Anti-Depressants and Birth Defects
On July 27, 2007 the U.S. government’s Centers for Disease Control issued a press release apparently promoting the sale of anti-depressants to pregnant women. "Use of certain antidepressants, selective serotonin-reuptake inhibitors most commonly known as SSRIs, during pregnancy does not significantly increase the risk for most birth defects," the CDC wrote.
The press release cited a new CDC study released in the New England Journal of Medicine and further stated, "a second study on SSRI and birth defects, also published in the June 28 issue of NEJM, did not find such an association with birth defects overall, but did find significant associations between specific SSRIs and several birth defects."
Since the CDC put out the press release, hundreds of headlines have flooded the internet citing the new studies as proof that there is a low risk of birth defects with SSRI use during pregnancy, and the results of the studies have been reported as breaking health care news by every major media outlet in the US.
The pharmaceutical industry as a whole has spent a fortune buying influence in the media since 1997, when the government lifted restrictions on direct-to-consumer advertising.
In an article titled, Physicians and Bribery, published by News Target on July 7, 2005, Dani Veracty says the real story about prescription drugs is not being told because the drug makers are influencing the budgets of the major media companies by pumping hundreds of millions of dollars into TV, magazine, newspaper and online advertising.
"Because of this," he states, "the media companies out there don’t want to say anything bad about these prescription drugs."
In the July-August Columbia Journalism Review, contributing editor Judy Lieberman, reported that at the end of 2004, drug-company ad revenue for Time Magazine totaled $67 million; for Newsweek $43 million; and for the New York Times took in $13 million. By 2004, she reported, advertising revenues for the five networks including CNN and Fox news was $1.5 billion.
The drugs in the NEJM studies included Prozac by Eli Lilly, Zoloft from Pfizer; Paxil by GlaxoSmithKline, Celexa and Lexapro from Forest Labs; Luvox by Solvay, Effexor by Wyeth, and generic SSRI makers include Barr Pharmaceuticals, Ranbaxy Labs and Genpharm.
Prior to the arrival of SSRIs on the market, depression was estimated to affect only 100 people per million and patients with depression sought help from a medical professional trained in psychiatry and the treatment of disorder.
However, the rate of depression is now estimated to be in the range of 50,000 to 100,000 cases per million, or between a 500 to 1,000-fold increase, according to Jane Currie in "The Marketization of Depression", published in the May 2005 journal Women and Health Protection.
In April 2004, the CDC reported that antidepressants topped the list of drugs prescribed to women at visits to doctor’s offices and outpatient departments, followed by estrogens and progestins, antiarthritics, and medicines for acid/peptic disorders, in the Journal of Women’s Health.
By 2005, the CDC recently reported, antidepressants were the most prescribed drugs in the US during visits to doctors and hospitals and were prescribed far more often than even medications used to treat high blood pressure, cholesterol, diabetes, and headaches.
Yet, a recent analysis of studies on the efficacy of 12 second-generation antidepressants including SSRIs and serotonin and norepinephrine reuptake inhibitors (SNRIs), released on January 25, 2007, by the Agency for Healthcare Research and Quality’s (AHRQ), a division of the US Department of Health and Human Services, offers little support for the wide-spread use of these medications.
The AHRQ reviewed efficacy in treating major depressive disorder, dysthymia and subsyndromal depression (including minor depression), and also evaluated comparative efficacy for maintaining remission and for treating accompanying symptoms such as anxiety or insomnia or neurovegetative symptoms.
The review included 187 studies deemed to be of good or fair quality, including 89 head-to-head randomized controlled trials, 57 placebo-controlled randomized studies, with 126 of the studies sponsored by drug companies and 17 funded by government agencies or independent sources, and analyzed the effectiveness of Cymbalta, Wellbutrin, Effexor, Celexa, Lexapro, Prozac, Luvox, Remeron, Serzone, Paxil, Zoloft, and Desyrel, many of which are now also sold in generic form.
Overall the analysis found that in controlled studies, during 6 to 12 weeks of treatment, well over a third of the patients, or 38 per cent, saw no improvement in their condition and 54 per cent had only partial improvement and did not achieve remission.
