Forest Labs Bogged Down With Celexa Legal Woes
Forest Labs Bogged Down With Celexa Legal Woes
Forest Labs Bogged Down With Celexa Legal Woes
By Evelyn Pringle
According to Forest Laboratories Annual Report for the year ending March 31, 2006, the company's antidepressant franchise, consisting of Celexa and Lexapro, accounted for 68% of the company's sales.
But the flip-side of the coin is that Forest Labs is currently facing a wide variety of legal problems involving civil lawsuits and government investigations that could result in fines and damage awards that will off-set the profits from its top selling drugs for many years to come.
Celexa and Lexapro belong to the relatively new class of antidepressants known as selective serotonin reuptake inhibitors (SSRIs). Celexa was developed by the Danish pharmaceutical firm, H. Lundbeck A/S and was introduced into the US market by Forest Laboratories and Parke-Davis in September 1998.
According to its Annual Report filed with the SEC on June 14, 2006, Forest Labs is a defendant in approximately 25 active product liability lawsuits, with most of the complaints alleging that Celexa or Lexapro caused or contributed to persons committing or attempting suicide.
"The suits," the Report states, "seek substantial compensatory and punitive damages."
Possibly unbeknownst to Forest, the company is set to be hit with the first Celexa birth defects lawsuit in Kentucky alleging that the company has engaged in "repeated and persistent fraud" by misrepresenting, concealing and otherwise failing to disclose, information concerning the safety and effectiveness of Celexa in treating pregnant women.
A plaintiff in the case, Lacee Shore, was prescribed Celexa during her first trimester of pregnancy by Dr. David Smith, another defendant to be named in the lawsuit, and as a result, Ms. Shore's baby, Gavin Shore, was born with serious heart birth defects.
Gavin was born on May 2, 2006 and diagnosed with Shone’s Complex, a form of congenital heart disease that consists of multiple anatomic defects that lead to the obstruction of blood flow from the left side of the heart to the body.
Doctors have performed surgeries in an effort to correct the heart defects but if he survives, Gavin will have to undergo another surgery at the age of 3, and another in his teenage years.
According to the Madison Foundation, although current advances in heart surgery have helped increase the survival rate of infants in recent years, the overall prognosis for infants with the Shown's Complex is still poor. "Infection, stroke, heart block (interruption of the electrical activity of the heart) and chronic heart failure are frequent complications of repeated surgeries," its web site explains.
According to Robert Kwok, the Houston, Texas attorney handling the lawsuit, “Little Gavin is a fly-weight contender in a heavy-weight fight against Shone’s Anamoly."
"A 1990 study by the University of Michigan shows the outlook for patients like Gavin is very poor," he states.
"One quarter of patients die after their second operation," he says, "and second operations are very often necessary because of the complexity of the heart problem."
In regard to Celexa, the Shore lawsuit accuses the defendants of, "misrepresenting the severity, frequency and discomfort of side effects; and manipulating statistics to suggest widespread acceptability, while downplaying the known adverse and serious health effects, including but not limited to, risk of birth defects to the fetus, particularly major congenital malformations, and damage to the heart in infants born to a women taking Celexa the first trimester of pregnancy, and other related illnesses and conditions."
According to Mr Kwok, “Forest Laboratories is selling the idea of a depression epidemic to doctors and women, creating a market for its antidepressant drugs, and then reaping billions of dollars in prescriptions."
"But they sure don’t put the same level of effort into the science of their drugs," he notes.
"We’re exposing the fact," he says, "that the drug company is putting profits ahead of safety.”
Attorney Kwok might just be the guy to accomplish this feat. He is certainly no lightweight in the legal arena. In 1998 at age 28, he became one of the youngest Texas attorneys to become Board Certified in Personal Injury Trial Law and over his career he has tried more than 65 jury trials to verdict.
In June 2004, he successfully argued for and won an $18,200,000 jury verdict against the Union Pacific Railroad.
And his justice seeking activities extend well beyond the court room. Mr. Kwok has served on the State Bar of Texas grievance committee, where he judged disciplinary proceedings against other attorneys and in 2005, he completed a full term as Commissioner Vice Chair for the Houston Police Department, where he judged internal affairs disciplinary proceedings against Houston Police Officers.
