Rooting for the Underdog

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In July of 2010, a 57-year-old partner at the law firm Reed Smith jumped in front of a subway train in Chicago and died. His widow, Wendy Dolin, sued the pharmaceutical companies GlaxoSmithKline (who originally manufactured Paxil) and Mylan (the drug company who manufactured paroxetine, the generic version that Stewart Dolin took), charging that the drug caused akathisia, which led to his suicide. GSK attorneys dismissed the testimony of the plaintiff’s expert witness as “junk science,” which argued for a link between the drug and suicide. However it seems the jury disagreed, since on April 20th, 2017 they awarded a $3 million verdict for the plaintiff.

Mylan was released from the suit by the trial judge, who ruled they had no control over the drug’s label. GSK continues to maintain the company wasn’t responsible since it hadn’t manufactured the drug taken by Dolin. A Chicago Tribune article quoted Wendy Dolin as saying the ruling was “a great day for consumers.” The trial was not just about the money for her. It was about awareness to a health issue. But this isn’t the end. “Officials from the pharmaceutical company said the verdict was disappointing and that they plan to appeal.” GSK continues to assert they weren’t responsible because they didn’t manufacture the drug taken by Dolin.

Writing for Mad in America, attorney and activist Jim Gottstein noted the legal significance of the case, as it established GSK did not inform the FDA or doctors that Paxil could cause people to commit suicide—a conclusion GSK continues to deny. A second legal hurdle overcome by the ruling is a Catch-22 dilemma since SSRIs, like Paxil, are now usually prescribed as generics. “The generic drug manufacturer [Mylan} isn’t liable because it was prohibited from giving any additional information and the original manufacturer [GSK] isn’t liable because it didn’t sell the drug.” You can read Jim Gottstein’s article for an explanation of how these legal hurdles were overcome.

Bob Fiddaman interviewed Wendy Dolin after the verdict and she described some disturbing tactics used by GSK attorneys. She said depositions that should have been a few hours long became eight hours, “in an attempt to wear people down.” She said GSK asked the same question over and over again, hoping to confuse or manipulate people. She alleged they also called her friends, trying to get them to say something negative about her relationship with her deceased husband.

As a therapist, as a mother and a compassionate human being, I am aware there was no purpose to have done such. I have talked to therapists, physicians and pharmaceutical lawyers and all agree there was nothing gained by this other than to show me that GSK would stop at nothing to intimidate me.

During the trial it came to light that 22 individuals had died in Paxil clinical trials, 20 by suicide; two other deaths were suspected to be suicide. “All 22 victims were taking Paxil at the time, and 80% of these patients were over the age of 30.” GSK tried to argue their “illness” caused their deaths and not Paxil. Wendy Dolin said the lawsuit showed that “akathisia is a real, legitimate adverse drug reaction.” The public needs to be aware of its signs and symptoms.

Wendy said she knew even before they went to trial, that GSK would appeal the ruling if they lost. She thought there was a GSK lawyer in the courtroom during the trial gathering information for the appeal process. She said it had been suggested this case could go all the way to the Supreme Court, because GSK is afraid of the legal ramifications of a guilty verdict. The process could take 5-7 years. She said: “Clearly this case has never been about money. For me, it has always been about awareness, highlighting akathisia and ultimately changing the black box warning to include all ages.”

Writing for STAT News, Ed Silverman suggested the new head of the FDA, Scott Gottlieb, should require a stronger warning label for Paxil. “For the past decade, Paxil’s label has not carried any information indicating the drug poses a statistically significant risk of suicidal behavior for anyone over 25.” Yet there is scientific evidence of such a risk. See Table 16 in the linked “Exhibit 40” document of his article (I assume it’s from the Dolin trial). Silverman said: “For public health reasons, the FDA should pursue a warning.”  A former FDA commissioner was quoted as saying it was hard for him to understand why the warning of increased suicidal risk was not in the label.

