critics. Incorporating more sober voices and balance in this way, however, often makes for a longer, more complicated story.
The relationships between pharmaceutical companies and non-profit organizations
Non-profit mental health organizations play a key role in the marketing strategies of pharmaceutical companies. These organizations help promote public awareness of and concerns about mental disorders and support for the drugs aimed at treating them.
Most prominent mental health non-profit organizations are heavily funded by the pharmaceutical industry, such as Mental Health America and the National Alliance on Mental Illness (NAMI). Even many much smaller groups around the country receive pharmaceutical funding. Secrecy about the exact amounts is common. NAMI, one of the largest and most politically influential U.S.-based mental health non-profits, became the target of a Congressional investigation in 2009, and it was revealed that 75% of NAMI’s tens of millions in funding was coming from pharmaceutical companies.
Of course, accepting pharmaceutical industry funding does not necessarily mean an organization or its employees are not being honest about their views. What this widespread industry financial support definitely does, though, is strengthen and amplify the public voices and influence of people and organizations with views and opinions that tend to paint more positive pictures of the effectiveness and safety of psychiatric drugs, while further marginalizing voices and organizations that have more neutral or critical perspectives.
So where can we turn for independent information about psychiatric drugs?
Once we are aware of the wide and deep reach of the pharmaceutical industry into so many of our normally trusted sources of health information, it becomes clear that it is difficult to find completely independent, reliable information about drugs. And even many otherwise more reliable, independent sources of general drug information are still not very reliable sources of information about psychiatric drugs specifically. This is in part the reason that Inner Compass Initiative has started this website.
Historically, there has been a general lack of attention being given to, and little funding available for people doing critical analyses of psychiatric drugs. As the use of psychiatric drugs in recent years has become ever more prevalent in the general population, though, with tens of millions of people in America alone now taking them, more independent health experts and organizations are becoming concerned and are beginning to turn their critical attention towards psychiatric drugs. ICI is compiling a list of online sources of information for its “Resources” section.
How Psychiatric Drugs are Researched and Marketed
This article overviews the typical route that drugs take as they move from initial discovery through clinical studies of safety and effectiveness into reports in medical journals and finally into the news media and marketplace. Key concerns at each step are explained to help you make more informed, independent evaluations when you hear about the relative safety or effectiveness of a psychiatric drug.
Why we all should be concerned about how psychiatric drugs are researched, developed, and marketed
The research, development and marketing of psychiatric drugs has become a very large and lucrative industry. In 2015, the sales of psychiatric drugs in the United States alone generated revenues of over $70 billion. With so much profit at stake, there’s an obvious risk that the best science and most altruistic motives may not always be steering this industry.
This risk has been proven to be real and substantial, and concerns about conflicts of interest and bias in the research and practice of medicine and psychiatry have in the past two decades become increasingly prominent topics of public discussion.
One 2010 analysis found that over 60% of all medical studies in the U.S. were funded by drug companies. In practice, this usually means that the drug company maintains significant influence, and often extremely tight control, over all of the crucial decisions including designing the trial, setting it up and recruiting participants, conducting the trial, collecting, statistically analyzing and summarizing the data, selectively publishing the results in medical journals and presenting findings to health regulators, physicians or the media. And the results are unequivocal: Every formal study of the topic has shown that when researchers are being funded by a drug company, their studies are much more likely to come to conclusions that favor that company’s drug.
That’s not entirely surprising. While pharmaceutical companies tend to portray themselves to the public as pure engines of innovative scientific research, several independent analyses have concluded that the pharmaceutical industry is likely spending about twice as much on marketing and promotion as on research and development. As part of that, trying to ensure that their clinical drug trials produce favorable findings about their drugs has become a key part of most brand-name pharmaceutical companies’ advertising and marketing plans, just as maximizing profits for shareholders is part of their corporate mandates.
The resulting drop in trustworthiness of medical research has become so widely recognized and concerning that all of the world’s leading medical journals have in recent years made high-profile efforts to try to institute stronger conflict-of-interest policies. But the journals have struggled in these efforts – They themselves are often financially reliant on drug company purchases of advertising and article reprints, while the majority of expert medical and psychiatric researchers also accept gifts, meals, funding, payments for participation in events, and/or research grants from the pharmaceutical industry.
