The Whistleblower and Penn: A Final Accounting of Study 352 – James Moore

Posted: January 5, 2020 at 7:52 am

Although the general story of ghostwriting in trials of psychiatric drugs is now pretty well known, the details of the corruption in specific trials are still emerging into the public record, often a decade or more after the original sin of fraudulent publication. The latest study to finally see the full light of day is GlaxoSmithKlines study 352.

Perhaps the most infamous ghostwritten study is GSKs study 329, which, in a 2001 report published in the American Journal of Psychiatry, falsely touted paroxetine (Paxil) as an effective treatment for adolescent depression. The company paid over $3 billion in penalties for fraud.

That same year, study 352 made its first appearance in the research literature. That was when Charles Nemeroff, who in the years ahead would become the public face of research misconduct, authored an article on the efficacy of paroxetine for bipolar disorder. It has taken 18 years for the full story of that corruption to become known, the final chapter recently emerging when a large cache of study 352 documentsemails, memos, and other internal correspondence between the key playerswas made public.

The documents reveal a web of corruption that went beyond the fraud of ghostwriting into the spinning of negative results into positive conclusions, and the abetting of that corruption by an editor of the scientific journal that published the article. The documents also reveal a whitewashing of the corruption by the University of Pennsylvania.

However, it was the publication of these documents that provided Jay Amsterdam, an investigator in the trial who turned whistleblower after he smelled a rat, with a chance to say case closed. Amsterdam and Leemon McHenry have now published two articles that provide a step-by-step deconstruction of the studythe ghostwriting, the spinning of results, the betrayal of public trust.

Here is the story of that whistleblowing.

Starting in the late 1970s, Amsterdam became a go-to guy for studying pharmaceutical interventions, especially antidepressants. By the time he got involved with study 352, he was running a prestigious bipolar disorder clinic at the University of Pennsylvanias Perelman School of Medicine. Hed published over 100 peer-reviewed articles, and had served as editor and author on multiple textbooks about mood disorders. He was a working psychiatrist, a lecturer and professor, and a full-time researcher.

Amsterdam received his MD in 1974 from Jefferson Medical College in Philadelphia. While still a post-doc, he began working almost immediately with the top researchers investigating treatments for mood disorders. William Dysonone of the early promoters of lithium for bipolar disorderwas one of Amsterdams mentors, as was Dysons colleague, Joseph Mendels. Dyson opened the bipolar disorder clinic that Amsterdam would eventually run.

In the early 1980s, hormone function was one of the chief hypotheses in mood disorders, and Amsterdam became a leading researcher in the burgeoning field of psychoendocrine studies. He conducted a number of studies on melatonin, among many other hormones. By the mid-1980s, Amsterdam was working under Karl Rickels, an ex-Nazi soldier who had been one of the chief investigators on pharmacological treatments for mental health since the 1950s. Amsterdam describes Rickels as a brusque, almost abrasive figure who worked almost exclusively with pharmaceutical industry money, investigating the efficacy of the drugs, but who remained proud of the fact that he did not have his papers ghostwritten. You should always write your own articles, he told Amsterdam. You know, no one has ever written an article for me.

During this time, Amsterdam was investigating various pharmaceutical treatments for depression and bipolar disorder, including tricyclic antidepressants, lithium, and newer SSRI antidepressants like fluoxetine (Prozac). By the late 1980s, Amsterdam had become a leading researcher in psychoimmunovirology, conducting some of the earliest studies on the hypothesis that exposure to viral disease was a cause of psychological disorders. While its unlikely that this is a cause for most psychological problems, some viral diseases like the Borna disease virus and the Epstein-Barr virus have been correlated with a slight increase in the likelihood of psychological problems. He began studying whether lithium might work by suppressing the effects of viral disease.

By 1993, Amsterdams mentor Dyson had passed away, and Amsterdam became the director of the bipolar disorders clinic at Penn. At the time, his clinic was a perfect fit for the needs of the pharmaceutical industry. It was large, so he had a pool of potential participants for trials. Amsterdam also describes the clinic as offering access to treatment-nave, or drug-free, patients with depression and bipolar disorders, who were good enrollees in industry studies.