But sucidality is not just a risk with Paxil (paroxetine). A meta-analysis done by Peter Gotzsche of the Cochrane Collaboration concluded that antidepressants doubled the risk of suicidality and aggression in children and adolescents. Gotzsche and his team of researchers reviewed the clinical study reports for duloxetine (Cymbalta), fluoxetine (Prozac and Sarafem), paroxetine (Paxil), sertraline (Zoloft), and venlafaxine (Effexor). Estimates of harm could not be accurately done because the quality of the clinical study reports varied drastically, limiting their ability to detect the harms. The true risk for serious harms was uncertain, they said, as the low incidence of these events and the poor design and reporting of the trials made it difficult to get accurate estimates.

A main limitation of our review was that the quality of the clinical study reports differed vastly and ranged from summary reports to full reports with appendices, which limited our ability to detect the harms. Our study also showed that the standard risk of bias assessment tool was insufficient when harms from antidepressants were being assessed in clinical study reports. Most of the trials excluded patients with suicidal risk and so our numbers of suicidality might be underestimates compared with what we would expect in clinical practice.

In April of 2016, the CDC released data indicating the suicide rate in the U.S. increased by 24% from 1999 to 2014. Overall, the age-adjusted suicide rate increased from 10.5 per 100,000 in 1999, to 13.0 per 100,000 in 2014. The rates increased for both males and females and for all ages from 10 to 74. The age-adjusted rates for males (20.7 per 100,000 population), was over three times that of females (5.8 per 100,000). Males preferred firearms as a method (55.4%), while poisoning was the most frequent method for females (34.1%). However, this was a lower percentage for both sexes than in 1999. See the following figure from the CDC Report noting suicide deaths by method and sex for 1999 and 2014.

This reverses a trend from 1985 to 2000, where the U.S. suicide rate was dropping. See the following chart taken from an NPR report on the same data.  The president-elect of the American Psychiatric Association (APA), Maria Oquendo, said she thought the late 1980s drop was probably due to the fact that new antidepressants (SSRIs) were more effective and had fewer side effects.

Karter noted how Oquendo and Christine Moutier (from the American Foundation for Suicide Prevention) both saw the addition of black box warnings of the potential for suicide in teenagers and young adults as contributing the rise in suicide rates. Moutier was more direct, stating the progress in depression treatment in the 80s and the 90s “was undone in recent years because of concerns that antidepressants could increase suicide risk.” Oquendo thought the increase of suicide deaths in younger populations was potentially due to the understandable reluctance of physicians to prescribe antidepressants to these individuals, “even when they’re aware the individual is suffering from depression.” She added how research showed the benefits outweigh the risks of prescribing antidepressants to children and adolescents.

But Justin Karter indicated this suggestion, that the warning labels led to a decreased number of antidepressant prescriptions for teenagers and adults, was inaccurate. Although several media outlets reported the increase in the suicide rate, they didn’t report the corresponding increase of Americans taking antidepressants, a rate that has nearly doubled.

There was a report published in the British Medical Journal in June of 2014 that indicated black box warnings on SSRIs had a paradoxical effect, with an increase in suicide attempts among youths. Mad in America cited 12 critics of the study and noted its multiple flaws. The unwarranted conclusion, namely lead to increasing the prescription of antidepressants to teenagers and youths, had the potential to do considerable harm. Mad in America concluded that it should never have been published. Among the problems with the study were the following:

The researchers’ stated conclusion, which was that a decrease in antidepressant prescribing in youth following the black box warning led to an increase in suicide attempts, isn’t supported by their own data. (1) There was not a significant decrease in SSRI prescriptions to teenagers and young adults following the black box warning. (2) Psychotropic drug poisonings are not a good proxy for suicide attempts. (3) This coding category actually tells of poisonings due to the use of psychiatric drugs, as opposed to their non-use. (4) Finally, there was no significant increase in the number of poisonings.