There is definitely plenty of evidence to support Mr. Kwok's assertion that SSRI makers are selling the idea of an epidemic of depression. According to, "The Marketization of Depression: The Prescribing of SSRI Antidepressants to Women," by Janet Currie, in the May 2005, Women and Health Protection, "SSRIs are also among the highest selling of all drugs in an industry that has been consistently ranked as one of the most profitable in the United States for the past twenty years."
"Prior to the introduction of SSRIs," Ms Currie reports, "depression was considered to affect only 100 people per million."
"Since the introduction of SSRIs," she states, "prevalence rates for depression are now considered to be in the range of 50,000 to 100,000 cases per million (a 500 to 1,000 fold increase)."
"Twice as many psychotropic drugs," she notes, "are prescribed for women as for men, and this holds true for the SSRI antidepressants."
One of the more recent marketing schemes put into play to recruit new SSRI customers is the designation of "National Depression Screening Days," in the US and Canada with advertisements for free depression screenings at sites set up in local communities. Funding for this scheme is provided by all the usual suspects including Forest Labs, Eli Lilly, Glaxo, Pfizer and Wyeth.
In Ontario, Canada, Mamdani et al found “tremendous cost implications” due to the shift from older antidepressants to the new SSRIs and that antidepressant costs rose by an estimated 347% between 1993 to 2000.
“Prescriptions have been written for Celexa for women from all walks of life," Mr Kwok says, "from Medicare recipients to college students.”
"That meant a lot of pregnant women were taking it," he points out, "and doing so without all the information they needed to protect themselves.”
The Shore lawsuit alleges that defendants "failed to warn the public and the medical community about the special risks of developing birth defects in newborns, cardiovascular defects, heart related birth defects, or other serious problems associated with the use of Celexa."
Critics say the over-selling of SSRIs could not be accomplished without the help of middle-man doctors who write the prescriptions. These days, they say, physicians in every field of medicine are corrupted by financial ties to drug makers.
According to Dr. Jay Cohen, a recognized expert on medications and side effects and the author of, "Over Dose: The Case Against The Drug Companies," the "drug companies have marketed SSRI antidepressants vigorously not only to psychiatrists, who are supposed to have some expertise with these drugs, but also to family practitioners, pediatricians, gynecologists, internal medicine specialists, and anyone else who can pen a prescription."
"But this doesn't mean that they possess in-depth knowledge of SSRIs or their actions and toxicities," he notes.
He says many doctors do not know the difference between major and minor depressions and that the latter responds to much lower SSRI doses. "Even psychiatrists are often appallingly ignorant about how SSRIs work," he contends.
"The drug companies are so entrenched in the education of medical students and the continuing education of doctors," he says, "it is no stretch for me to claim that we now have a "medical-pharmaceutical complex."
"In it," he notes, "doctors' education and information is so controlled by the drug industry, doctors don't even know how limited their information is."
According to Dr. Cohen, "New generations of doctors are taught that they know everything important about medications, when in fact they don't."
"Thus," he concludes, "doctors aren't informed about obvious SSRI reactions and therefore don't warn patients."
According to world renowned SSRI expert, Dr. David Healy, author of, Let Them Eat Prozac, The Antidepressant Era, and The Creation of Psychopharmacology, medical conventions of groups like the American Psychiatric Association have become promotional and marketing “circuses,” with drug companies sponsoring limousine service, luxury hotel accommodations, meals, all registration and committee meetings, social events, publications, special lectures, and product samples.
In regard to the group's meeting in 2002, the Washington Post reported: "In the days leading up to the American Psychiatric Association's meeting in Philadelphia, pharmaceutical companies mailed attendees hundreds of free phone cards, as well as invitations to museums, jazz concerts and fancy dinners."
"And in several dozen symposiums during the weeklong meeting," the Post said, "companies paid the APA about $50,000 per session to control which scientists and papers were presented and to help shape the presentations."
Bought and paid for doctors speak to the media to tout the benefits of the drugs and downplay the results of the negative studies and conduct seminars for other doctors funded by drug companies to promote the off-label use of their employer's drugs.
These doctors sit on the boards of foundations and professional bodies and decide which drugs will be approved for medication formulary lists in Clinical Practice Guidelines and thus, which drugs will be covered by government health care programs and insurance companies.