Amsterdam was happy to work with the industry at that time. One year, he offered his entire crop of mood disorder research participants to Eli Lilly for their study on fluoxetine (Prozac) for relapse prevention. According to Amsterdam, he told them theyd have to pay all his operating costs for the year. Well take care of you, Lillys spokesperson responded. Amsterdam says, I gave them 139 patients, well-diagnosed, well-treated. And actually, my clinic was the only site that differentiated Prozac from placebo for relapse prevention. I really gave them their moneys worth.

Amsterdam was also on industry panels for over a dozen pharmaceutical companies, giving sponsored talks. It wasnt until the early 2000s that industry representatives began urging him to deviate from his prepared talks. Once he began to experience pressure to spin his results in favor of the drug, he said, I stopped giving talks.

But he never saw it as systemic corruption. Instead, each time, it looked like one company, or one representative, was under pressure to deliver better results, and so put the pressure on him to tell a better story about the companys drug. I was never anti-pharma, he said. He was happy to take their money, as long as he could continue to deliver accurate data.

In the 1990s, all was going well for Amsterdam. And he thought little about it when, in 1995, Rickels asked if he could help out a junior colleague at Penn, Laszlo Gyulai. Gyulai was involved in a study for GlaxoSmithKline (then SmithKlineBeecham) of paroxetine (Paxil) to see if it would improve depressive symptoms in patients with bipolar disorder who were already taking lithium. According to Amsterdam, Gyulais clinic had less than a dozen patients, so it was no surprise that he was struggling to recruit participants for the study. Rickels framed it as a favorhe was embarrassed by Gyulais recruitment numbers and wanted Amsterdams help.

I (told Rickels) that I would be willing to be an investigator on the study, Amsterdam recalled. I said that I would be willing to recruit patients and help him if I am the co-principal investigator, if my names listed as co-principal investigator on the consent form, if Laszlo turns over 80% of the revenue for each patient I recruit. If I end up being one of the principal recruiters in the study, I want to be acknowledged as an author, I want to see the data, I want to co-write the paper.

Rickels agreed, and soon GSKs people contacted Amsterdam and helped set up his clinic as the 19th site for the research study. Gyulai had recruited just seven patients over a few years. Amsterdam recruited 12 in just a few monthsno surprise again, since his clinic served over a thousand patients.

Amsterdam was deeply involved in the work with those 12 patients, prescribing their medications, checking their dose, giving the assessment measures to see how well the medications were working. Then, just a few months later, the study was cancelled by GSK.

Amsterdam called up his contact at GSK, research director Cornelius Pitts. But Pitts just told him to stop enrolling participants. I couldnt get any information about why it came to an end, Amsterdam said.

Even a year later, when Amsterdam asked Gyulai where the data from that study was, Gyulai told him we dont have it yet. Amsterdam moved on with his life. It was just one of many projects I was working on.

In 2001, Amsterdam was working on a grant proposal to the NIMH to study fluoxetine (Prozac) as a treatment for bipolar disorder when a member of his research lab mentioned that a study was about to be published in The American Journal of Psychiatry on a similar subjectSSRIs for bipolar disorderthat could provide solid background for the grant-writing process.

Amsterdam hunted down the paper, and quickly realized that some of the listed authors were from his own department at Penn. One was Dwight Evans, chair of psychiatry at Penn. Another was Laszlo Gyulai.

Amsterdam called Evans office and requested a copy of the article from his secretary. Soon the fax machine spit out the cover page, which had a handwritten note at the top. Dear Jay, with compliments. Dwight.

As Amsterdam read the study, he was overwhelmed by a sense of dj vu. I started reading the abstract, and I said to myself, this sounds really familiar. And then I kept reading and Im thinkingI did this study! And Im looking and looking, and I cant find my name. And then I began to get suspicious.

The lead author on the study was Charles Nemeroff, and while Nemeroff had yet to become publicly identified for his regular participation in ghostwriting exercises, Amsterdam knew that he was part of what many liked to call the psychiatric mafia,psychiatrists that had close ties to industry. So that aroused his questions about the integrity of the article. Even more to the point, he couldnt understand why Gyulai was listed as an author.