Additionally, Kantor et al., in “Trends in Prescription Drug Use Among Adults in the US” reported data from the National Health and Nutrition Examination Survey (NHANES) indicated that the use of antidepressants increased from 6.8% to 13% between 1999 and 2012. Yet, as Justin Karter reported, “The American Psychiatric Association guidelines continue to suggest medications as the preferred treatment for moderate to severe depression.”

If you’re still not convinced, take some time to read through a series of scientific articles submitted by Peter Breggin in his affidavit for another Paxil-related suicide trial. The topics covered included exhibits of Paxil causing suicidal behavior as well as SSRIs and SSRI withdrawal causing suicidality. There is another section on Dr. Breggin’s website that is an “Antidepressant Drug Resource & Information Center” with even more relevant articles.

Given the above discussion on antidepressants, the recent court ruling in Illinois awarding $3 million to Wendy Dolin has the potential to lead to an unknown number of future lawsuits, if it is upheld upon appeal. This could end up costing the pharmaceutical companies that brought now off patent SSRIs and SNRIs to market untold millions and possibly billions of dollars in further awards. So you can bet that GlaxoSmithKline has plenty of pharma companies (and their legal representatives) rooting for GSK to overturn the ruling in the Dolin case. Me, I’m rooting for the underdog here—the 13% of Americans who are taking antidepressant medications without clearly knowing the potential they have to make their depression and its consequences worse.


The Cycle of Antidepressant-Induced Helplessness

© Everett Collection, Inc. | dreamstime.com

© Everett Collection, Inc. | dreamstime.com

Lawyers for GlaxoSmithKline (GSK) recently referred to evidence presented by a well-respected expert, Dr. Joseph Glenmullen, as “junk science.” He was irrational enough to testify that there was a connection between suicidality (the likelihood of an individual completing suicide) and suicide attempts. The case is one where the widow of a lawyer sued GSK because her husband committed suicide shortly after taking a generic version of the antidepressant. “Since there is no way Dr. Glenmullen can establish causation based on suicide data, he relies instead on data on ‘suicidality’ and suicide attempts, which are not appropriate surrogates for reaching conclusions about suicide.”

The above was taken from a brief news report on Mad in America, “Paxil Manufacturer Calls Evidence of Suicide Risk ‘Junk Science.’” The article said GSK has routinely overstated the drug’s efficacy. A widely cited 2001 study funded by GSK known as “Study 329” was recently reanalyzed and these results then published in the British Medical Journal. The reanalysis showed that the original claim by Study 329 that Paxil (paroxetine) was safe and effective for adolescents was wrong. The September 16, 2015 BMJ press release also noted where GKS had been fined $3 billion ($1 billion criminal, $2 billion civil) for fraudulently promoting paroxetine, among other violations.

Using previously confidential documents, researchers reanalyzed the original data from Study 329 and found that paroxetine was not more effective than placebo in treating major depression in adolescents. They concluded: “paroxetine was ineffective and unsafe in this study.” And yet for fourteen years Study 329 has been cited as demonstrating the safety and efficacy of paroxetine to treat adolescent depression. The BMJ Editor-in-Chief said the publication of the reanalyzed data “set the record straight” while it also “shows the extent to which drug regulation is failing us.”

All antidepressant medications are required to include a warning similar to what follows, which was taken from the Medication Guide for Paxil:

PAXIL and other antidepressant medicines may increase suicidal thoughts or actions in some children, teenagers, or young adults within the first few months of treatment or when the dose is changed.

Psychiatrist Peter Breggin noted in “The Proven Dangers of Antidepressants” that the FDA warning cautioning about the risks of newer antidepressants (Prozac, Zoloft, Paxil, Luvox, Celexa, and Lexapro, as well as Wellbutrin, Effexor, Serzone, and Remeron) followed a public hearing with dozens of family members and victims testifying about suicide and violence committed by individuals taking these medications.

While stopping short of concluding the antidepressants definitely cause suicide, the FDA warned that they might do so in a small percentage of children and adults. In the debate over drug-induced suicide, little attention has been given to the FDA’s additional warning that certain behaviors are “known to be associated with these drugs,” including “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania.