In a review of North American and European Clinical Practice Guideline for a variety of treatment areas, including depression, Choudhry et al (2002) found that nearly 60% of the Guideline authors had relationships with the drug companies whose drugs were considered in the guidelines and in the majority of cases, no conflict of interest disclosures were made in the guidelines to indicate the possible bias of the authors.
Clinical research has also become privatized and funded by the drug companies. According to John Abramson, a clinical instructor at Harvard Medical School and the author of "Overdosed America," three-quarters of the clinical studies published in the three most respected medical journals, the New England Journal of Medicine, the Journal of the American Medical Association, and the Lancet are now commercially funded.
"As a result," he says, "our medical knowledge grows not in the direction that best improves our health but toward corporate profits, the way that plants grow toward sunlight."
And drug companies do much more than buy advertising in these medical journals. According to the editor of the Lancet, drug makers also pay millions of dollars for reprints of articles favorable to their product for sales representatives to hand out to doctors.
In the case of Celexa, a decision to bar the use of the drug with pregnant women would drastically lower Forest's profits. In May 2005, researchers from the University of Pittsburgh, estimated in the Journal of American Medical Association, that in any given year at least 80,000 pregnant women in US are prescribed SSRIs.
At a February 9, 2006 news conference, Dr Sandra Kweder, of the FDA, told reporters that women of reproductive age are the "biggest users of antidepressant drugs."
The Shore lawsuit also names the doctor who prescribed the Celexa as a defendant and accuses him of failing to exercise the ordinary care and diligence exercised by other doctors in similar circumstances by continuing to prescribe Celexa after "a multitude of literature and studies" confirmed the association of Celexa and birth defects and without alerting the plaintiff of the dangers of drug.
And the warnings about SSRI use during pregnancy have been many and continuous over the last decade. As far back as 1996, a study published in the NEJM that compared 228 pregnant women taking the SSRI, Prozac and 254 women who did not take the drug, between 1989 and 1995, found that among the 97 infants exposed to Prozac who were evaluated for minor anomalies, the incidence of three or more anomalies was significantly higher than among the 153 infants examined who were born to women who did not take Prozac, by a 15.5% to 6.5% margin.
In 2003, a study in the American Journal of Psychiatry reported that SSRIs medications readily cross the placental barrier and expose the infant to increased serotonin levels during early development.
In February 2004, a study published in the journal Pediatrics, said pregnant women who used SSRIs could be damaging the brains of their unborn babies and specifically noted the changes in heart rates. The study of 34 mothers and their babies found direct evidence of a link between fetal exposure to SSRIs and disrupted neurological development. The researchers linked abnormal heart rhythms, sleeping patterns, and levels of alertness to the drugs.
Lead researcher Philip Zeskind, a professor of pediatrics at the University of North Carolina-Chapel Hill, said that a study of 34 babies might be small, but that the results were "alarming" and demanded a follow-up.
His team compared 17 babies born to mothers who took Celexa, Prozac, Paxil, or Zoloft with 17 babies born to mothers who had never taken SSRIs.
Babies exposed to the drugs tended to be locked in one "sleep state," Professor Zeskind said, and showed "fewer of the smooth and predictable changes in heart rate that normally occur in newborn infants."
Five months later on June 9, 2004, nearly two years before the birth of Gavin Shore, Web MD reported that the FDA was concerned by reports suggesting that SSRIs may cause adverse health effects in newborns when mothers take the drugs late in pregnancy.
Web MD said the FDA had received hundreds of preliminary reports of adverse effects in newborns over the last decade and had received reports involving all SSRIs on the market, including Prozac, Paxil, Luvox, Zoloft, and Celexa.
The reports suggest, Web MD noted, that infants whose mothers took the medications can experience drug withdrawal symptoms or toxicity after delivery. Effects were wide-ranging, and the most common included trouble eating, irritability, body rigidity, and respiratory trouble, said Kathleen Phelan, a safety evaluator in the FDA's division of drug risk evaluation.
In July 2004, these reports prompted the FDA to change the labeling for the entire SSRI class of drugs, warning that some newborns exposed to SSRIs had developed problems requiring respiratory support, prolonged hospitalizations, and tube feeding.