In light of this clear lack of efficacy, it should be noted that as early as August 2004, the FDA label for SSRIs warned that "anxiety, agitation, panic attacks, insomnia, irritability, hostility, aggressiveness, impulsivity, akathisia (psychomotor restlessness), hypomania, and mania have been reported in adult and pediatric patients being treated with antidepressants for major depressive disorder as well as for other indications, both psychiatric and nonpsychiatric"
According to one of the world’s leading experts on SSRIs, Dr Peter Breggin, author of The Antidepressant Fact Book, "few physicians realize that meta-analyses have shown that antidepressants work no better than placebos at lifting depression."
So in the case of pregnant women he says, "The risk/benefit ration weighs a placebo effect against increased parental suicide and violence, and babies with congenital defects, babies undergoing withdrawal reactions, and babies whose brains have been forever changed by being soaked in SSRIs during their development."
Dr Breggin also notes that the NEMJ researchers failed to consider the serious withdrawal reaction in newborns and the potentially disastrous consequences of SSRI use by pregnant women. "Withdrawal reactions confirm that the brain of the fetus has been bathed in SSRIs and that it has suffered significant functional changes," he warns.
"It should be no surprise that it is not good to bathe the growing brain in toxic drugs like SSRIs," he says, "because serotonin is intimately involved in the development of the brain in utero and SSRIs inhibit normal brain cell development."
Experts say, SSRI use creates an unnecessary risk for fetus. Dr David Healy, another leading authority on SSRIs, and the author of The Creation of Psychopharmacology, and The Antidepressant Era, says, "the overwhelming majority of women who are prescribed SSRIs are at little or no risk for suicide or other adverse outcomes from their nervous state."
He points out that every pregnant woman may have symptoms of depression such as anxiety, disturbed sleep, fatigue, or a loss of interest in sex. "But having depressive symptoms and being depressed are two different things," he states.
Dr Healy also notes the lack of efficacy shown with SSRIs, and says the risks of the neonatal withdrawal syndrome and serious birth defects to the infant far outweigh any benefits of their use by expectant mothers.
Houston Attorney, Robert S. Kwok is outraged by the new campaign to promote the use of SSRI with pregnant women: "It’s ludicrous to think a woman is at greater risk of depression during her pregnancy and should take antidepressants despite the proven risk to her developing fetus," he states, "yet physician ‘opinion leaders’ with industry ties are actively trying to convince doctors and patients of just that." *
Mr Kwok represents the family of Gavin Shore, a baby born with a severe cardiac defect known as Shone’s Anomaly after his mother was prescribed the SSRI Celexa during pregnancy and says Gavin’s mother was not warned that taking an SSRI could double the risk of her baby being born with a severe heart defect.
Although some of the reports citing the NEMJ studies in media mentioned that Glaxo money was involved in funding the CDC study, most neglected to mention the financial contributions of the other drug companies for the study, or the steady stream of drug money that flows to the medical facilities and researchers involved in the studies.
When combined, the named universities, hospitals and researchers involved have received money from Lilly, Pfizer, Wyeth, Glaxo, Aventis, Sanofi Pasteur, and the three companies that make generic versions of SSRIs.
The CDC study lists Harvard Medical School and Massachusetts General Hospital as participating and the Harvard Medical School receives nearly 25 per cent of its funding from non-government sources, including nearly $3.5 million from Aventis Pharmaceuticals, $2.5 million from Bristol-Myers Squibb, and $2.1 million from Merck, according to an April 12, 2006 report in The Phoenix.
In addition, The Phoenix noted, SEC filings showed Harvard stock holdings of $16 million with Merck, $8 million of Bristol Myers Squibb, $34 million of Johnson & Johnson, and $33 million of Pfizer.
In one NEJM study, Dr Jan Friedman reported receiving honoraria for consulting from i3 Research, which is actually a huge conglomerate of "research" firms with names that begin with i3. The April 12, 2006 Phoenix reported that a firm called i3 Innovus, which co-authored 16 medical-journal articles in 2005, "provides integrated scientific strategies and solutions throughout the pharmaceutical product lifecycle."
The Phoenix also noted that this i3 firm had a Boston office for its vice-president of US operations, Milton Weinstein, who also happened to be a professor at Harvard Medical School and Harvard School of Public Health.
The same group of industry-backed research institutions credited in the NEJM CDC study, began the campaign to boost the sale of SSRIs to pregnant women more than a year ago when "experts" at Harvard and Mass General published a study whose effect was to dilute the finding of a mounting number of studies that found serious birth defects to be associated with the use of the drugs by pregnant women.
