01/5/18

In the Dark About Antidepressants

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In 2011, antidepressants were the third most commonly prescribed medication class in the U.S. Mojtabai and Olfson noted in their 2011 article for the journal Health Affairs that much of the growth in the use of antidepressants was driven by a “substantial increase in antidepressant prescriptions by nonpsychiatric providers without an accompanying psychiatric diagnosis.” They added how the growing use of antidepressants in primary care raised questions “about the appropriateness of their use.” Despite this concern, antidepressant prescriptions continued to rise. By 2016, they were the second most prescribed class of medications, according to data from IMS Health.

A CDC Data Brief from August of 2017 reported on the National Health and Nutrition Examination Survey. The Data Brief provided the most recent estimates of antidepressant use in the U.S. for noninstitutionalized individuals over the age of 12. As indicated above, there was clear evidence of increased antidepressants use from 1999 to 2014. 12.7% of persons 12 and over (one out of eight) reported using antidepressant medication in the past month. “One-fourth of persons who took antidepressant medication had done so for 10 years or more.”

Women were twice as likely to take antidepressants. And use increased with age, from 3.4% among persons aged 12-19 to 19.1% among persons 60 and over. See the following figures from the CDC Data Brief. The first figure notes the increased use of antidepressants among persons aged 12 and over between 1999 and 2014. You can see where women were twice as likely to take antidepressants as men.

Figure 1

The second figure shows the percent of individuals aged 12 and over who took antidepressant medication in the past month between 2011 and 2014. Note how the percentages increase by age groups for both men and women, with the highest percentages of past month use for adults 60 and over for both men and women.

Figure 2

The third figure shows the length of antidepressant use among persons aged 12 and over. Note that while 27.2% reported using them 10 years or more, 68% reported using antidepressants for 2 years or more. “Long-term antidepressant use was common.” Over the fifteen-year time frame of the data, antidepressant use increased 65%.

Figure 3

The widespread use of antidepressants documented above is troubling when additional information about antidepressants is considered. A February 2017 meta-analysis done by Jakobsen et al., and published in the journal BMC Psychiatry, found all 131 randomised placebo-controlled trials “had a high risk of bias.” There was a statistically significant decrease of depressive symptoms as measured by the Hamilton Depression Rating Scale (HDRS), but the effect was below the predefined threshold for clinical significance of 3 HDRS points. Other studies have indicated that differences of less than 3 points on the HDRS are not clinically observable. See “Antidepressant Scapegoat” for more information on the HDRS. Jakobsen et al. concluded:

SSRIs might have statistically significant effects on depressive symptoms, but all trials were at high risk of bias and the clinical significance seems questionable. SSRIs significantly increase the risk of both serious and non-serious adverse events. The potential small beneficial effects seem to be outweighed by harmful effects.

In his review of the Jakobsen et al. study for Mad in America, Peter Simons noted where these results add to a growing body of literature “questioning the efficacy of antidepressant medications.” He pointed to additional studies noting the minimal or nonexistent benefit in patients with mild or moderate depression; the adverse effects of antidepressant medications; the potential for antidepressant treatment to potentially worsen outcomes. He concluded:

Even in the best-case scenario, the evidence suggests that improvements in depression due to SSRI use are not detectable in the real world. Given the high risk of biased study design, publication bias, and concerns about the validity of the rating scales, the evidence suggests that the effects of SSRIs are even more limited. According to this growing body of research, antidepressant medications may be no better than sugar pills—and they have far more dangerous side effects.

Peter Gøtzsche, a Danish physician and medical researcher who co-founded the Cochrane Collaboration, wrote an article describing how “Antidepressants Increase the Risk of Suicide and Violence at All Ages.” He said that while drug companies warn that antidepressants can increase the risk of suicide in children and adolescents, it is more difficult to know what that risk is for adults. That is because there has been repeated underreporting and even fraud in reporting suicides, suicide attempts and suicidal thoughts in placebo-controlled trials. He added that the FDA has contributed to the problem by downplaying the concerns, choosing to trust the drug companies and suppressing important information.

He pointed out a meta-analysis of placebo-controlled trials from 2006 where the FDA reported five suicides in 52,960 patients (one per 10,000).  See Table 9 of the 2006 report. Yet the individual responsible for the FDA’s meta-analysis had published a paper five years earlier using FDA data where he reported 22 suicides in 22,062 patients (which is 10 per 10,000). Additionally, Gøtzsche found there were four times as many suicides on antidepressants as on placebo in the 2001 study.