To make matters even more concerning, the pharmaceutical industry now provides more than half of the annual funding of the Food and Drug Administration (FDA)—the very government agency that is tasked with approving and regulating drugs in the United States. Some have argued that this has put our own public drug regulator in a conflict of interest, where many FDA employees see themselves as responsible for catering to companies’ needs. And not coincidentally, it has become common practice for senior pharmaceutical industry executives to actually gain employment at the FDA, and for senior officials to leave the FDA to work for pharmaceutical companies.
Consequently, in the same way that we need to be skeptical of glowing claims we may hear about consumer products like breakfast cereals, soft drinks or cars, we have to be skeptical of claims about psychiatric drugs. But it’s not always easy to critically appraise the claims of pharmaceutical companies, researchers and mental health practitioners; it’s vital to be able to understand the intersections of money, power, policy, research practices, regulation, industry, media, and non-profit organizations that steer the research and marketing of drugs. So in this essay, we’ll help you do just that, explaining how drugs are typically researched, approved by the FDA, brought to market, and promoted throughout society. Along the way we’ll highlight the many points in the process where manipulation, deception, and corruption occur far too commonly, and give real examples to elucidate these issues and help you empower yourself to think more critically about the safety, efficacy, and scientific evidence base of psychiatric drugs.
Related reading:
Dorsey, E. Ray, Jason de Roulet, Joel P. Thompson, Jason I. Reminick, Ashley Thai, Zachary White-Stellato, Christopher A. Beck, Benjamin P. George, and Hamilton Moses. “Funding of US Biomedical Research, 2003-2008.” JAMA 303, no. 2 (January 13, 2010): 137–43. doi:10.1001/jama.2009.1987.
Ferris, LE, and RH Fletcher. “Conflict of Interest in Peer-Reviewed Medical Journals: The World Association of Medical Editors Position on a Challenging Problem.” Journal of Young Pharmacists : JYP 2, no. 2 (2010): 113–15. doi:10.4103/0975-1483.63143.
Gagnon, Marc-André, and Joel Lexchin. “The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States.” PLOS Medicine 5, no. 1 (January 3, 2008): e1. doi:10.1371/journal.pmed.0050001.
Light, Donald W., Joel Lexchin, and Jonathan J. Darrow. “Institutional Corruption of Pharmaceuticals and the Myth of Safe and Effective Drugs.” SSRN Scholarly Paper. Rochester, NY: Social Science Research Network, June 1, 2013.
International Committee of Medical Journal Editors. “Sponsorship, Authorship, and Accountability.” (August 2007).
Ruff, Kathleen. “Scientific Journals and Conflict of Interest Disclosure: What Progress Has Been Made?” Environmental Health 14 (2015): 45. doi:10.1186/s12940-015-0035-6.
Schott, G; Pachl, H; Limbach, U; Gundert-Remy, U; Ludwig, W; Lieb, K. “The Financing of Drug Trials by Pharmaceutical Companies and Its Consequences: Part 1. A Qualitative, Systematic Review of the Literature on Possible Influences on the Findings, Protocols, and Quality of Drug Trials.” Dtsch Arztebl Int, 2010; 107 (16): 279-85 DOI: 10.3238/arztebl.2010.0279
Wazana A. "Physicians and the pharmaceutical industry: is a gift ever just a gift?" JAMA. 2000;283:373–380. doi: 10.1001/jama.283.3.373.
World Association of Medical Editors. “Conflict of Interest in Peer-Reviewed Medical Journals.” (July 25, 2009)
How psychiatric drugs are discovered or developed
In the 1940s, medically-oriented psychiatrists relied primarily on interventions like doctor-induced insulin coma, electroshock, and lobotomies, and had at their disposal very few chemical substances to administer to psychiatric patients. This would start to change in the 1950s. A surgeon named Henri Laborit noticed that chlorpromazine, an antihistamine that was being used to treat nausea, allergies and other conditions, seemed to alter mental states and induce calm in his patients before surgery. Word spread, and chlorpromazine was soon being given to psychiatric patients in U.S. mental institutions under the brand name Thorazine. The drug became one of the most widely prescribed early neuroleptics or tranquilizers – which today are more commonly called antipsychotics.