In response to a study in the February 2006, New England Journal of Medicine that showed infants exposed to SSRIs in the womb were 6 times more likely to be born with the life-threatening lung disorder, persistent pulmonary hypertension, a study appeared in the Journal of the American Medical Association the same month warning that stopping SSRIs could greatly increase the risk of pregnant women relapsing into depression.
On February 1, 2006, the Associated Press described the methods used by the Massachusetts gang when conducting the JAMA study and said researchers "followed 201 pregnant women with histories of major depression who were taking drugs such as Prozac, Zoloft, Effexor and Paxil."
"Because of ethical concerns," the article said, "the researchers did not randomly assign the women to either stop or continue medication."
Instead, the AP reported, the women decided what to do and then the "researchers watched what happened."
But the actual report on the study shows that of the 201 participants, 13 miscarried, 5 terminated their pregnancy, 12 were lost to follow-up prior to the end of pregnancy, and 8 chose to withdraw from the study.
So when reporting on the few pregnant women that remained, the study said mothers were 5 times more likely to suffer a relapse than those who continued taking the drugs.
However, a highly relevant finding rarely mentioned, in what turned out to be this diminutive study, is that 26 per cent of the women who remained on the drugs became depressed anyways.
The study authors noted that of the 82 women who continued antidepressant treatment throughout pregnancy, 21 or 26 per cent relapsed. But there were only 65 women in the group that discontinued the drugs, so the results logically showed a higher rate of relapse when 45 became depressed.
Moreover, nearly 2 years before the study was published in JAMA, on January 13, 2004, the lead author, Dr Lee Cohen was quoted in the New York Times as saying about 75 to 80 per cent of pregnant women who go off antidepressants will relapse during the pregnancy.
Six months after JAMA ran the study, the July 11, 2006 Wall Street Journal three some light on why the 13 "experts" might encourage pregnant women to keep taking SSRIs, in stating the lead author, Dr Cohen, who was a Harvard Medical School professor and director of the research program at Massachusetts General, was a longtime consultant to the three antidepressant makers, a paid speaker for seven, and his research work was funded by four drug companies.
In fact, the Journal reported, "the study and resulting television and newspaper reports of the research failed to note that most of the 13 authors are paid as consultants or lecturers by the makers of antidepressants," and "the authors failed to disclose more than 60 different financial relationships with drug companies."
And just like clock-work, the study was widely cited in other journals promoting the sale of SSRIs to pregnant women. "In summary, it seems clear that the risks of not receiving adequate antidepressant treatment thus far outweigh the risks of adverse events, not only in infants but in mothers as well," wrote Dr Pierre Blier of the University of Ottawa in an editorial in the Journal of Psychiatry and Neuroscience, 2006;31(4):226-8.
"The population," he warned, "should therefore learn to fear the illness more than the antidepressant."
But as it turns out, Dr Blier conflicting interests included among others, being a consultant with Lilly, Forest Labs, Janssen, Wyeth and Sanofi-Aventis, and a contract employee with Forest Labs. He was also in the speaker’s bureau for Lilly, Forest Labs, and Wyeth, and received grant funding from Lilly, Forest Labs and Wyeth.
The JAMA study, along with a brief note from Dr Cohen himself, was also featured in the Spring 2006 issue of Massachusetts General Hospital’s Center for Women’s Health Newsletter, in a publication that downplayed the risk of just about all the birth defects discovered in recent years including heart birth defects and the infant withdrawal syndrome.
Since 1990, JAMA has required authors of studies to list all financial interests and has published the disclosures. In an online editorial in July 2006, JAMA editor, Dr Catherine DeAngelis announced her intention to enforce the policy in part by publicizing any author’s failure to follow the rules and specifically noted that 3 consecutive nondisclosures involved authors from Harvard Medical School and included Dr Cohen’s study.
On July 11, 2006, citing material promoting the events, the Wall Street Journal reported that the Massachusetts General psychiatry academy planned to conduct Continuing Medical Education seminars in a dozen cities across the US, with Dr Cohen overseeing a segment on the treatment of pregnant women with psychiatric disorders.