As far as Amsterdam knew, Gyulai had only enrolled a handful of patients, and so he wondered whether Gyulai had somehow overstated his involvement in the study. Had he falsified data, or plagiarized another researchers work to do so?

Amsterdam called up his department chairDwight Evansto report his concerns. The universitys policy required that the provost or assistant provost for research be informed that such a concern had been raised and should be investigated. But in this instance, Evans told him that he and Rickels would investigate the matterno need, apparently, to take this matter to the university higher-ups. Evans asked Amsterdam what he wanted from the investigation.

I said, Id like an apology and I want Laszlo Gyulai to be sanctioned for plagiarism, Amsterdam told him.

In a letter dated April 3, 2001, Rickels informed Amsterdam of what he had learned from his investigation. Yes, Amsterdam was a co-investigator in the trial, and he had enrolled more patients than Gyulai; and yes a ghostwriting firm, STI, had written two drafts of the paper before it asked Gyulai if he would agree to be the papers first author; yes, STI had later replaced Gyulai with Nemeroff as the first author; and yes, there were academic investigators in the trial who had never reviewed or even seen the submitted manuscript.

Although the letter seemed like an admission of scientific fraud, given the evident ghostwriting of the paper, there was no departmental censure of Gyulai. Amsterdam then wrote both Evans and Rickels to express his displeasure. Am I to assume that it is okay in this department for a junior faculty member to abscond with data from a full professor and publish it without any ramifications? he asked.

Although Gyulai was never sanctioned, he did send Amsterdam a letter of apology. In it, Gyulai wrote that he understood Amsterdams concerns about plagiarism, but stated that he (Gyulai) was the primary investigator of the Penn site and did some work on early drafts of the article. Gyulai complained that first authorship was taken away from me and that he wished that GlaxoSmithKline had allowed Amsterdam to have input on the paper.

At that point, Amsterdam let it go. He wouldnt revisit the study again until 2010, when his own professional life came under attack.

In 2008, Senator Charles Grassley (R-Iowa) of the US Senate Finance Committee began to investigate financial conflicts of interest in scientific research. Paul Thacker, an investigative journalist, was the point man for Grassleys investigation and his 2010 committee report, which resulted in significant changes to the rules used by academic institutions to define research misconduct.

The picture of corruption that emerged thanks to Grassleys investigation, and other investigations into industry-funded trials, told of how academic medicine had been horribly corrupted, with psychiatry the specialty that was most compromised.

Pharmaceutical companies would hire ghostwriting firms to manipulate data and write articles spinning the results. The drug companies would then get academic psychiatrists, who were described by the companies as thought leaders, to agree to be the authors of the study in order to lend credibility to those misleading results. These same experts would then be paid to give talks promoting the companys drug. They would be paid handsomelyin some cases, hundreds of thousands of dollarsto serve the pharmaceutical companys commercial interests in this way.

Charles Nemerofflead author on the study 352 paperbecame the poster boy for this type of research misconduct. At the time, Nemeroff was an internationally-famous researcher with hundreds of publications and awards. He was chair of the psychiatry department at Emory University.

Grassleys investigation helped put a dollar amount on this corruption. He reported that Nemeroff was receiving millions of dollars from the pharmaceutical industry, and failing to disclose that pay according to conflict-of-interest rules. As reported in The New York Times, Nemeroff was found in 2008 to have violated federal research ethics rules by hiding $1.2 million, which, if appropriately disclosed, would have prevented him from being the primary investigator on the government grants he was also receiving.

It was business-as-usual for Nemeroff, whod already weathered two scandals in which hed promoted new treatments in scientific journals without disclosing in one case that he owned the patent on that treatment or that in the second case that he was being paid by the company behind the treatment.

After yet another investigation, Nemeroff was found to have violated Emorys policies, and was forced to resign from his position there. But he immediately moved to the University of Miami, where he soon began the process again.

According to Thacker, Nemeroff continued to receive tens of thousands of dollars from various pharmaceutical companies, while also receiving additional government grant money to test their products. In his case, it seemed that there was little financial penalty for violating federal rules and engaging in research misconduct.