"What we want them to do is realize there are things that happen to neonates when moms take these drugs that need to be considered," said Katherine Wisner, MD, a professor of psychiatry and obstetrics at the University of Pittsburg and a member of the FDA pediatric drug advisory panel.
On February 4, 2005, BBC News reported a study in the journal Lancet, in which researchers had screened the World Health Organization's database on adverse drug reactions for cases of neonatal convulsions and neonatal withdrawal syndrome and found that by November 2003, a total of 93 cases of maternal SSRI use in babies born with convulsions or withdrawal syndrome had been reported.
When these cases were analyzed, 64 were associated with Paxil, 14 with Prozac, nine with Zoloft, and 7 with Celexa.
Also writing in the Lancet, researchers at Yale University School of Medicine said it would be wrong to assume that withdrawal syndrome was only associated with Paxil use.
Dr Vladislav Ruchkin said: "From a pessimistic extreme, these reports might jointly herald the beginning of the end for the uncontested SSRI hegemony of the past decade."
He warned that until further research refuted the findings, it would be best to focus on non-drug therapies with pregnant women.
On September 1, 2005, BBC reported that Danish and US scientists found the use of SSRIs in the first three months of pregnancy was linked to a 40% increased risk of birth defects such as cleft palate, and that cardiac birth defects appeared to be 60% more likely when women used SSRIs.
In the study of 1,054 women who took SSRIs during pregnancy, scientists found that the use of the drugs late in pregnancy was also associated with a 40% increased risk of premature birth which in turn studies show, leads to a high rate of infant mortality.
The October 2006, issue of Pediatrics, citing a study by CDC researchers, reported that preterm birth is the leading cause of infant mortality in the US, accounting for at least a third of all babies' deaths in 2002.
The contribution of prematurity to infant mortality may be twice as high as originally estimated, said William Callaghan, MD, MPH, and CDC colleagues, in Pediatrics.
The researchers reviewed the top 20 causes of infant deaths in 2002, and found that 34% of the deaths occurred in preterm infants. The top cause of death overall was: Congenital malformations, deformations, and chromosomal abnormalities, occurring in 5,630 infants, 49.5% of whom were preterm.
In addition, the October 3, 2006 issue of the Archives of Pediatrics and Adolescent Medicine reported a study that found some low birth weight infants with no visible disability at birth were found to have subtle motor and cognitive deficits at age 16.
The authors noted that “independent of social risk, specific prenatal, perinatal and neonatal biological risk factors are associated with cognitive and motor outcomes as late as adolescence runs counter to the view that, absent severe disability, early biological risk factors are of little importance in later life."
On December 8, 2005, the FDA issued a health advisory saying exposure to the SSRI, Paxil, in the first trimester of pregnancy may increase the risk of congenital malformations citing a Swedish study of 6,896 women that found a doubling of cardiac birth defects among infants born to mothers who use Paxil, compared to infants in the general population.
On April 7, 2006, the BBC reported that a Canadian study from the University of Ottawa, of almost 5,000 mothers found those who used SSRIs during pregnancy were twice as likely to have a premature baby and almost twice as likely to have low birth weight babies and stillbirths.
In July 2006, the FDA addressed 2 studies related to the use of SSRIs during pregnancy. "The first study," it said, "illustrates the potential risk of relapsed depression after stopping antidepressant medication during pregnancy."
The women who stopped their medicine, the FDA noted, were five times more likely to have a relapse of depression during pregnancy than the women who continued to take the antidepressants while pregnant. The study cited was lead by Dr Lee Cohen and other authors, and was published February 1, 2006 in the Journal of the American Medical Association.
However, on July 11, 2006, the Wall Street Journal disclosed that the study in JAMA claiming that pregnant women who stopped taking SSRIs were likely to relapse, was published by authors with financial ties to the makers of the SSRIs.
The study, the WSJ said, "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."
"The lead author -- Lee S. Cohen," the Journal wrote, "is a longtime consultant to three antidepressant makers, a paid speaker for seven of them and has his research work funded by four drug makers."
“The study reported financial relationships,” the article noted, “for two of the 13 authors of the study, Emory's Drs. Stowe and Jeffrey Newport.”
“But at least seven others have relationships that were not disclosed,” it wrote. Among the most significant of the missing disclosures, the Journal said, are those of author, Lori Altshuler, director of the Mood Disorders Research Program at UCLA, who as it turns out is a speaker or consultant to at least five antidepressant makers.
