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An Anti-depressing Tale

For a day the news was aflutter: the Washington Post, New York Times, and Time Magazine have all reported that a close reexamination of a 2001 study for the drug Paxil revealed untold dangers of the drug to teenage users. Paxil, GlaxoSmithKline’s chief antidepressant, is prescribed to millions of Americans including, for a period of time, hundreds of thousands of adolescents.  The question at hand – did the original research team know of the dangers back in 2001?

This new paper shook up public confidence in the science that we rely upon to advise decision making. For Paxil in particular it is a long and messy tale of questionable science practices, mishandling of data, potential misleading of the public, and eventually consequences for GSK. Here I broke down the story, briefly explaining what the drug Paxil is, how it works, how it can be so dangerous to teens, and I provide some of the scandal and intrigue behind the whole affair.

How Paxil Works

Paxil, a molecule called paroxetine, is in a class of mood-altering drugs known as selective serotonin reuptake inhibitors (SSRIs).  SSRI development was driven by the theory that depression is caused by insufficient amounts of the neurotransmitters serotonin and norepinephrine. While earlier drugs worked in a similar fashion, these drugs were specifically targeted to increase the amount of the neurotransmitters signaling from one neuron to the next.

Basically, consider serotonin and norepinephrine as “happiness molecules” which must be released from one neuron and taken up by another, transmitting a “happiness signal”.  The neurons that release these signals, however, may also reabsorb some.  Like my grandmother used to say, “The Neuron Giveth, and the Neuron Taketh Away.”  What reabsorption means though is a decreased amount of neurotransmitter available for that other neuron – the happiness signal gets weaker. SSRIs prevent the upstream neuron from reabsorbing the signal, as depicted in the cartoon below.

Neuroscientists might cringe at the simplicity of this figure, but essentially SSRIs allow the maximal amount of neurotransmitters to reach an effector neuron, responsible for controlling feelings.

Neuroscientists might cringe at the simplicity of this figure, but essentially SSRIs allow the maximal amount of neurotransmitters from a signaling neuron (“Stimulus”) to reach an effector neuron (“Emotion/Output”) responsible for controlling feelings.

This ‘monoamine theory’ of depression, presented in simplified form here, does not account for all effects of the drug. For a more detailed account of what may be causing the time-delayed effects and other nuances of the science, look at this presentation from the Psychopharmacology Institute.

SSRIs

Including the first SSRI approved in 1987 (Prozac by Eli Lilly) there have been a total of six drugs produced, five of which are still on the market. Of them, Paxil was the third to receive approval. In this class, as with many drugs, there is a constant battle between specificity (hitting only the right target) and potency (hitting the target hard enough).

While Paxil is the most potent inhibitor, it is also one of the least selective, meaning it can alter the actions of numerous other proteins in neurotransmission. Paxil also has one of the highest drug interaction profiles, and is the SSRI with the most severe pregnancy complications (though both Prozac and Paxil were shown to be linked with severe congenital heart defects in infants in a study released just this July).  More drug comparisons can be found here.

When Good Drugs Go Bad

So if Paxil is by and large a good and effective drug which can help many adults deal with the symptoms of depression what gives it the side effects that other drugs don’t have? A 2012 paper made the case that antidepressants hold more hidden risks and side effect than ever discussed; the study cites serious behavioral side effects, from dampened sex drive to anxiety to suicidal thoughts. An analysis of all SSRIs and SNRIs (selective norepinephrine reuptake inhibitors) showed a 1-2% increase in suicidal thoughts (though no one enrolled in a study ever completed a fatal suicidal act). This ‘minimal’ increase raised the question of how much benefit must a drug produce to warrant the risk.

Why Paxil May Affect Youths

As to why adolescents taking medication are more susceptible to suicidal thoughts than adults, it is a complicated question that relates to the developing of the adolescent brain. The exact mechanism isn’t fully understood, but it is believed the already hormone-susceptible brain of teens can easily be driven to extreme emotional reactions with chemical modification. With an estimated 2.5% of American youth on some form of antidepressant, this is not a side-effect to be considered lightly. SSRIs are far and away preferred for youths compared to TCAs and other antidepressants. Some advocate for cognitive behavioral therapy and counseling before medication, but often both are prescribed together.

The diagnosis of adolescent depression is on the rise, with approximately 2% of American youth considered to have symptoms of depression.  Further, among the ~40,000 men and women ages 15-24 the instance of adolescent suicide is around 5,000 a year in the US (triple the rate in 1960). While these teens need medical assistance, it is important not to aggravate the problem with potentially harmful drugs.

Teen depression is on the rise, as are the most severe manifestations such as suicides.

Teen depression is on the rise, as are the most severe manifestations such as suicides.

There are some animal studies that seek to explain the mechanism of youth intolerance. They indicate animals have detectable changes in neuronal protein expression in the hippocampus and amygdala (important regions of the brain for emotional response and decision making) of young test animals; such a response is not found in older animals exposed to SSRIs. Brain plasticity, or adaptability, is highest in early life, meaning your brain is not done forming until around age 25. Adolescent animal brains reflect the plasticity of human adolescents, and the impairments noted in animals inform side effects in humans as well. Altering the brain’s functions with SSRIs in this vital time period could plausibly lead to serious behavioral results, as was noted in animal models.

Paxil’s Past and Study 329

When Paxil was first approved in 1992 there were questions about its safety for adolescent users. Despite several studies in the 1990s, the drug manufacturer SmithKline Beecham (now GlaxoSmithKline or GSK) could not show conclusively the drug was safe. Finally, in 2001, a study was published by a group from Brown University, which is now referred to as the infamous Study 329. In this study, the researchers took adolescents with major depression and put them on a double blind 8-week study where they took either Paxil, Tofranil (a tricyclic antidepressant (TCA) which is similar but less specific), or a placebo.

