When the US government cracked down on drug companies promoting antidepressants for children and teens

One in a series of three blog posts about Pharma’s promotion of medication for treatment of depression in young children and teens.

antidepressantsThis post concerns legal action by the US federal government in which two pharmaceutical companies pleaded guilty and had to pay large sums of money because of their promotion of misleading claims about about the efficacy and safety of antidepressants for children and adolescents.

This post is part of a three-part series exploring The discrepancy between Pharma’s promotion of antidepressants to children and adolescents and the evidence generated by clinical trials. The series is intended to be useful to anyone who wants to acquire a more in-depth understanding of how the pharmaceutical industry has misled professionals and mental health consumers about the efficacy and risk of antidepressant treatment for children and adolescents. I pay particular attention to re-analyses of data  from previously published in major psychiatric journals that showed claims in these journals about the effectiveness and safety of these medications for young people were exaggerated.

 Examination of other things I’ve written about antidepressants should establish that I don’t have an ax to grind and I certainly don’t consider myself anti-medication or antipsychiatry.

 One of my previous blog posts  discussed a study I had done with colleagues examining how psychotherapy compared with pill placebo, the standard comparator for antidepressants. We found that psychotherapy and antidepressants had modest, but comparable advantages over pill placebo.

Another of my blog posts discussed a study I had done with colleagues examining in 29 countries whether trends over time in the prescription of antidepressants were associated with trends in rates of suicide. We found it rather consistently that increases in prescription of antidepressants were associated with decreases in rates of suicide.

The present series was prompted by the publication of an article that described how previously confidential documents revealed that professionals employed by Forest Laboratories had ghostwritten an article in American Journal of Psychiatry. Authorship was then attributed to prominent mental health professionals, some of whom were paid for additional consultation and promotional activities. This particular AJP article was pivotal in convincing professionals and the public to accept the antidepressant citalopram (Celexa) for children and adolescents.

antidepressants-2Part one, the first blog in the series will soon be posted at Mind the Brain. It  provides a detailed “deconstruction” of the ghostwritten article claiming to demonstrate the citalopram was effective and safe for children and adolescents. The authors of this article relied on access to company documents released in a lawsuit and reanalysis of the data from the study. The re-analyses suggested that the drug was ineffective for both children and adolescents and its use was associated with significant adverse effects, including suicidal thoughts and behavior in some patients. The documents clearly demonstrated that Forest Laboratories were aware of the lack of benefits and the existence of risks with these medications, but suppressed and distorted findings in a ghostwritten article.

The second blog post will also be soon posted here at Quick Thoughts. It provides a rich set of links to other materials related to the American Journal of Psychiatry article that was systematically “deconstructed” in the new article, as well as the actual legal documents obtained in a civil action.

Additionally, the second blog post has links to materials related to another reanalysis reported in The BMJ of data from an article in Journal of the American Academy of Child & Adolescent Psychiatry and the controversies around both the original article and the re-analyses.

As with the deconstruction of the article concerning citalopram in American Journal of Psychiatry, the reanalysis reported in The BMJ failed to show that paroxetine (marketed as Paxil in the US and Seroxat in the UK) was safe and effective as claimed for children and adolescents.

This blog post summarizes two key legal actions resulting in the pharmaceutical companies Forest Laboratories and GlaxoSmithKline paying large fines for exaggerating benefits and hiding risks of antidepressants for young people. These misrepresentations involved publishing misleading articles in major medical journals and promoting off-label (unapproved) use in children and adolescents, when efficacy and safety had only been established for adults.

For what follows, it’s important to know that the antidepressant citalopram is a selective serotonin reuptake inhibitor (SSRI) that is actually a mixture of two enantiomers, molecules that are almost identical but are actual mirror images of each other, R-citalopram and S-citalopram. Forest laboratories claimed that that the S enantiomer, or S-citalopram was the more active antidepressant and began marketing it as Lexapro. Critics noted that Forest Laboratories’ tradename patent was expiring for citalopram 2003 and so other companies could have soon been in a position to market a generic citalopram. Isolation and approval of S-citalopram (Lexapro) would mean another patent would be effective until 2012. Evidence that Lexapro is actually more effective or has a mild or side effect profile is mixed.

Forest Laboratories and citalopram

In 2010, Forest Laboratories agreed to pay $313 million and plead guilty to “one criminal felony count of obstructing justice, one criminal misdemeanor count of distributing an unapproved drug in interstate commerce, and one criminal misdemeanor count of distributing a misbranded drug in interstate commerce.” The settlement was for three drugs, including the two antidepressants, Celexa and Lexapro.

Regarding Celexa, the criminal information and the False Claims Act complaint filed by the United States allege that Forest Pharmaceuticals promoted the drug for unapproved pediatric use. Despite a limited approval only for adult depression, Forest Pharmaceuticals promoted Celexa for use in treating children and adolescents suffering from depression. The government alleges that Forest Pharmaceuticals publicized and circulated the positive results of a double-blind, placebo-controlled Forest study on the use of Celexa in adolescents while, at the same time, Forest Pharmaceuticals failed to discuss the negative results of a contemporaneous double-blind, placebo-controlled European study on the use of Celexa in adolescents.

The government further alleges that Forest Pharmaceuticals’ off-label promotion consisted of various sales techniques, including directing its sales representatives to promote pediatric use of Celexa in sales calls to physicians who treated children and adolescents, and hiring outside speakers to talk to pediatric specialists about the benefits of prescribing Celexa to children and teens.

The False Claims Act complaint also alleges that Forest engaged in such marketing conduct in connection with Lexapro, which, at that time, also lacked any approvals for pediatric use. The civil complaint further alleges that Forest used illegal kickbacks to induce physicians and others to prescribe Celexa and Lexapro. Kickbacks allegedly included cash payments disguised as grants or consulting fees, expensive meals and lavish entertainment. The civil complaint alleges that as a result of the foregoing conduct, Forest caused false claims to be submitted to federal health care programs.

Lexapro was approved for use for acute and maintenance treatment of Major Depressive Disorder in adolescents, 12 – 17 years of age, on March 19, 2009.

Anyone who had purchased Celexa for someone under 18 from 1998 to 2013 or Lexapro from 2002 to 2013 became eligible for partial to full refunds.

GlaxoSmithKline and paroxetine

In the largest health care fraud settlement to date, GlaxoSmithKline agreed in 2012 to plead guilty and pay $3 billion to resolve allegations of fraud and failure to report safety data for a number of drugs, including paroxetine for depression in teenagers and adolescents. The settlement specifically said about paroxetine:

In the criminal information, the government alleges that, from April 1998 to August 2003, GSK unlawfully promoted Paxil for treating depression in patients under age 18, even though the FDA has never approved it for pediatric use. The United States alleges that, among other things, GSK participated in preparing, publishing and distributing a misleading medical journal article that misreported that a clinical trial of Paxil demonstrated efficacy in the treatment of depression in patients under age 18, when the study failed to demonstrate efficacy. At the same time, the United States alleges, GSK did not make available data from two other studies in which Paxil also failed to demonstrate efficacy in treating depression in patients under 18. The United States further alleges that GSK sponsored dinner programs, lunch programs, spa programs and similar activities to promote the use of Paxil in children and adolescents. GSK paid a speaker to talk to an audience of doctors and paid for the meal or spa treatment for the doctors who attended. Since 2004, Paxil, like other antidepressants, included on its label a “black box warning” stating that antidepressants may increase the risk of suicidal thinking and behavior in short-term studies in patients under age 18. GSK agreed to plead guilty to misbranding Paxil in that its labeling was false and misleading regarding the use of Paxil for patients under 18.