Deadly Medicines and Organised Crime
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52 Medawar C, Herxheimer A. A comparison of adverse drug reaction reports from professionals and users, relating to risk of dependence and suicidal behaviour with paroxetine. Int J Risk Saf Med. 2003/2004; 16: 5–19.
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55 Healy D. Reply to D.Wilkinson – Loss of anxiety and increased aggression in a 15-year-old boy taking fluoxetine. J Psychopharmacol. 1999; 13: 421.
56 Orriols L, Delorme B, Gadegbeku B, et al. Prescription medicines and the risk of road traffic crashes: a French registry-based study. PLoS Med. 2010; 7: e1000366.
57 FDA Approved Labeling Text for NDA 21-875/NUVIGIL™ (armodafinil) Tablets. 2007 June 15. Available online at: www.accessdata.fda.gov/drugsatfda_docs/label/2007/021875lbl.pdf (accessed 17 July 2013).
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59 Gilbody S, House A, Sheldon T. Screening and case finding instruments for depression. Cochrane Database Syst Rev. 2005; 4: CD002792.
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61 Brody H. Hooked: ethics, the medical profession, and the pharmaceutical industry. Lanham: Rowman & Littlefield; 2008.
62 Medawar C, Hardon A. Medicines out of Control? Antidepressants and the conspiracy of goodwill. Netherlands: Aksant Academic Publishers; 2004.
63 van Marwijk H, Allick G, Wegman F, et al. Alprazolam for depression. Cochrane Database Syst Rev. 2012; 7: CD007139.
64 Montejo A, Llorca G, Izquierdo J, et al. Incidence of sexual dysfunction associated with antidepressant agents: a prospective multicenter study of 1022 outpatients. Spanish Working Group for the study of psychotropic-related sexual dysfunction. J Clin Psychiatry. 2001; 62(Suppl. 3): 10–21.
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67 Boseley S. They said it was safe. The Guardian. 1999 Oct 30.
68 Healy D. Pharmageddon. Berkeley: University of California Press; 2012.
69 Internal Eli Lilly memo. Bad Homburg. 1984 May 25.
70 Virapen J. Side Effects: death. College Station: Virtualbookworm.com Publishing; 2010.
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91 Wikipedia. GlaxoSmithKline. Available online at: http://en.wikipedia.org/wiki/GlaxoSmithKline (accessed 20 June 2012).
92 Herxheimer A. Turbulence in UK medicines regulation: A stink about SSRI antidepressants that isn’t going away. In: Glavanis K, O’Donovan O, editors. Power, Politics and Pharmaceuticals: drug regulation in Ireland in the global context. Cork: Cork University Press; 2008.
93 Grassley CE. Paxil. Speech at the US Senate. 2008 June 11.
94 Riddle MA, King RA, Hardin MT, et al. Behavioral side effects of fluoxetine in children and adolescents. J Child Adolesc Psychopharmacol. 1990/1991; 1: 193–8.
95 Brynner R, Stephens T. Dark Remedy: the impact of thalidomide and its revival as a vital medicine. New York: Perseus Publishing; 2001.
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97 Glass J, Lanctôt KL, Herrmann N, et al. Sedative hypnotics in older people with insomnia: meta-analysis of risks and benefits. BMJ. 2005; 331: 1169–73.
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99 Nielsen M. Selective Serotonin Reuptake Inhibitors (SSRI) – sales, withdrawal reactions and how drug regulators reacted to this with benzodiazepines as comparator [PhD thesis]. Copenhagen: University of Copenhagen; 2013.
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18
Pushing children into suicide with happy pills
Glaxo study 329
In 2001, GlaxoSmithKline published a trial in children and adolescents, study 329.1 This study reported that Paxil (Seroxat) was effective with minimal side effects, and it was widely believed and cited, no less than 184 times by 2010, which is remarkable. However, the trial was fraudulent. We know this because the Attorney General of New York State sued the company in 2004 for repeated and persistent consumer fraud in relation to concealing harms of Paxil,2 which opened the company’s archives as part of a settlement.
Glaxo lied to its sales force, telling them that trial 329 showed ‘REMARKABLE Efficacy and Safety’,3 while the company admitted in internal documents that the study didn’t show Paxil was effective. The study was negative for efficacy on all eight protocol-specified outcomes and positive for harm. These indisputable facts were washed away with extensive data manipulations, so that the published paper, which – although it was ghostwritten – had 22 ‘authors’, ended up reporting positive effects.3,4 The data massage produced four statistically significant effects after splitting the data in various ways, and it was clear that many variations were tried before the data confessed. The paper didn’t leave any trace of the torture; in fact, it falsely stated that the new outcomes were declared a priori.
For harms, the manipulations were even worse. The internal unpublished study report that became available through litigation showed that at least eight children became suicidal on Paxil versus one on placebo. This was a serious and statistically significant harm of Paxil (P = 0.035). There were 11 serious adverse effects in total among 93 children treated with Paxil and two among 87 children treated with placebo, which was also significant (P = 0.01, my calculation; the paper didn’t say that this difference was statistically significant). This means that for every 10 children treated with Paxil instead of placebo, there was one more serious adverse event (the inverse of the risk difference, 11/93 – 2/87, is 10). However, the abstract of the paper ended thus:
‘Conclusions: Paroxetine is generally well tolerated and effective for major depression in adolescents.’