"In total," the WSJ stated, "the authors failed to disclose more than 60 different financial relationships with drug companies."
"Dr. Cohen and some of his coauthors," the Journal wrote, "subsequently hit the lecture circuit, telling physicians about their findings while also spotlighting flaws in other recent studies that have found increased risks to babies born to mothers who use antidepressants."
The July 2006, FDA also advised of a second study published on February 9, 2006, in the New England Journal of Medicine, that focused on newborns with persistent pulmonary hypertension (PPHN), a serious and life-threatening lung condition.
According to the FDA, babies with PPHN have high pressure in their lung blood vessels and are not able to get enough oxygen into their bloods stream, and often need intensive medical care.
In the study, the FDA said, "PPHN was six times more common in babies whose mothers took an SSRI antidepressant after the 20th week of the pregnancy compared to babies whose mothers did not take an antidepressant."
Critics say the Cohen study was strategicly published in JAMA around the same time that the PPHN study appeared in the NEJM warning of the alarming breathing problem and that Dr Cohen and many of the other authors immediately set out to discount the findings of the PPHN study in lectures and seminars.
On July 19, 2006, the FDA also issued a new warning that said when SSRIs are taken together with triptans, drugs used to treat migraine headaches, a life-threatening condition called serotonin syndrome may occur.
According to the FDA, the condition causes serious changes in how the brain, muscles and digestive system work due to high levels of serotonin in the body.
In the Shore lawsuit, the complaint points out in language relevant here, that the defendants had a duty "to monitor epidemiological and pharmaco-vigilance data regarding their marketed drugs."
The lawsuit alleges that when the drug company defendants learned that there was a substantial risk of birth defects associated with Celexa, they had a duty to inform doctors, regulatory agencies, and the public whether they learned of the information through clinical trials, other outside sources, or pharmaco-vigilance activities.
According to experts, FDA regulations establish only “minimum safety standards” and they do not require that a company have proof of causality before a warning is added to a drug label. The regulations in fact, they say, mandate a warning whenever there is an “association” between a drug and a potentially lethal condition, pursuant to 21 C.F.R. §201.57(e).
Experts predict that juries will view the failure to warn about the potential dangers of SSRIs to the unborn fetus as the most reprehensible. “This situation is even more devastating than what we saw with Vioxx," Mr Kwok says, "because the victims are so young."
"Their whole lives - if they survive," he states, "will be under threat of illness and additional surgery, with a very poor prognosis.”
“The financial implications of a case like this," Mr Kwok says, "are huge for Forest Laboratories."
"They have convinced women to depend on Celexa the way a diabetic needs insulin," he states. "As a result, their profits have been huge."
"They should’ve kept testing the drug while it was making all that money - testing its effects on different groups," he says, "trying to improve its safety."
"However," he states, "they left out the group that deserves the highest level of protection - pregnant mothers and their unborn children.”
According to Ms Curry, the belief that depression is actually a “deficiency” disease, akin to diabetes, has been so aggressively promoted that there is frequently an "uncritical acceptance" of the value of prescribing SSRIs, even for children.
"There is no scientific evidence that there is a serotonin “imbalance” in people who are depressed," she says, "that they have a serotonin dysfunction or that they need serotonin drugs to operate normally."
"In the early 21st century," she points out, "we still know very little about the complexities of brain function."
"There are trillions of synapses in the brain and hundreds of brain chemicals," she notes. "Little is known about how these chemicals inter-relate or act on neurons."
In "Serotonin and Depression: A Disconnect between the Advertisements and the Scientific Literature," published in the November 2005, Public Library of Science Journal, Jeffrey Lacasse, of the Florida State University College of Social Work, and Jonathan Leo, of the Lake Erie College of Osteopathic Medicine, state: "To our knowledge, there is not a single peer-reviewed article that can be accurately cited to directly support claims of serotonin deficiency in any mental disorder, while there are many articles that present counterevidence."
"Furthermore," the authors note, "the Diagnostic and Statistical Manual of Mental Disorders (DSM), which is published by the American Psychiatric Association and contains the definitions of all psychiatric diagnoses, does not list serotonin as a cause of any mental disorder."