In the 2000s, Amsterdam was becoming increasingly ill. He was almost completely blind, as he suffered from a severe form of glaucoma, but he was still trying to lecture, conduct research, and see patients. During this time, he conducted research on the class of antidepressants known as MAOIs (monoamine oxidase inhibitors), which have been less utilized due to concern about drug interactions with other antidepressants and certain cold medicines, and dietary restrictions such as alcohol and cheese. However, Amsterdam believes that MAOIs are less dangerous than previously believed.

In 2003, he was working with Somerset Labs to test their MAOIs. He did a trial that showed the drug beat the placebo, and they wanted to publish the results. He began to draft the article, but they suggested he outsource it to a ghostwriting company. They told him they were paying this company $30,000 to write the article, so there was no need for him to do it. But Amsterdam remembered Rickels advice: always write your own articles. He wrote the article himself, then sent it to the company.

It was during this time that he began to slowly move away from taking pharmaceutical industry money. He began to drop off the industry panels, as the reps asked him to spin his results more and more when giving talks. This pressure went against his grain as an objective academic.

I could see that pharma had changed. My respect for it had changed, too, he says. I dont want to do shitty research, which is what the drug company research is now.

Science is not the discovery of that new drug. Thats hubris. Science is the replication of that finding, over and over again. I hear colleagues saying we want to show that this drug works. I say, no, you want to show that the placebo theyre testing it against doesnt work. And when I started to say that to industry people, they stopped giving me studies.

By 2006, Amsterdam had had enough. He was done taking pharmaceutical industry money, and funded his research after that entirely with government grant money.

He also began to investigate iatrogenic harms of antidepressantsthe notion that the drugs used to treat the condition are, instead, making it more chronic and resistant to future treatment. He began asking questions: Why did those who continued to take the drug long-term have more risk of relapse than those who decided to stop taking the drug? Why did those who tried more drugs have higher risk of relapse?

According to Amsterdam, People that get repeated antidepressant treatment develop a tolerance to drugs, and, probably as a result of this, weve created the field of treatment resistant depression.

He says that would have been an unthinkable conclusion when he was taking industry money: The pharmaceutical industry would have shut down that research in every way possible.

In the spring of 2010, Amsterdams professional life began to fall apart. Later that year, as he struggled to understand why his career at Penn suddenly came under attackan attack seemingly led by his chairman Dwight Evanshe came to see it as connected to the complaint hed made nine years earlier about the ghostwriting of study 352.

The first shot was fired on April 6, 2010, when Evans suddenly called Amsterdam and told him to go to the Office of Affirmative Action immediately. What did I do? Amsterdam asked. Evans responded by telling him not to ask questions. Just go there.

At his meeting with the head of the affirmative action office, Amsterdam was told he was being investigated for several complaints made against him. However, the head of the office wouldnt tell him any details. Youll learn in due time, Amsterdam was told. I have nothing in writing but youll know from the questions youre asked.

This was the start of what became something of a Kafkaesque experience for Amsterdam. A flood of complaints were suddenly directed at him, all of them emanating from Evans office, and yet he was never formally told of these complaints, or their specifics. Instead, he would be called into the Office of Affirmative Action and questioned about numerous different subjects. Amsterdam inferred from these sessions that the complaints included allegations of retaliation against his staff, racial discrimination, unapproved research activities, photocopying sensitive documents, continuing medical education fraud, and sexual harassment against staff members.

One of the more bizarre episodes occurred on May 13, 2010. Amsterdam was summoned to the affirmative action office by associate director Patrice Miller. As she wrote later that day in an official letter, she did not find any information to support a finding of sexual harassment. While Amsterdam may have been glad to hear this, he was also perplexed. This was the first time that he was aware that a complaint of this type had been made.

The most serious complaint made against Amsterdam was that hed had an inappropriate relationship with a female patient. If this complaint were substantiated, he could have lost his license to practice.

Mad in America spoke to that woman. She confirmed every aspect of Amsterdams relating of this matter to MIA. She is a professional artist and asked that MIA not use her name.