Such accidental discoveries have been typical of the psychiatric drug industry. Unlike in certain areas of medicine where researchers are able to target a specific, biologically detectable pathology such as a bacterial infection, there are no biological markers of any kind for what are commonly called “mental disorders”. (Read more about this issue in ICI’s “How Mental Disorders are Diagnosed”.) Therefore, new psychiatric drug possibilities are not found by honing in on underlying biological abnormalities and working to eradicate or resolve them pharmacologically. New drugs are generally “stumbled upon” when researchers simply happen to observe a drug altering mental, emotional, or behavioral states in research subjects. Researchers sometimes subsequently develop a biological hypothesis about what the particular drug may be doing to help “treat” mental or emotional states and, if the drug becomes successful in the marketplace, other pharmaceutical companies may then develop chemically similar drugs and market them in similar ways.
For example, the idea that depressed feelings were caused by low levels of the neurotransmitter serotonin was developed after it was observed that selective serotonin reuptake inhibitors (SSRIs) – drugs that in part temporarily increase the levels of serotonin re-circulating in the brain – seemed to slightly alleviate depressed feelings in some people. This biochemical hypothesis about depression was almost immediately disproven by subsequent research but, due to intensive marketing and public relations efforts by the pharmaceutical industry, the idea that low serotonin levels are related to depression has endured to this day in the media, among mental health organizations, and even in the minds of many average physicians and psychiatrists as if it were long-established fact.
Similarly, when it was identified that many of the antipsychotic drugs in part disrupted dopamine activity in the brain, it was then that drug companies, the American Psychiatric Association, and many practicing psychiatrists began to promote the hypothesis that the experiences related to a diagnosis of schizophrenia or psychosis might be caused by a “chemical imbalance” of excessive dopamine. This hypothesis, too, has never been proven.
Related reading:
López-Muñoz, Francisco, Cecilio Alamo, Eduardo Cuenca, Winston W. Shen, Patrick Clervoy, and Gabriel Rubio. “History of the Discovery and Clinical Introduction of Chlorpromazine.” Annals of Clinical Psychiatry: Official Journal of the American Academy of Clinical Psychiatrists 17, no. 3 (September 2005): 113–35.
Hirschfeld, R. M. “History and Evolution of the Monoamine Hypothesis of Depression.” The Journal of Clinical Psychiatry 61 Suppl 6 (2000): 4–6.
A brief snapshot of the drug approval process in the United States and the risks of off-label prescribing
Before any new pharmaceutical drug can be sold in the United States by prescription, it must be approved as relatively safe and effective for its intended use by the U.S. Food and Drug Administration (FDA).
But there’s a very large, commonly used loophole allowing circumvention of this entire process: The drug doesn’t actually have to be approved as safe or effective for all of the uses for which doctors may end up prescribing it. Physicians can prescribe “off-label” – meaning they can prescribe drugs for indications that are not approved by the FDA and are not listed on the official drug label. Many psychiatric drugs, in fact, fall into this category. They were approved as relatively safe and effective for very specific uses – in certain cases simply for short-term, non-psychiatric uses such as controlling epileptic seizures – yet now are being widely prescribed by doctors and psychiatrists for a wide range of psychiatric uses and for long periods of time. This common practice presents unknown risks to patients.
However, even when a drug has been approved by the FDA for certain psychiatric uses, that doesn’t always mean it’s truly safe and effective for those uses, either. Let’s walk through the process of FDA approval to understand why that’s the case.
Though physicians can prescribe whatever drugs they deem to be in the best interests of their patients, for a pharmaceutical company to be legally allowed to market a drug to doctors and to the public as relatively safe and effective for a particular, specific use, the pharmaceutical company must get FDA approval to do that. FDA approval can often mean billions of dollars in additional profits for a drug company, not only because it can lead to exclusive marketing rights, but also because FDA approval often is, in the minds of physicians and the public, a “stamp of approval” of safety and effectiveness.