According to the article, the American Psychiatric Press Textbook of Clinical Psychiatry addresses serotonin deficiency as an unconfirmed hypothesis, stating, “Additional experience has not confirmed the monoamine depletion hypothesis”
"In short," the PLoS article states, "there exists no rigorous corroboration of the serotonin theory, and a significant body of contradictory evidence."
For thirty years, Harvard trained psychiatrist, Dr. Peter Breggin has served as an expert in civil and criminal actions against the manufacturers of psychiatric drugs. His work has provided the scientific basis for the original combined Prozac litigation and label changes on many psychiatric drugs. He is also the author of "The Antidepressant Factbook.
Dr. Breggin says, "There is no evidence whatsoever that depression is caused by a biochemical imbalance."
He states that he is outraged, "that so many people have been damaged or killed by the effects of the false biochemical diagnoses and toxic medications."
Researchers say getting studies with negative findings on SSRIs published is like pulling teeth. For instance, it took 18 months to get a study published in the September 2006 journal, Public Library of Science (PLoS), that determined that SSRIs can cause some people to become violent and even homicidal.
Dr Healy and David Menkes from Cardiff University in Britain, and Andrew Herxheimer from the Cochrane Centre, conducted the study to determine the risk of violent behavior in people taking SSRIs.
Dr Healy reports that, "even though PLoS is braver than most journals and less influenced by industry than most, it still took close to 18 months for this article to appear."
"The hold up," he says, "is the journal - whether PLoS or BMJ being terrified of industry and a legal action against them."
"This stands in contrast" he points out, "to the good news about drugs which industry manages to get out rapidly in the best quality, highest impact factor journals, apparently authored by the biggest name academics in the field."
There are many other serious adverse side effects associated with SSRIs that never seem to make the headlines. A 1999 study showed a 200% increased risk of upper gastrointestinal bleeding for people exposed to SSRIs within 30 days of the diagnosis of upper gastrointestinal bleeding compared to people not on the drugs, according to the August 31, 2006 Health Sentinel.
In addition, the Sentinel said, 5 other published studies that examined an association between SSRIs and gastrointestinal bleeding all showed and increased risk. "In these studies," it reported, "the increased relative risk of gastrointestinal bleeding between SSRI users and non-users ranged from 50% to 260%."
In addition to all the revelations over the last decade about the harm that SSRIs are known to cause, many studies have shown the drugs to be no more effective than a placebo in treating depression across all populations.
Overall, critics say efforts to assess the risks and effectiveness of SSRIs have been stymied by the unwillingness of drug makers to make clinical trial available to researchers. However, in recent years documents have surfaced as a result of litigation that show the drug makers have known all the long that SSRIs are dangerous and ineffective.
Experts contend that the value of any drug must be determined by weighing its benefits against its potential risks and its capacity for harm. With SSRIs, Dr. Healy says the treatment effects are modest while the burden and costs of harm have never been defined.
Dr. Breggin notes that a comprehensive review conducted on all studies of SSRIs submitted for approval to the FDA, show that when the studies are taken as a whole, the SSRIs do not work.
A little known secret, he says, is that a drug company may perform twenty studies in attempt to show efficacy and as long as two studies show a positive effective, the FDA will approve the drug.
"If a drug company cannot massage their self-generated data sufficiently to obtain a positive result in two out of twenty clinical trials," Dr. Breggin notes, "the company’s paid consultants and employees don’t deserve to stay employed."
"And of course, they won’t stay employed," he points out, "if they fail to meet the company’s needs to promote new products."
This “little known secret” is evidenced by internal FDA documents related to the approval of Celexa. According to a March 26, 1998 Memorandum written by, Thomas Laughren, Team Leader for the FDA's Psychiatric Drug Products, Division of Neuropharmacological Drug Reports, for Celexa (citalopram) there were a total of 17 clinical trials, including 2 uncontrolled trials, 6 active controlled trials showing no difference between treatments, and 2 placebo controlled trials that were too small to be considered studies.
The memo discussed 5 short-term trials (85A, 91206, 86141, 89303, and 89306) and 2 long-term studies (89304 and 89305). “In summary,” Dr Laughren wrote, “I consider studies 85A and 91206 positive support for the claim of short-term antidepressant efficacy for citalopram.”