She first met Jay Amsterdam around 1993, when she became his patient through the clinic. Severely depressed, she was a participant in many clinical trials of different drugs as they attempted to find something that worked for her. Most drugs didnt, although some worked for a time before their effects wore off. Eventually, after escaping an emotionally abusive relationship and continuing drug trials, she found her mental health becoming more stable. She attributes a lot of her improvement to Amsterdam. He was such a great doctor, she said. He saved my life, you knowfinally not being depressed.

Because she had been in treatment for many years, she remained in contact with Amsterdam, whom she describes as approachable, friendly, and very professional. Amsterdam was a fan of her artwork, and bought some of her paintings.

In 2010, she learned about the allegations against Amsterdam that supposedly involved her. I was absolutely floored, she said. Nauseated, floored. You know, I considered him a dear friend. He saved my life.

According to both this woman and Amsterdam, the allegation arose from a misrepresentation of some off-the-cuff language he had used in an email to her. Amsterdam had recently purchased one of her paintings, and in the email, he referred to the painting as booty (colloquially, to refer to an item of value). The investigative committee pointed to that word as having a sexual connotation, and thus evidence that Amsterdam had an inappropriate relationship with this female patient.

More than anything I felt terrible for Jay and [his wife] Debbie, she told MIA. This was ridiculous. It was uncalled for, mean-spirited, fabricated.

She wanted to sue Penn, but couldnt find lawyers willing to take on a case like this against the stone wall of Penns legal team. They defamed me, she said, and they should have been punished for it.

Furthermore, during Penns investigation of this matter, someone in Evans office photocopied and circulated her private medical information to various members of the university administration. This, of course, was a violation of HIPAA laws. They stole my emails, my health records, the woman said.

Amsterdam provided Mad in America with documents detailing the history of allegations and complaints made against him, and written records showing that there was an absence of any resolution substantiating the complaints. Even so, the stress of the situation, the sheer volume of complaints, and the feeling that everyone in the university was targeting him for some unknown reason led to a worsening of Amsterdams health in 2011. Acting upon his doctors advice, he took a medical leave.

Once on leave, Amsterdam struggled to figure out why his professional life had suddenly collapsed around him. Although he was now unable to see, his wife Debbie helped him search the internet for information about Penn and Evans. One day, she found an article about a court case in Philadelphia that led him into a larger dive into Evans involvement in the ghostwriting scandal.

In this case, a child had been born with a congenital heart defect after the mother used paroxetine while pregnant. The family sued GSK, accusing the company of hiding data about the harms of the drug. GSK lost the case, and ended up paying a $2.5 million penalty.

GSK, it seemed, had engaged in research misconduct. That article led Amsterdam and his wife to other articles citing UK psychiatrist David Healy, who had testified against GSK in the trial. In one article, Healy named several academic researchers who were on pharmaceutical executives speed-dial lists. One name immediately jumped out to Amsterdam as soon as his wife read it aloud: Dwight Evans.

Now, for Amsterdam, the light bulb was starting to turn on.

In the spring of 2010, when Amsterdam had been hit by the first complaint, Senator Charles Grassley was readying the release of his report on medical ghostwriting. In that report, which was released on June 24, 2010, Grassley noted that during his investigation he had asked Penn Medical School about its policies on ghostwriting, and Penn had informed Grassley that it had policies against plagiarism and it considered [ghostwriting] to be the equivalent of plagiarism.

This inquiry from Grassley surely would have raised anxiety in Penns psychiatry department. Not only had Amsterdam charged Gyulai with stealing his data, but Evans was also listed as an author of the Study 352 report, and yet Rickels, in a letter to Amsterdam, had told of how the paper had been ghostwritten by STI.

Moreover, as Evans likely knew in the spring of 2010, Grassley and his lead investigator, Paul Thacker, already had their sights set on him related to another instance of his authoring a ghostwritten paper. This instance of ghostwriting became public that fall, when Thacker, in a letter to NIH director to Francis Collins, told of how Evans had signed off on an editorial written by Scientific Therapeutics Information (STI), with the ghostwriting firm billing GlaxoSmithKline for its services.