Breggin was himself an expert witness in a 2012 court case that awarded $1.5 million medical malpractice verdict to a family of a man who committed suicide. He testified how antidepressants such as Paxil and Effexor could increase suicide risk in adults.

After reviewing extensive records and interviewing Mr. Mazella’s wife Janice, I concluded that Dr. Beals was negligent in reportedly prescribing Paxil for 10 years without seeing the patient, in failing to warn the patient and his wife about the serious risks associated with Paxil, in his doubling the Paxil dose and adding Zyprexa by telephone, and then in abandoning the patient during his decline. I also concluded that a hospital psychiatrist was negligent in not recognizing that Mr. Mazella was suffering from adverse drug effects and in discharging him without proper follow up two weeks before his death.

In his discussion on “The Proven Dangers of Antidepressants” linked above, Breggin also commented how there has been little attention to the additional FDA warning that additional behaviors are known to be associated with antidepressants, including “anxiety, agitation, panic attacks, insomnia, irritability, hostility, impulsivity, akathisia (severe restlessness), hypomania, and mania.” He noted how he has repeatedly documented how the stimulation and activation profile of antidepressants can lead to out-of-control behavior, including violence.

In his article, “Antidepressant-Induced Mania,” psychologist Philip Hickey described how circular reasoning about activation from antidepressants becomes evidence of “an underlying latent bipolar disorder.” He indicated that psychiatry retrospectively applies their explanation as follows: “Before the individual showed any signs of mania, he must have had bipolar disorder because he became manic at a later date.” The hypothesis cannot be verified because the occurrence of a manic or hypomanic episode is the primary criterion for the bipolar diagnosis.

Yet there has been recent evidence that manic/hypomanic episodes can be caused by the use of antidepressant medications. Hickey reviewed a Psychiatric Times article written by Ross Baldessarini that reported on a meta-analysis that he and his colleagues did on antidepressant-associated mood-switching. Bipolar disorder is often seen as beginning with at least one episode of major depression, followed by an episode of mania or hypomania. This ‘switching’ of mood may occur during treatment with an antidepressant or other mood-elevating agent. And it is especially common among juveniles and young adults using an antidepressant for a mood disorder (depression or anxiety) or a stimulant for attention. “Such pathological shifts of mood and behavior may represent adverse drug actions or a manifestation of undiagnosed bipolar disorder.”

Hickey noted that Baldessarini et al. found that manic or hypomanic episodes were 5.6 times more common per year for individuals diagnosed with major depression who were taking antidepressants and others with the same diagnosis who were not taking them. After citing several quotations from the Baldessarini et al. study and the Psychiatric Times article, Hickey said: “What the authors are pointing out here is that antidepressants are clearly implicated in the ‘excess’ incidents of mania/hypomania, and they have even raised the question of a direct causal link.”

Baldessarini even suggested that when antidepressant-related manic episodes occur, the continued use of antidepressants might contribute to recurrent manic episodes. Although it is widely assumed that mood-stabilizing drugs are highly effective in preventing antidepressant-associated mood switching, it is not conclusively proven to be true. “Moreover, there is very limited evidence that prolonged antidepressant treatment provides substantial protection against recurrences of bipolar depression and that it might contribute to emotional instability or rapid cycling.”

When you add the research of Irving Kirsch, who has shown that antidepressants have little or no therapeutic effect at all (See “Do No Harm with Antidepressants”), we are left with a class of drugs that are no more effective than the placebos used in their clinical trials. As we saw here, they could also activate what they are taken to prevent or stabilize—depressive symptoms such as suicidality. Moreover, their use could also lead to mania or hypomania and thus elevate the initial diagnosis of major depression to the more serious one of bipolar disorder. And the icing on the cake is that if antidepressants are continued, they may contribute to further emotional instability or rapid cycling. This is a cycle of what Peter Breggin called iatrogenic helplessness generated by antidepressants. Here is his description in Brain-Disabling Treatments in Psychiatry:

The concept of iatrogenic helplessness and denial includes the patient’s and the doctor’s mutual denial of the damaging impact of the treatment as well as their mutual denial of the damaging impact of the patient’s underlying psychological and situational problems. Overall, iatrogenic helplessness and denial accounts for the frequency with which psychiatry has been able utilize brain-damaging technologies, such as electro-shock and psychosurgery, as well as toxic medications.