An early draft of the paper prepared for JAMA didn’t discuss serious adverse effects at all! JAMA rejected the paper, and later drafts mentioned that worsening depression, emotional lability, headache and hostility were considered related or possibly related to treatment. The published paper did mention the serious adverse effects, but only headache in one patient was considered by the treating investigator to be related to paroxetine treatment. I have my doubts about whether the treating investigators really made these decisions. As the adverse events were reported to the company and appeared in earlier drafts, it’s more likely that it was people employed by Glaxo that interpreted the drug’s harms so generously. In the published paper, five cases of suicidal thoughts and behaviour were listed as ‘emotional lability’ and three additional cases of suicidal ideation or self-harm were called ‘hospitalisation’.
At least three adolescents threatened or attempted suicide, but this wasn’t described in the paper. Its first author, Martin Keller, wrote that they were terminated from the study because of non-compliance.2 There were other issues the published paper said nothing about. For one of the suicidal teenagers, the treating psychiatrist asked a researcher involved with the study to break the blind, which he refused although the protocol provided for this. Another ‘non-compliant’ teenager ingested 82 tablets of paracetamol, which is a deadly dose. Most curiously, another teenager was enrolled with the same trial number as the suicidal one, although this should be impossible, but perhaps the new patient took what remained of the study drug? This raises the uncomfortable question whether some patients who had fared badly were excluded from the trial. When the FDA demanded the company to review the data again, there were four additional cases of intentional self-injury, suicidal ideation or suicide attempt, all on paroxetine.
Keller is some character. He double-billed his travel expenses, which were reimbursed both by his university and the drug sponsor. Further, the Massachusetts Department of Mental Health had paid Brown’s psychiatry department, which Keller chaired, hundreds of thousands of dollars to fund research that wasn’t being conducted. Keller himself received hundreds of thousands of dollars from drug companies every year that he didn’t disclose. A social worker found a computer disc in the hallway and opened it to see to whom she should return it. She realised that adolescents were listed as if they had been enrolled in a study, which wasn’t true. It seemed they were made up, which would have been tempting given that $25 000 was offered by the drug company for each vulnerable teenager. The president of a chapter of the National Alliance for the Mentally Ill, supposed to be a patient advocacy group but heavily supported by big pharma, lectured for patients and their relatives on drug company money, which he didn’t reveal, and the honoraria were whitewashed.2
Keller never admitted there was anything wrong with the way he reported study 329. And his misdeeds didn’t harm his career. His department has received $50 million in research funding and a spokesperson from Brown said that ‘Brown takes seriously the integrity of its scientific research. Dr Keller’s research regarding Paxil complied with Brown’s research standards.’ Well, thanks for letting us know that, with such ethical standards, we should never apply for a job at Brown’s.
The role of the journal, Journal of the American Academy of Child and Adolescent Psychiatry, was similarly depressing. Although the journal’s editors were shown evidence that the article misrepresented the science, they refused to convey this information to the medical community and to retract the article, thereby jeopardising their scientific standing and moral responsibility to prescribers and patients.4 An explanation for this passivity can likely be found by following the money that goes to the journal’s owner.
What caused the greatest public uproar was that Glaxo pushed its drug for use in children, although it not only didn’t work in children, it was also very harmful, and it wasn’t even approved for use in children. The illegal marketing involved withholding trials showing Paxil was ineffective.5 An internal company document showed that the company knew what it was doing: ‘It would be commercially unacceptable to include a statement that efficacy had not been demonstrated, as this would undermine the profile of paroxetine.’4
The ruthless marketing worked. From 1998 to 2001, five million prescriptions a year were being written for
Paxil and Zoloft for children and adolescents.6 We should remember that there are real tragedies behind the numbers and real people who have paid with their lives for the companies’ unscrupulous lies, frauds and crimes:7
Matt Miller was unhappy. Having moved to a new neighborhood and a new school, Matt was thrust into unknown territory without his support system of old friends with whom he had grown up. That summer, Matt was prescribed Zoloft … and was told to call his doctor in a week. On a Sunday night, after taking his seventh pill, Matt went to his bedroom closet, where there was a hook just a little higher than he was tall. Matt hung himself, having to lift his legs off the floor and hold himself there until he passed out. He was only thirteen years old.
Jeremy Lown, a teenager, suffered from Tourette’s syndrome. To treat his uncontrollable tics and verbal outbursts, his neurologist prescribed Prozac. Three weeks after starting the medication, Jeremy hanged himself in the woods behind his house.8
Candace, a 12-year-old girl, was prescribed Zoloft because she suffered from anxiety. She was a happy child that had never been depressed or had suicidal ideation. She hanged herself after 4 days.9
Vicky Hartman was given a sample pack of Zoloft by her child’s doctor. She didn’t suffer from any mental disorder but mentioned she needed a ‘pick-me-up’ to help with stress. Soon after starting the medication, she shot her husband and herself.8
A man hanged himself after taking Prozac, which his cardiologist had prescribed for chest pain, and a woman shot herself after taking the Prozac her family doctor had prescribed for migraine.
Twenty-year-old student Justin Cheslek had trouble sleeping and was prescribed sleeping pills by his doctor.10 A few days later, he complained to the doctor that the pills made him feel groggy and ‘depressed’. The doctor gave him Paxil, and Justin told his mother that Paxil made him feel awful, wound up, jumpy and unable to sit still or concentrate. Two weeks later, the doctor gave him another SSRI, Effexor (venlafaxine), which caused a seizure after the first tablet. Justin still felt ‘really, really bad’ and 3 weeks after he took his first Paxil tablet, he hanged himself. Justin had no history of depression and if he hadn’t used the term ‘depressed’, he might not have been prescribed SSRIs. He just had trouble sleeping. In the days before his death, Justin described a feeling of wanting to jump out of his skin, a symptom typical of akathisia, which may lead to suicide.