Thacker wrote:

According to the documents, Sally Laden of STI wrote an editorial for Biological Psychiatry in 2003 for Drs. Dwight Evans, Chairman of the Department of Psychiatry at the University of Pennsylvania School of Medicine, and Dennis Charney, then an employee at the NIH and now Dean of Research at the Mt. Sinai School of Medicine at New York University.

In an email to a GSK employee, Ms. Laden wrote, Is there a problem with my invoice for writing Dwight Evans editorial for the [Depression and Bipolar Support Alliance]s comorbidity issue to Biological Psychiatry? Yet, when published, the authors Evans and Charney only stated, We acknowledge Sally K. Laden for editorial support.

In his letter, Thacker urged Collins to approve new policies that would recognize ghostwriting and plagiarism as research misconduct. He encouraged Collins to consider enforcement mechanisms such as disciplinary action and dismissal for the researchers involved.

Evans was now on the hot seat. Thackers complaint to Collins told of plagiarism for hire. Yet, Penn, in response to Thackers new revelation, took no action against Evans. As Thacker said in a subsequent article published a few months later, Penn just blew it off as though it were a matter of no account.

Thacker, in his latest article, publicly named Evans and Penn as an example of the corruption in academic medicine that needed to be cleaned up. Students should really be pissed off that professors get away with this type of fraud when students receive steep penalties, he wrote. What makes this all even more bizarre and insulting is that Dr. Evans is on the board of Penns Scattergood Program for the Applied Ethics of Behavioral Healthcare, a program dedicated to healthcare ethics.

Once Amsterdam learned of Thackers articles, he could put together a timeline that provided a likely explanation for why he had been hit with all those complaints in the spring of 2010. All of those complaints had emanated from Evans office, at a moment when Evans had reason to be worried about Grassleys investigation of ghostwriting, and if Thacker continued his digging, he might stumble upon the very studystudy 352that Amsterdam had complained about in 2001. And thator so it would seemwould mean big problems for Penn and Evans.

I think what happened is that Evans got all wigged out, Amsterdam said. He remembered the fact that he plagiarized, in 2001, an article in The American Journal of Psychiatry. And he knew that I knew, and that I knew he swept it under the rug by not taking it to the university, with his crony, Rickels. And he knew that if I were called to testify before Congress, I would tell them what happened.

Amsterdam didnt wait for Grassleys call. On July 8, 2011, he filed a whistleblower complaint with the federal Office of Research Integrity (ORI) alleging that Evans and the other authors had committed plagiarism by placing their names on that ghostwritten paper published in 2001.

Given Rickels 2001 letter to Amsterdam, which confessed that STI had written the initial drafts of the article, and that many academic investigators in the trial hadnt reviewed or seen the submitted article, it seemed that Penn would need to censure Evans. The ghostwriting element was clear. Even Gyulai had stated in his letter of apology that the ghostwriting firm had given first authorship to Nemeroff, and Penn had told Grassley that it considered agreeing to author a ghostwritten article to be a form of plagiarism.

But Penn just dismissed Amsterdams complaint with a wave of its institutional hand.

In a letter to Amsterdam dated December 5, 2011, the university admitted that the two researchers had published ghostwritten articles, and while it noted that the ghostwriting firms authors should have been listed on the publications, it decided that there had been no misconduct because Penn, at that time, did not have a formal policy prohibiting faculty and researchers from appending their names to ghostwritten work.

In its statement to the press, the university was even more adamant. A Science article published on March 2, 2012 had this headline: Penn Clears Two Faculty Psychiatrists of Research Misconduct Charges.

There was, the university stated in its press release, no plagiarism and no merit to the allegations of research conduct because Gyulai and Evans had helped conduct the research and analyze the results and contributed to the paper, which had presented the research findings accurately. As for Amsterdam, the university stated, he should not have been listed as a co-author or in the acknowledgements, because his role did not meet the journals guidelines for authorship.

The universitys response to Amsterdams whistleblowing did not impress Thacker and the leaders of the Project on Government Oversight. POGO sent a letter to the office of the President of the United States stating that the president of Penn, Amy Gutmann, had ignored the evidence against Evans. They just blew it off, Thacker wrote.