FDA approval involves a four-step process:
On the surface, this drug approval process might seem straightforward and reliable. In reality, this is far from the case. There are many points throughout the FDA drug approval process that leave a lot of room for important information about a drug to be missed entirely and for misleading or biased results to emerge. Phase 4 real-world surveillance of adverse effects, for example, is often not enforced by the FDA and drug companies simply never do it or do it only spottily. But since Phase 3 is the most important phase, in the next section we’ll explore in detail how even the medical “gold standard” research method of double-blinded, randomized, placebo-controlled clinical trials can easily be made to produce misleading, biased results favoring a psychiatric drug.
How clinical trials can easily produce falsely favorable findings about drugs – And how often it happens
The double-blinded, randomized, placebo-controlled drug trial is widely used in medicine and psychiatry as a “gold standard’ method for removing bias from studies. Unfortunately, it is still very easy and common for such studies to be biased. And every study of this issue has shown that drug company funding of a clinical trial tends to lead to more favorable findings about the company’s own drug. But how does this happen?
A long-time editor of the British Medical Journal published an instructive list of “Examples of Methods for Pharmaceutical Companies to Get the Results They Want from Clinical Trials”. We’ve added examples from his list and from other sources to our own list below. After that, we’ll look at examples of these techniques being used in actual clinical trials for psychiatric drugs.
How Researchers Can Bias Clinical Trials to Make Psychiatric Drugs Seem Safer and More Effective than They Actually Are
Unfortunately, the types of manipulations described above are not uncommon in psychiatric drug studies. Indeed, many meta-analyses of large numbers of studies of psychiatric drugs show that these kinds of practices are in fact more the rule than the exception. Some of the selected representative examples below include references to many other examples.
Some Typical Examples of Bias and Manipulation in Influential Psychiatric Drug Trials
During both trials submitted to the FDA for the approval of the anticonvulsant Lamictal (lamotrigine) for treating people diagnosed with bipolar disorder, the researchers changed their primary way of measuring the drug’s effectiveness many times, including once more after the trials were completed. The FDA medical review noted that the drug would have failed to beat placebo if not for the final, last-minute change in what the researchers were measuring.
Source: U.S. Food and Drug Administration. “Medical Review: Lamictal.” (June, 2003)
A 2014 study in BMJ Open reviewed 142 clinical trials of antipsychotic and antidepressant drugs where detailed trial information had been provided to government regulators by law, and then examined how forthright the study authors were when they published these same studies in medical journals for the scientific community and general public. The BMJ Open study found that half or more of the published versions of these studies omitted mentioning deaths or suicides that had occurred during the trials, omitted mentioning serious adverse drug effects that had been identified during the trials, and/or omitted mentioning the trials’ less positive longer-term findings.
Source: Hughes, Shannon, David Cohen, and Rachel Jaggi. “Differences in Reporting Serious Adverse Events in Industry Sponsored Clinical Trial Registries and Journal Articles on Antidepressant and Antipsychotic Drugs: A Cross-Sectional Study.” BMJ Open 4, no. 7 (July 9, 2014). doi:10.1136/bmjopen-2014-005535.
A 2006 study in the American Journal of Psychiatry found that, out of 33 studies and official medical reports comparing different antipsychotic drugs to each other, 90% of them concluded that the drug produced by the funder of the study or report was the best drug. The AJP researchers noted that this created “contradictory conclusions” when competing drug companies funded studies of each other’s drugs. The AJP researchers identified many instances of bias and manipulation in both the trials and the published studies, such as choosing trial participants in biased ways, using clearly inappropriate dosages, withholding data, making positive claims in abstracts that didn’t correspond to negative information provided deeper in the study, and using terms like “equally effective” very loosely.