“While 3 other placebo-controlled short-term trials (86141, 89303, and 89306) were negative, and not easily interpretable since there were no active control arms,” he said, “I feel there were sufficient reasons to speculate about the negative outcomes and, therefore, not count these studies against citalopram.”
He also noted support of the effectiveness from 2 positive relapse prevention trials. “Overall,” he wrote, “I consider these results sufficient to support claims of both short-term and long-term antidepressant effectiveness of citalopram.”
However, a May 4, 1998, memo from Paul Leber, Director of Division of Neuropharmacological Drug Projects, on the subject of “Approvable Action on Forrest Laboratories NDA 20-822 Celexa,” was much less enthusiastic and said the pubic had a right to know the truth about all the clinical trials on Celexa submitted to the FDA.
Dr Leber noted that Study 86141, a 6 week long placebo controlled study in elderly patients, Study 89303, a 6 week study in some 190 patients, and Study 89306, a 6 week long placebo controlled trial all failed to provide results confirming the positive findings of Studies 85 and 91206.
He said that the Clinical Efficacy Trials subsection of the drug labeling should not only describe the clinical trials that showed Celexa’s adequate effects, but should also mention the “well controlled clinical studies that failed to do so.”
“I believe it is useful for the prescriber, patient, and 3rd party payer to know,” Dr Leber wrote, “without having to gain access to official FDA review documents, the citalopram's antidepressants effects were not detected in every controlled clinical trial intended to demonstrate those effects.”
“I am aware,” he said, “that clinical studies often fail to document the efficacy of effective drugs, but I doubt the public, or even the majority of medical community, are aware of this fact.”
“I am persuaded,” he wrote, “they not only have a right to know, but should know.”
“Moreover,” Dr Leber concluded, “I believe that labeling that selectively describes positive studies and excludes mention of negative ones can be viewed as being potentially "false and misleading."
Many studies have shown the various SSRIs to be ineffective. In April 2002, a study in the Journal of American Medical Association compared the effectiveness of the SSRI, Zoloft, the herb St. John’s Wort, and a placebo and found the placebo treated patients had a 31.9% rate of remission of symptoms, while Zoloft’s rate was only 24.8%, which barely beat out St. John’s Wort rate of 23.9%.
In what should have served as the final nail in the coffin for the dishonest myth about the great success of SSRIs for treating depression, in June 2005, the Washington Post, citing a study primarily funded by the National Institute of Mental Health, that reported: "Despite a dramatic increase in treatment of psychiatric disorders during the past 10 years, there has been no decrease in the rate of suicidal thoughts and behavior among adults."
According to Attorney Kwok, "Women are prescribed psychotropic drugs at twice the rate of men."
"You’d think that would mean something like twice the science went into how these drugs affect women’s health," he notes.
"But that isn’t the case," he says, "because new moms are finding out too late that the Celexa they took was putting their unborn baby in grave danger.”
Andrew Herxheimer, from the Cochrane Centre, is a clinical pharmacologist and the author of, "Communicating with Patients about Harms and Risks." He refers to Celexa as just another me-too drug. "I don't know what there is that makes it different from other SSRIs or special in any way," he states.
He notes that before a decision is made to prescribe a drug, its benefits and harms must be weighed, ideally by the clinician and the patient together, he says. And the clinician is expected to know or find out about the nature and probability of each benefit and harm, and how to maximize benefits and minimize harms.
According to Mr Herxheimer, three major areas that should be covered by doctors when helping patients decide whether to take a drug are: (1) obtaining reliable information about benefits and harms; (2) effectively communicating probabilities to the patient; and (3) determining what to do to reverse or mitigate harmful effects when they occur.
Too often he says, information on specific populations like pregnant women is not provided. "Because controlled trials compare treatments they usually report only group means and test their significance," he explains. "This gives clinicians no help in treating people who are more or less sensitive to the drug than average."
"Clinicians should identify how
much the benefits matter to their patient," he advises,
whether a specific harm is particularly threatening or would be intolerable to that particular patient."
"A patient who is offered a treatment with serious implications," he says, "needs time and encouragement to think, and to talk to other people, before making a decision."
Mr Herxheimer also points out that reliable information about the potential dangers of drugs is hard to come by. "Companies do not want to do more work than regulators require, and once they have marketed a drug they hesitate to pay for more research," he says, "especially if the results might be inconvenient."