Primarily, the results they reported showed definitively that Paxil improved scores on all metrics of depression. When the group reports all side-effects they omit ‘thoughts of suicide’; phrases like ‘serious adverse effects’ and ‘emotional lability,’ which represents 6% of the cohort, are used instead. The FDA later learned that 10 out of 93 participants taking Paxil endured ‘suicidal ideation’ (compared to 1 out of 87 on the placebo). This result was intentionally downplayed in the paper which, according to proceedings of a Senate inquiry, was in part due to co-authorship by PR specialists hired by GSK .

The original paper reads “because these serious adverse effects were judged by the investigator to be related to the treatment in only 4 patients (paroxetine, 1; imipramine, 2; placebo, 1), causality cannot be determined conclusively.” In essence they indicated only one suicidal ideation episode was Paxil-related, compared to two with the Tofranil, and one in placebo.  They go on to compare the results in the Paxil group to other studies of adults with depression and conclude it fared quite well.

This didn’t completely quell skepticism.  The lead author, Martin Keller, admitted in 2006 to having received undeclared money from GSK while conducting his research (read more). After publication GSK sales reps used this paper to promote prescription of the drug to adolescents. Doctors who agreed were rewarded with spa trips, meals and more reports show, techniques often employed to push a product (read more).

Meanwhile, suicides linked to the drug began to tally, and court cases began awarding settlements to the victim’s families. The FDA put a blackbox label on Paxil saying it wasn’t suitable for adolescent use. Talk of SSRIs being responsible for myriad behavioral problems, violence and suicide became hot-button news. In 2012 GSK was fined $3 billion for wrongfully advertising the drug, which was the largest fine ever levied against a pharmaceutical company…and less than 25% of the total revenue Paxil has produced for GSK.

This court decision came after GSK had already dodged a bullet in a 2008 litigation by citing a loophole in the law. At that time, the law didn’t require them to disclose the suicidal ideation information any more clearly than they did. (read on, and on).

GSKA Fresh Look

Given the long-standing controversy there wasn’t much surprise when the news broke September 15, 2015 that the original Paxil study was further flawed in its execution. Many had long called for the retraction of Study 329 due to conflicts of interest and purportedly misreported findings. This new reanalysis of the original data, which GSK had recently released to scientists in full, speaks to a notably different conclusion than 329.

From the Washington Post:

   Using 77,000 pages of previously unavailable documents, a team of researchers concluded that paroxetine, marketed as Paxil by drugmaker GlaxoSmithKline, was no more effective than a placebo and considerably more dangerous than the original study indicated…they said the mistakes were so egregious it was difficult to see how they could have occurred unintentionally.

The reanalysis found the reports of suicidal ideation were ‘miscoded’, or misidentified by the original researchers.  As such, the risk published grossly understated the risk apparent from the trial, or so the group believes.

Many of study 329’s authors still stand by the results saying that the study was not flawed and that the research was done in good faith. Yet many must have noticed the overstated results and how they were used. The new reanalysis points out:

In 2002, a US Food and Drug Administration officer who formally reviewed the trial reported that “on balance, this trial should be considered as a failed trial, in that neither active treatment group showed superiority over placebo by a statistically significant margin.” Yet this same year, according to the New York State Attorney General’s office, which sued GSK, over two million prescriptions were written for children and adolescents in the United States, all off-label, after a marketing campaign that characterized Study 329 as demonstrating “REMARKABLE Efficacy and Safety.”

Perhaps the research team is not fully at fault, but the fact that this level of error is possible in a peer-reviewed journal, leading to an article that has been cited over 300 times by other groups and continues to be cited today, is both jarring and discomforting. The paper has come under intense fire online and has been highlighted on Retraction Watch among other sites.

Impact on Science as a Whole

The Paxil study, its exclusion and misrepresentation of important data, and the media attention cast upon the inappropriate prescription of the drug have rightfully called research practices into question. This undermines the trust society puts into science and science research, which inevitably undercuts efforts to improve science funding in an age of drastic cutbacks. Moreover, it’s a terrible ethical problem pitting large corporations against the patients they purport to help.

Ethics journals have widely discussed this case and posed the question, “who is responsible?” Universities, journals, peer-reviewers, collaborators, PR-firms, sales reps, and even individual clinicians have their hands sullied with this drug and its side effects. One recent article tackles this issue head on, and almost aims to leave the reader feeling distrustful of institutionalized science, a result which is tragic but sadly understandable.

Medically this recent release will have very little effect though, as most clinicians have long since stopped prescribing Paxil to anyone near adolescent age. Instead, this release is a reminder that there may be more afoot under the cover of pharmaceutical companies than we’d like to think. Doctors should always act out of the patients best interests, and the patient must be the focus of medical research, analysis, and publication; similarly any risk to a patient taking a drug must be disclosed. This sounds like common sense, however when then State Attorney General Elliot Spitzer sued GSK for not publicly disclosing the results of all three of their Paxil trials the company refuted the idea.  Their defense was this frightening fallacy: having to disclose all data, both positive and negative, would intimidate researchers from taking risks and stunt scientific advancement. (Read the journal Nature’s printed reaction to the suit).

Transparency is of dire importance, however, when patients put their bodies and minds at risk with new medications. Hopefully this affair is a reminder to patients to use discretion, to clinicians to heavily consider prescriptions, and pharmaceutical companies to focus on delivering safe, effective drugs to the people who need them.

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