Source: Heres, Stephan, John Davis, Katja Maino, Elisabeth Jetzinger, Werner Kissling, and Stefan Leucht. “Why Olanzapine Beats Risperidone, Risperidone Beats Quetiapine, and Quetiapine Beats Olanzapine: An Exploratory Analysis of Head-to-Head Comparison Studies of Second-Generation Antipsychotics.” American Journal of Psychiatry 163, no. 2 (February 1, 2006): 185–94. doi:10.1176/appi.ajp.163.2.185.
A 2015 study in JAMA Psychiatry examined clinical trials for nine different antidepressants that that had been submitted to the FDA by drug companies seeking approvals for treating people diagnosed with anxiety disorders. Over a quarter of the studies did not show even slightly positive findings about the drugs; nevertheless, these negative studies were usually either never published or, when they were published in psychiatry journals they were made to sound more positive about the drug than they actually were.
Source: Roest AM, de Jonge P, Williams CD, de Vries Y, Schoevers RA, Turner EH. “Reporting Bias in Clinical Trials Investigating the Efficacy of Second-Generation Antidepressants in the Treatment of Anxiety Disorders: A Report of 2 Meta-analyses.” JAMA Psychiatry. Published online March 25, 2015.
There were only three trials submitted to the FDA to prove the effectiveness of the ADHD drug Concerta – one trial was just four weeks in length and two trials were only one week in length. All three trials involved many young children who were already taking Ritalin, a drug with the same active ingredient as Concerta, methylphenidate. For the trials, the main drug group simply switched from Ritalin to Concerta. But to create the placebo group, the researchers forced a large number of the children to abruptly stop taking their Ritalin. Since methylphenidate is known to cause physical dependence, many children in the placebo group would likely have been suffering acute physical and mental drug withdrawal effects, thereby making Concerta look both safer and more effective compared to placebo than it actually was.
Source: U.S. Food and Drug Administration. Concerta Drug Approval Package: Medical Review. (2000)
Studies published in the British Medical Journal in 2008 and 2012 found that when medical researchers – including those of psychiatric studies – knew for certain which patients were taking the drugs and which patients were taking placebo, those researchers tended to significantly inflate and exaggerate positive effects of the drugs.
Sources:
Gøtzsche, Peter C. “Unblinding in SSRI Trials due to Side Effects Is an Important Source of Bias.” The British Journal of Psychiatry, December 7, 2016.
Wood, Lesley, Matthias Egger, Lise Lotte Gluud, Kenneth F. Schulz, Peter Jüni, Douglas G. Altman, Christian Gluud, Richard M. Martin, Anthony J. G. Wood, and Jonathan A. C. Sterne. “Empirical Evidence of Bias in Treatment Effect Estimates in Controlled Trials with Different Interventions and Outcomes: Meta-Epidemiological Study.” BMJ 336, no. 7644 (March 13, 2008): 601–5. doi:10.1136/bmj.39465.451748.AD.
Hróbjartsson Asbjørn, Thomsen Ann Sofia Skou, Emanuelsson Frida, Tendal Britta, Hilden Jørgen, Boutron Isabelle et al. “Observer bias in randomised clinical trials with binary outcomes: systematic review of trials with both blinded and non-blinded outcome assessors.” BMJ 2012; 344 :e1119
A 2015 study in the Journal of Clinical Epidemiology reviewed 185 meta-analyses of clinical trials of antidepressants for treating people diagnosed with depression. (Meta-analyses are often cited as the best summaries of all the available clinical evidence.) This JCE study found that 79% of the meta-analyses involved authors with one or more significant conflicts of interest, and 29% of these meta-analyses had authors who were actually employees of pharmaceutical companies assessing their own company’s antidepressants. The meta-analyses were 22 times less likely to include negative statements about a drug in the abstract’s conclusions if the research team included even just one co-author who was employed by the manufacturer of one of the drugs being evaluated.
Source: Ebrahim, Shanil, Sheena Bance, Abha Athale, Cindy Malachowski, and John P. A. Ioannidis. “Meta-Analyses with Industry Involvement Are Massively Published and Report No Caveats for Antidepressants.” Journal of Clinical Epidemiology 70 (February 1, 2016): 155–63. doi:10.1016/j.jclinepi.2015.08.021.