Critics say that even the studies that are published can not be trusted. On April 10, 2004, the British Medical Journal, citing Jurendi et al, criticized the authors of studies on SSRIs for exaggerating benefits and downplaying the harm the drugs caused. As one example, Jurendi pointed to a clinical trial of 93 children on Paxil which produced eleven serious adverse events in children taking the drug compared with only two in children in the placebo group.
Yet, despite this significant difference in adverse events, and the fact that seven of the Paxil children were admitted to the hospital, when the study was published the authors stated that Paxil "was generally well tolerated in this adolescent population, and most adverse effects were not serious."
Less than 3 months after the article appeared in the BMJ, Paxil maker, GlaxoSmithKline was charged with fraud by New York State Attorney General, Eliot Spitzer, for hiding studies that "not only failed to show any benefit for the drug in children but demonstrated that children taking Paxil were more likely to become suicidal than those taking a placebo."
According to Mr Spitzer, the company had in fact conducted at least 5 studies on the use of Paxil with children, but only published one, and even that study showed mixed results. In the end, Paxil paid more than $2 million to the state of New York to settle the charges and agreed to publish all clinical trials online.
That same summer, Forest Labs barely weaseled out of a similar fraud case. On June 29, 2004, the company received a request from Mr Spitzer asking in part, for information about how the company tested and promoted drugs like Celexa for off-label uses.
Because the FDA has not approved the use of SSRIs for pediatric depression, Forest was barred from promoting the drugs for such uses. However, doctors are allowed to prescribe the drugs off-label, and in 2004, Celexa happened to be the fourth most prescribed drug for children diagnosed with depression.
At the time, a representative of Mr. Spitzer's office, quoted in the June 30, 2004, New York Times, said Mr. Spitzer was particularly interested in how Forest tested and promoted Celexa and Lexapro for the off-label treatment of pediatric depression.
In another similarity to the Paxil case, Mr. Spitzer's investigation was announced a week after the Times reported that Forest did not tell a medical journal about a failed clinical trial of Celexa use in children when it published an article about a positive trial on Celexa with pediatric patients for which some of the article's authors were Forest employees.
The basic finding of the failed study was that Celexa showed no more effectiveness than a placebo when used to treat depression in pediatric patients.
On September 7, 2004, Mr. Spitzer announced that a settlement had been reached with Forest to resolve the inquiry into whether the company concealed information about the safety and effectiveness of Celexa and Lexapro. As part of the settlement, Forest agreed to post all studies on the drugs online, but somehow got away without having to pay any fines.
A month later in October 2004, the FDA finally ordered a black box label for all SSRIs, the strongest warning available, describing the increased risk of suicidal thoughts and behavior among children, and in July 2005, the agency issued a pubic health advisory that stated: “Several recent scientific publications suggest the possibility of an increased risk for suicidal behavior in adults who are being treated with antidepressant medication.”
In 2000, Gwen Olson, the author of "Rx Drug Pusher," walked away from the pharmaceutical industry, after spending 15 years selling drugs that she now admits are deadly. She states that there is "rampant economic incentive to over-prescribe drugs."
Ms Olson left her job when her bosses wanted her to sell Celexa. In clinical studies, she says, the drug had been shown to increase the risk of suicidal thinking and behavior in children and adolescents who had depression.
She notes that other side effects of SSRIs are also more harmful to children because of their developing organs. "They are three times as likely to react to these drugs as an adult is," she says.
According to Ms Olson, SSRIs alter the pathology of brain chemistry and are extremely addictive and she warns parents that once children get started on these drugs they may never get off and will end up being lifelong customers for the pharmaceutical industry.
After 15 years as a self-identified pusher for the pharmaceutical industry, it would probably be safe to assume that this lady knows what she is talking about.
Families seeking legal advice for infants born with birth defects to mothers who were prescribed Celexa during pregnancy can contact Robert Kwok & Associates, LLP at (713) 773-3380; http://www.kwoklaw.com/about.php
By Evelyn Pringle
(This article is written as part of a series on Celexa related litigation and is sponsored by Robert Kwok & Associated, LLP)
(Evelyn Pringle is a
regular columnist for OpEd