Iatrogenic refers to something induced inadvertently by a physician, medical treatment or diagnostic procedures. Breggin has been challenging the iatrogenic nature of psychiatric treatment for essentially his entire professional career as a psychiatrist. In 1983 he wrote in The Iatrogenics Handbook that iatrogenic denial involved the infliction of brain damage and dysfunction upon the patient to encourage them to deny both the existence of his problems and the iatrogenic brain damage. “I developed the brain-disabling hypothesis which states that all the major psychiatric treatments disable the normal brain rendering the individual more helpless and hence easier to manage or to ignore.”


Modern Alchemy with Antidepressants

19867524_sA study published in the open access journal, PLOS One by Sugarman et al. once again replicated previous studies showing that there was very little clinical difference between an antidepressant and placebo. In a way this is old news. One of the study’s authors, Irving Kirsch previously reported these findings. You can read more on this antidepressant research here and here. I’ve also looked at a 60 Minutes broadcast that interviewed him in “Thor’s Psychiatric Hammer: Antidepressants.” Kirsch has also published a book on the topic: The Emperor’s New Drugs: Exploding the Antidepressant Myth. But here is the significance of the Sugarman et al. study. It was the first evaluation to use “a complete database of published and unpublished trials sponsored by the drug’s manufacturer.”

In 2004, GlaxoSmithKline  (GSK) was required as part of a lawsuit settlement to post online the results of all clinical trials involving its drugs. The 2004 lawsuit was because the company had withheld data on the ineffectiveness and potential danger of Paxil (paroxetine) when given to adolescents and children. But it doesn’t seem GSK learned their lesson. In 2014 the company agreed to plead guilty to criminal charges and pay $3 billion in fines for promoting its antidepressant drugs, Paxil and Wellbutrin for unapproved uses and failing to report safety data about Avandia. So Sugarman et al. were able to use the data GSK made available to do the research reported here.

The current analysis is the first evaluation of the efficacy of an SSRI medication in the treatment of multiple anxiety disorders, and the first to utilize a complete database of published and unpublished trials sponsored by the drug’s manufacturer. Our results indicated that paroxetine presented a modest benefit over placebo in the treatment of anxiety and depression, with mean change score differences of 2.3 and 2.5 points on the HRSA [Hamilton Rating Scale for Anxiety] and HRSD [Hamilton Rating Scale for Depression], respectively.

The study’s results found that individuals receiving placebo reported 79% of the magnitude of change with the individuals receiving paroxetine. This was consistent to previously reported magnitudes of 76% for placebo compared to paroxetine. Replicating this previous finding, namely greater than 75% of the drug response, suggested that: “the magnitude of the placebo effect is especially large in the treatment of anxiety and depression.” Given the similarities between paroxetine and other SSRIs, it is possible that similar magnitudes of placebo effects will be found with them. Further research is required to support this proposition. Nevertheless, “the current analysis indicates that the published literature represents an overestimate of the true efficacy of paroxetine in the treatment of anxiety.”

The glass-half-full reporting of the differences between drug and placebo have emphasized that statistically significant differences were found. The problem is, those differences were so small, that their clinical significance was questionable. According to the criteria of NICE, the National Institute of Health and Clinical Excellence, “the mean difference between paroxetine and placebo in the current analyses fell short of clinical significance for the treatment of both anxiety and depression.” Sugarman et al. reviewed these concerns and concluded that changes of three points or less on the HRSD did not correspond to a clinically detectable change and appeared to be “of marginal clinical significance.”