In 2001, the Journal of the American Academy of Child and Adolescent Psychiatry published an extremely influential study (“Study 329"), authored by some of the most reputable and high-profile child psychiatrists in the U.S. and Canada, that determined that the antidepressent Paxil (paroxetine) was safe and effective for children and adolescents. But during a coincidental U.S. Department of Justice fraud investigation into the drug company, internal company documents provided a rare glimpse behind the scenes of a major pharmaceutical company’s drug trials. As was stated in the 2012 legal settlement, and affirmed in an independent re-analysis that was published in the British Medical Journal in 2015, the data in the Study 329 Paxil trial clearly showed the exact opposite of what the original researchers had written: The drug was not any better than placebo, and it caused suicidal thoughts in some children and increased the rates of many other harms. However, the Study 329 researchers and/or the drug company co-authors had repeatedly changed the measures of effectiveness they were using until they found ones that favored the drug, suppressed key data about adverse drug effects, coded serious adverse drug effects in ways that reduced their significance, and coded some adverse events that were likely caused by the drug as being caused by depression, among other manipulations. Despite these findings, Study 329 has never been retracted.
Sources:
Restoring Study 329: Scientific Integrity Though Data Based Medicine.
U.S. Department of Justice. “Press Release: GlaxoSmithKline to Plead Guilty and Pay $3 Billion to Resolve Fraud Allegations and Failure to Report Safety Data.” (July 2, 2012)
Keller, Martin B., Neal D. Ryan, Michael Strober, Rachel G. Klein, Stan P. Kutcher, Boris Birmaher, Owen R. Hagino, et al. “Efficacy of Paroxetine in the Treatment of Adolescent Major Depression: A Randomized, Controlled Trial.” Journal of the American Academy of Child & Adolescent Psychiatry 40, no. 7 (July 1, 2001): 762–72. doi:10.1097/00004583-200107000-00010.
In conclusion, just because many clinical trials may claim to show that a psychiatric drug is safe and effective and the FDA has approved the drug, it does not necessarily mean that the drug actually is safe and effective. Indeed, without delving deeply into the study details oneself, it is impossible to know what the terms “safe” and “effective” were even referring to during any particular study. (To learn more about the ways in which “safe” and “effective” have been used in drug trials submitted to the FDA for each class of psychiatric drug, explore ICI’s “Interventions” section.)
How prescribers learn about drugs, and why we should be concerned about it
After completing their basic medical education, doctors and psychiatrists continue to get information about new drugs in a variety of ways. Most of these blur the boundaries between education and advertising in ways that even the most knowledgeable experts can sometimes not easily unravel.
The pharmaceutical industry has been estimated to spend on average up to $61,000 per year per U.S. practicing physician and psychiatrist in providing free sample drugs, visits from company representatives, gifts, meals, trips, etc. This also includes seminars, workshops, Continuing Medical Education (CME) and other professional development activities for doctors, the vast majority of which are funded and run by pharmaceutical companies or by their contracted third-party communications and public relations firms. In many cases, drug companies not only pay for physician or psychiatrist “key opinion leaders” to lead these sessions, but they pay for the time and expenses of average family physicians and general-practice psychiatrists to attend.
Surveys have shown that the majority of practicing physicians accept and participate in these kinds of relationships with the pharmaceutical industry. ProPublica provides a free (though far from comprehensive) “Dollars for Docs” online app to search financial disclosures about pharmaceutical company payments to specific physicians. Numerous studies have shown that physicians tend to believe that they are not being unduly or improperly influenced or manipulated in such situations, while they usually in fact are. Even small gifts like pens or free lunches, or personal visits from pharmaceutical company sales representatives, have been shown to significantly alter physicians’ prescribing habits even against best practices. It’s unclear why this is, but it’s possibly because it’s not so much about the gifts as about the friendly, trusting relationships that get built between the pharmaceutical company representatives and the physicians and psychiatrists.