At that time, Gutmann was the chair of Obamas Bioethics Commission, and Thacker asked how she could be expected to function capably in that position, given this brush-off. Dr. Gutmanns bona fides on bioethicsto borrow a phrase from Penns own spokespersonappear to be unfounded.

After filing his complaint with the federal office of Research Integrity, Amsterdam teamed up with bioethicist Leemon McHenry to write a peer-reviewed article about the 2001 paper. They looked at the way the data from study 352 had been analyzed, and then how it was presented in the article itself. Their article was published in 2012 in the International Journal of Risk & Safety in Medicine. In it, Amsterdam and McHenry wrote that they show how primary and secondary outcome analyses were conflated, turning a negative clinical trial into a positive studywith conclusions and recommendations that could adversely affect patient health.

The study, they wrote, was designed to test GSKs drug, paroxetine (Paxil) against both an older antidepressant, imipramine, and a placebo control. The participants were people with a bipolar disorder diagnosis who were taking a full dose of lithium, but not responding to lithium treatment. The goal was to see if Paxil could improve depression when lithium wasnt working.

However, the study was plagued with problems from the start. The researchers struggled to enroll enough participants (hence the recruitment of Amsterdam, to gain access to his prestigious bipolar disorders clinic). Even with Amsterdams help, the researchers didnt enroll enough participants to meet the original requirement.

Still, GSK continued the study. Each of the 117 participants was randomly assigned to one of three groups: Paxil, imipramine, or placebo. The original test was to see how the groups did, on average, on both the Hamilton Rating Scale for Depression (HRSD, a common measure of depression severity), and the Clinical Global Impression Severity scale (CGI/S, a subjective, 7-point scale of how ill a clinician considers their patient).

The researchers also used the Young Mania Rating Scale (YMRS) to assess whether Paxil caused manic or hypomanic episodesa well-known harmful side effect of SSRIs.

However, the results showed no beneficial effect for either Paxil or imipramine. Improvement was no better than placebo on any of the scales used.

This was a failed study. But rather than publish that finding, GSKs ghostwriters looked for other ways to put a positive spin on the study. Finally, a statistician working for GSK hit on an idea that might produce a positive resultssplitting the participants into two groups, one on high doses of lithium, and one on low doses of lithium.

This was a post-hoc analysis (conducted after the study was over), so the researchers couldnt actually randomize participants to receive a specific dose. Moreover, all the participants were stabilized on a dose that was considered within the normal range. Nonetheless, the statistician arbitrarily separated those with a slightly higher dose from those with a slightly lower dose.

However, even then, the statistician couldnt find an effect when looking at how many people experienced a response to the drugs. Response in this case was defined as having a HDRS score of 7, or a CGI/S score of 2. Neither Paxil nor imipramine were significantly better than placebo and that was true for both the high-lithium and the low lithium group.

However, GSKs statistician still had one more data-mining exercise to try. The average change on the HDRS and the CGI/S scales for both Paxil and imipramine was greater than for placebo, and this difference was statistically significant.

Although the published report of Study 352 did note that no statistically significant differences in response rates were seen among those receiving paroxetine, imipramine, or placebo, it was the average change on the two scales that was featured in the abstract of the article, which was used to support this bottom-line conclusion: Antidepressant therapy may be beneficial for patients who cannot tolerate high serum lithium levels or who have symptoms that are refractory to the antidepressant effects of lithium.

This post-hoc data mining is known to be unethical, and if presented as a bottom-line finding, a type of research fraud. The joke within research circles is that if you torture the data long enough you can always find the result you want, and it was that process of data manipulation that Amsterdam and McHenry documented in their analysis of the study.

There were other research sins to be found in the published article. For instance, the researchers didnt report the YMRS data that was used to assess the risk of drug-induced mania/hypomania, which is a scientific sin of omission, one that in company-sponsored trials was regularly used to hide adverse effects of the sponsors drug.

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The Whistleblower and Penn: A Final Accounting of Study 352 - James Moore

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