In “Precursors to Suicidality and Violence in Antidepressants” Gøtzsche co-authored a systematic review of placebo-controlled trials in healthy adults. The study showed that “antidepressants double the occurrence of events that can lead to suicide and violence.” Maund et al. (where he was again a co-author) demonstrated that the risk of suicide and violence was 4 to 5 times greater in women with stress incontinence who were treated with duloxetine (Cymbalta).

Although the drug industry, our drug regulators and leading psychiatrists have done what they could to obscure these facts, it can no longer be doubted that antidepressants are dangerous and can cause suicide and homicide at any age. Antidepressants have many other important harms and their clinical benefit is doubtful. Therefore, my conclusion is that they shouldn’t be used at all. It is particularly absurd to use drugs for depression that increase the risk of suicide when we know that psychotherapy decreases the risk of suicide. . . . We should do our utmost to avoid putting people on antidepressant drugs and to help those who are already on them to stop by slowly tapering them off under close supervision. People with depression should get psychotherapy and psychosocial support, not drugs.

Peter Breggin described “How FDA Avoided Finding Adult Antidepressant Suicidality.” Quoting the FDA report of the 2006 hearings, he noted where the FDA permitted the drug companies to search their own data for “various suicide-related text strings.” Because of the large number of subjects in the adult analysis, the FDA did not—repeat, DID NOT—oversee or otherwise verify the process. “This is in contrast to the pediatric suicidality analysis in which the FDA was actively involved in the adjudication.” Breggin added that the FDA did not require a uniform method of analysis by each drug company and an independent evaluator as required with the pediatric sample.

Vera Sharav, “a fierce critic of medical establishment,” the founder and president of the Alliance for Human Research Protection (AHRP), testified at the 2006 hearing. She reminded the Advisory Committee that the FDA was repeating a mistake they had made in the past.  She said in the past the FDA withheld evidence of suicides from the Advisory Committee. German documents and the FDA’s own safety review showed an increased risk of suicides in Prozac. “Confirmatory evidence from Pfizer and Glaxo were withheld from the Committee.”  Agency officials “obscured the scientific evidence with assurances.”

What the FDA presented to you is a reassuring interpretation of selected data by the very officials who have dodged the issue for 15 years claiming it is the condition, not the drugs. What the FDA did not show you is evidence to support that SSRI safety for any age group or any indication. They are all at risk. They failed to provide you a complete SSRI data analysis. They failed to provide you peer-reviewed critical analyses by independent scientists who have been proven right. FDA was wrong then; it is wrong now. Don’t collaborate in this. [But they eventually did]

Breggin commented that the FDA controlled and monitored the original pediatric studies because the drug companies did not do so on their own and failed to find a risk of antidepressant-induced suicidality in any age group. “Why would the FDA assume these same self-serving drug companies, left on their own again, would spontaneously begin for the first time to conduct honest studies on the capacity of their products to cause adult suicidality?”

In a linked document of two memos written by an Eli Lilly employee in 1990, Dr. Breggin noted where the individual questioned the wisdom of recommendations from the Lilly Drug Epidemiology Unit to “change the identification of events as they are reported by the physicians.” The person went on to say: “I do not think I could explain to the RSA, to a judge, to a reporter or even to my family why we would do this especially to the sensitive issue of suicide and suicide ideation. At least not with the explanations that have been given to our staff so far.” Those suggestions included listing an overdose in a suicide attempt as an overdose, even though (here he seems to be quoting from a policy or procedural statement) “when tracking suicides, we always look at all overdose and suicide attempts.” Eli Lilly brought the first SSRI, Prozac, to market in 1986.

Next time you hear someone say that the FDA studies only showed increased suicidality in children and young adults as opposed to adults, remember that the adult studies, unlike the pediatric studies, were not controlled, monitored or validated by the FDA. This is one more example of the extremes the FDA will go to in order to protect drug companies and their often lethal products.

The problems with antidepressants, most of which are SSRIs—selective serotonin reuptake inhibitors—were at least partially known as Prozac and its cousins were being developed and brought to market in the early 1990s. As the above discussion indicated, there seems to have been a disregard of the potential for multiple negative side effects from their use, up to and including the various forms of suicidality. The sleight-of-hand done by the drug companies, and apparently the FDA, means that many individuals are in the dark about the adverse side effects stemming from their SSRI medications.

06/30/17

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.