Furthermore, the educational programs and ‘Best Practices’ guidelines of many professional associations and societies for physicians and psychiatrists are often directly or indirectly funded by drug companies. For example, some 68% of the Task Force members for the American Psychiatric Association’s latest edition of the Diagnostic and Statistical Manual of Mental Disorders reported having financial ties to pharmaceutical companies, and at least 56% of those who posted disclosure statements admitted having industry ties such as holding stock in pharmaceutical companies or serving on the boards of pharmaceutical companies.
Those physicians and psychiatrists who are concerned about all of these conflicts of interest will seek out more independent sources of information about new drugs, but those are often less readily available because there is not much funding for such organizations.
Another common way that average physicians and psychiatrists learn about drugs is through illegal off-label promotion. While physicians and psychiatrists are free to prescribe drugs off-label in their own practices, there are laws in the U.S. that forbid pharmaceutical companies from marketing their drugs for off-label purposes or otherwise attempting to actively persuade doctors to prescribe off-label—that is, for uses that are not approved by the FDA and listed on the drug product label. But despite federal laws to prevent these practices, they are widespread. For example, numerous U.S. Department of Justice investigations have revealed drug companies illegally promoting antipsychotics for use in dementia patients and even paying kickbacks to doctors for doing so. Antipsychotics are not approved for tranquilizing and controlling the behavior of elderly people with dementia – and in fact the labels specifically warn against the practice because the drugs have been shown to increase mortality among the elderly – yet in the wake of illegal promotional efforts by pharmaceutical companies antipsychotics have in recent years become one of the most commonly prescribed drugs in nursing homes.
When drug companies market illegally in this way and are caught, the companies can be fined and face other sanctions. The fines are often small, though, compared to how much money the companies can make by doing this promoting, which is likely the reason this illegal practice has not abated over many years. (Public Citizen has compiled a list of the many fraud penalties paid by pharmaceutical companies over the past several decades.) For example, in 2012 the drug company GlaxoSmithKline (GSK) was fined $3 billion primarily for marketing its antidepressants Paxil and Wellbutrin for unapproved uses and withholding safety data on their diabetes drug Avandia, the biggest such fine in U.S. history. For perspective, GSK’s profits that year alone were three times that amount, over $9 billion.
Related reading:
Almashat, Sammy et al. “Twenty-Five Years of Pharmaceutical Industry Criminal and Civil Penalties: 1991 Through 2015 (Chart Book).” Public Citizen. (March 31, 2016)
Cosgrove, L., Bursztajn, H. J., & Krimsky, S. (2009). Developing unbiased diagnostic and treatment guidelines in psychiatry [Letter to the Editor]. The New England Journal of Medicine, 360, 2035-2036.
Gagnon, Marc-André, and Joel Lexchin. “The Cost of Pushing Pills: A New Estimate of Pharmaceutical Promotion Expenditures in the United States.” PLOS Medicine 5, no. 1 (January 3, 2008): e1. doi:10.1371/journal.pmed.0050001.
Mintzes, Barbara, Joel Lexchin, Jason M. Sutherland, Marie-Dominique Beaulieu, Michael S. Wilkes, Geneviève Durrieu, and Ellen Reynolds. “Pharmaceutical Sales Representatives and Patient Safety: A Comparative Prospective Study of Information Quality in Canada, France and the United States.” Journal of General Internal Medicine 28, no. 10 (October 2013): 1368–75. doi:10.1007/s11606-013-2411-7.
Norris P, Herxheimer A, Lexchin J, Mansfield P. Drug Promotion: What We Know What We Have Yet to Learn. World Health Organisation and Health Action International. Geneva: 2005.
U.S. Department of Justice. “Press Release: Johnson & Johnson to Pay More Than $2.2 Billion to Resolve Criminal and Civil Investigations.” (November 4, 2013)
Wazana A. "Physicians and the pharmaceutical industry: is a gift ever just a gift?" JAMA. 2000;283:373–380. doi: 10.1001/jama.283.3.373.