So paroxetine has only a slight benefit over placebo in treating symptoms of anxiety and supports previous work indicating that it has just a modest benefit over placebo when treating depression. Given the known side effects with standard medications used to treat anxiety and depression, their use as a first-line treatment for these problems seems questionable. “The obvious alternative for the treatment of both anxiety and depression is psychotherapy intervention.” But direct comparisons have not generally shown a significant difference between depression treatment modalities (medication or psychotherapy). Similarly inconclusive findings were noted for anxiety treatment.

Allen Frances said there were two differences between medieval alchemy and the pharmaceutical industry today. First is the well-oiled, massively financed, worldwide, and devastatingly effective marketing machine. Second is the requirement for a DSM diagnosis.

A significant portion of the $12 billion spent each year on antidepressants in the United States rewards the drug companies for promoting the overly widespread use of what to many patients are no more than highly advertised, oversold, and very expensive placebos prescribed for a fake diagnosis. (Allen Frances, Saving Normal)

In 2010, there was a study published a Scandinavian psychiatric journal with the provocative title: “Antidepressant Medication Prevents Suicide in Depression.”  It concluded from studying 18,922 suicides in Sweden between 1992 and 2003, “that a substantial number of depressed individuals were saved from suicide by postdischarge treatment with antidepressant medication.” Sixteen months after publication, it was formally retracted by the authors for “… unintentional errors in the analysis of the data.”

Psychologist Phillip Hickey reported that after a five month legal battle, he was able to get access to the correct data. The original study found that among completed suicides treated for depression in psychiatric care in the last five years before their suicide, 164 (15.2%) had antidepressants in their blood when they committed suicide. The corrected data indicated that 603 (56%) had antidepressants in them when they committed suicide. The “unintentional error” was huge—an increase of 439 people (268%).

And yet, the study’s author said that no conclusion from the study could be drawn “regarding antidepressants’ effects on suicide risk in any direction.” In other words, you couldn’t conclude that antidepressants prevented or facilitated suicide risk. Hickey reported that at the time of writing the original article, its author has financial ties to Lundback, Eli Lily and GSK (GlaxoSmithKline).

In another study, found in The British Journal of Psychiatry, a team of UCLA researchers randomized 88 participants into double-blind groups for 8 weeks of treatment (placebo or medication) with supportive care; and a separate group receiving supportive care alone. Expectations of medication effectiveness, general treatment effectiveness and therapeutic alliance were also measured. The groups receiving medication or placebo plus supportive care were not significantly different. However, both had significantly better outcomes than the supportive care alone group. Expectations of medication effectiveness were predictive of only the placebo response. Therapeutic alliance predicted participant response to both medication and placebo.

The lead author of the study, Andrew Lechter, said that the results indicated that if you think a pill is going to work, it probably will work. He noted that belief in the effectiveness of the medication was not related to the likelihood of benefitting from it. “Our study indicates that belief in ‘the power of the pill’ uniquely drives the placebo response, while medications are likely to work regardless of patients’ belief in their effectiveness.” He speculated that factors like direct-to-the-consumer advertising could be shaping peoples’ attitudes about medication. “It may not be an accident that placebo response rates have soared at the same time the pharmaceutical companies are spending $10 billion a year on consumer advertising.”

It seems that Lechter is saying that the drug response was independent of the expectations of medication effectiveness, while the placebo response was driven be the prior expectations of the participants, as they were influenced by factors like direct-to-the-consumer advertisings. If true, this would seem to challenge, to a certain extent, the results noted above and in Kirsch’s previous research. Replication of the results is needed before Lechter’s conclusions from his research are accepted. It should be pointed out that paroxetine (Paxil) was approved by the FDA in May of 1996, while direct-to-the-consumer advertising of medications did not begin until 1997. Therefore, it would not have had an effect upon the paroxetine data reported above. I would also feel more comfortable with Lechter’s interpretations of his data if he didn’t have as extensive an association with the pharmaceutical industry. See the “Declaration of interest” in the linked abstract from The British Journal of Psychiatry.