One of the funding sources for the seminars was revealed less than a year later on May 1, 2007, when the Journal reported the major recipients of the $11.8 million that Eli Lilly gave out during the first three months of 2007, and said the largest single grant "was $825,000 to Massachusetts General Hospital’s psychiatry department for a year-long educational program with more than 150,000 registrants."
It should be noted that Lilly introduced the first SSRI, Prozac, in the late 1980s and its current best-selling antidepressant Cymbalta earned the company $1.3 billion in 2006.
The financial ties between the researchers and SSRI makers was brought to the attention of the JAMA editor by Dr Adam Urato and a letter from Dr Urato was also published in JAMA, stating that since the study dealt in part with the question of stopping antidepressants during pregnancy, the readers should be aware of the potential for pro-drug bias.
The Cohen study is still being cited to promote the use of SSRIs with pregnant women, and as recently as April 26, 2007, in a paper by Dr Claudio Soares, director of Women’s Health Concerns Clinic, McMaster University, Ontario in Journal Watch Women’s Health, a publication put out by the NEJM.
"Results of a recent prospective study of pregnant women," he wrote, "who were taking antidepressants at or near the time of conception demonstrated that women who opted to discontinue treatment during pregnancy were five times more likely to relapse than were those who stayed on treatment."
"Despite the cautionary remarks commonly made by most regulatory agencies and medical societies about the use of psychotropic medications during pregnancy," Dr Soares states, "considerable data supporting the efficacy and reproductive safety of antidepressants have accrued."
"Conversely," he warns, "evidence suggests that untreated depression has negative consequences for both mother and child."
"In summary," Dr Soares states, "clinicians should bear in mind the mounting evidence about the adverse effects of uncontrolled depression during pregnancy."
But here too, Dr Urato, wrote a response to this obvious sales pitch objecting to the total lack of citations to studies that support the assertion that the risks of birth defects associated with SSRI are rare and that the benefits of SSRIs use to avoid relapse into depression outweigh the risks.
But most concerning, Dr Urato wrote, "is the complete lack of financial disclosure information to go along with the article."
"As I was reading this piece," he wrote, "I kept thinking to myself "’Boy, this sounds like it was written by someone working for the antidepressant makers.’"
And sure enough, Dr Urato found that Dr Soares is on the Speaker’s Bureau for Forest Labs, Wyeth, Glaxo, and Pfizer and has received honoraria as a research consultant for Sepracor, Glaxo, Wyeth, and Neurocrine.
Mr Kwok is also highly critical of the increasingly common practice of using "opinion leaders" like Dr Soares to sell SSRIs to pregnant women, but states, "there will come a time when the drug manufacturers will have to face the music on SSRIs causing PPHN, and that time is coming soon."
He says his firm has an abundance of new cases that prove it’s no coincidence that pregnant mothers on SSRIs have an increased likelihood of giving birth to babies with PPHN in families where there is no history of respiratory illness.
"Just yesterday," Mr Kwok states, "I spoke to a mother who birthed a baby with a serious breathing disorder that requires regular use of a nebulizer, a device used to administer medication via liquid mist to the airways, commonly used in treating asthma and other respiratory diseases."
"This young mother is now at risk of losing her job," Mr Kwok reports, "since her infant requires full time care."
He says doctors should be instructed to screen patients who are pregnant or planning to become pregnant and inform them of the risks of SSRIs to a developing fetus. "At least educate this "class" of women," he says, "so they may make informed personal decisions."
"Sure, the loss of this "class" may cost the drug manufacturers some profit," he notes, "but it’s the right thing to do and it will save many families a lifetime of torture caring for a sick child like we see over and over again."
The need to recapture pregnant women as customers is crucial for some SSRI makers. For instance, Forest Labs reported that Lexapro and Celexa accounted for 68 per cent of the firm’s total sales for the year ending March 31, 2006, in its Annual Report filed with the SEC.
Back in May 2005, researchers from the University of Pittsburgh estimated that in any given year at least 80,000 pregnant women in US are prescribed SSRIs, in JAMA.
Families seeking legal advice for infants born with heart or lung birth defects to mothers who were prescribed Celexa during pregnancy may contact Robert Kwok at Robert Kwok & Associates, LLP at (888)466-5965; http://www.kwoklaw.com/about.php]
*This article is written as part of a series on Celexa related litigation and is sponsored by Robert Kwok & Associates, LLP.
EVELYN PRINGLE can be reached at email@example.com