How psychiatric drugs are marketed through the news media
The United States is one of the only countries in the world that allows ‘direct-to-consumer’ advertising of pharmaceutical drugs. As a result, Americans are exposed to billions of dollars worth of prescription drug advertising in the media every year. But these ads aren’t the only channel through which drug companies influence us about their products. More subtle and arguably even more effective advertising for drugs comes through the regular programming and news stories of these same major media outlets. While it’s obvious that an advertisement will be biased and promotional in nature, many who hear about a particular illness or a drug’s safety and effectiveness on a TV program, read about it in a magazine or newspaper, or learn about it at a website like WebMD are more likely to regard the source as independent and trustworthy. News or media coverage of illnesses and drugs is, in effect, “free advertising” at its best for drug companies, because news stories come with a stamp of approval from an apparently independent source. Knowing this, the pharmaceutical industry cultivates relationships with news media, often by contracting third-party communications and media relations firms and working in collaboration with reputable researchers, universities and other institutions that they fund.
How does it work? You can peer into the process yourself by looking at a widely used source of mental health-related news releases, the “Mind and Brain” section of the website ScienceDaily.
First, a study is published that puts a positive light on the company’s drug or highlights the dangers of a disease, disorder or condition which the company’s drug treats, and then a news release highlighting the most dramatic or compelling aspects of the study’s findings are distributed. Professional reporters can usually obtain a more confidential “early view” of the news release and of the study itself. Typically the news release doesn’t look like it came from a pharmaceutical company or media relations firm but instead from a reputable university or research institute that was involved in the study. These news releases usually provide quotes, contact information for sources, and relevant background. Sometimes a quick call to the primary source listed also leads to contact information for celebrities or ordinary people who’ve been diagnosed with the condition or who’ve claimed to benefit from the drug. Notably, many medical journals now have policies asking authors to disclose their sources of funding and conflicts of interest, but if you follow health news, you have likely noticed that it is extremely rare for news reports to include any such disclosures from authors, experts, celebrities or any of the sources involved in the story.
All of this helps busy health reporters produce quick and compelling stories that often serve to promote drug treatments, unless an individual reporter takes the time to actually read the entire study, dig more deeply, and contact independent expert sources and critics. Incorporating more sober voices and balance in this way, however, often makes for a longer, more complicated story.
The relationships between pharmaceutical companies and non-profit organizations
Non-profit mental health organizations play a key role in the marketing strategies of pharmaceutical companies. These organizations help promote public awareness of and concerns about mental disorders and support for the drugs aimed at treating them.
Most prominent mental health non-profit organizations are heavily funded by the pharmaceutical industry, such as Mental Health America and the National Alliance on Mental Illness (NAMI). Even many much smaller groups around the country receive pharmaceutical funding. Secrecy about the exact amounts is common. NAMI, one of the largest and most politically influential U.S.-based mental health non-profits, became the target of a Congressional investigation in 2009, and it was revealed that 75% of NAMI’s tens of millions in funding was coming from pharmaceutical companies.
Of course, accepting pharmaceutical industry funding does not necessarily mean an organization or its employees are not being honest about their views. What this widespread industry financial support definitely does, though, is strengthen and amplify the public voices and influence of people and organizations with views and opinions that tend to paint more positive pictures of the effectiveness and safety of psychiatric drugs, while further marginalizing voices and organizations that have more neutral or critical perspectives.
So where can we turn for independent information about psychiatric drugs?
Once we are aware of the wide and deep reach of the pharmaceutical industry into so many of our normally trusted sources of health information, it becomes clear that it is difficult to find completely independent, reliable information about drugs. And even many otherwise more reliable, independent sources of general drug information are still not very reliable sources of information about psychiatric drugs specifically. This is in part the reason that Inner Compass Initiative has started this website.
Historically, there has been a general lack of attention being given to, and little funding available for people doing critical analyses of psychiatric drugs. As the use of psychiatric drugs in recent years has become ever more prevalent in the general population, though, with tens of millions of people in America alone now taking them, more independent health experts and organizations are becoming concerned and are beginning to turn their critical attention towards psychiatric drugs. ICI is compiling a list of online sources of information for its “Resources” section.