Paxil belongs to the class of antidepressant drugs known as selective serotonin re-uptake inhibitors (SSRIs).
At birth, Adrian was suffering from several life-threatening congenital heart defects. Beginning when he was eight days old, Adrian underwent three open heart surgeries in attempt to repair his heart. Each surgery lasted several hours and each time his parents were informed that his chance of survival was low.
In March 2005, Adrian underwent another surgery and a pacemaker was installed. He was discharged from the hospital on April 3, 2005, just weeks before his first birthday.
As Adrian continues to grow, his attorneys say, he will need repeated surgeries to replace a conduit, maintain his pacemaker, receive artificial replacement valves inserted into his heart and he is also said to be at risk of needing a heart transplant.
The California based Baum Hedlund law firm filed this latest lawsuit and represents many families whose children were born with heart birth defects to mothers who took Paxil. The firm's birth defect team is also investigating cases concerning lung, cranial and abdominal birth defects related to Paxil.
The law firm has been handling SSRI-related cases since 1990. Baum Hedlund partner, Karen Barth Menzies, leads the firm's SSRI Litigation Department and is lead counsel for the Plaintiffs' Steering Committee (MDL-1574) Paxil Products Liability Litigation. She is also leading the team of birth defect attorneys handling the Paxil cases.
In 2005, Ms Menzies was named one of the National Law Journal's Top 40 Under 40, for her "extraordinary achievements" and "impressive track record" in "stepping up her fight in the past few years, advocating that pharmaceutical companies should warn about the alleged risks of antidepressant drugs."
The Vasquez lawsuit complaint alleges that Glaxo, "promoted and maintained Paxil on the market with the knowledge of Paxil's unreasonable risk to the public in general and specifically to plaintiff."
The complaint also charges that Glaxo, "by directly and indirectly advertising, marketing, and promoting Paxil for the treatment of women during pregnancy and by placing this drug in the stream of commerce knowing that Paxil would be prescribed to pregnant women in reliance upon the representations ... that Paxil was safe and effective for the treatment of women during pregnancy and without significant risk to the fetus."
The lawsuit also alleges that Glaxo "did not timely warn the medical community and consumers generally that taking Paxil during pregnancy is associated with a significant increased risk of birth defects and abnormal development of the unborn child."
Legal experts predict that lawsuits involving SSRI-related birth defects will be hard for drug companies to defend against because of the steady stream of studies in recent years that have documented the many adverse effects of SSRI use on the unborn fetus; making it impossible for the drug makers to feign ignorance.
Although there have been many studies evaluating SSRI effects on newborns, medical researchers say they do not have enough information to determine what effects SSRI exposure in the womb may have on the overall long-term health of infants.
In 2003, scientists reported that SSRIs readily cross the placental barrier and expose the infant to increased serotonin levels during early development, in a study published in the American Journal of Psychiatry (2003; 160:993-996)
Early the following year, on February 22, 2004, the Chicago Sun-Times reported that pregnant women who use SSRIs could be damaging the brains of their unborn babies after a study published in the American Journal of Pediatrics found direct evidence of a link between fetal exposure to SSRIs and disrupted neurological development.
"Researchers linked abnormal sleeping patterns, heart rhythms and levels of alertness to drugs called selective-serotonin re-uptake inhibitors," the Sun-Times wrote.
The study's lead researcher, Philip Zeskind, a professor of pediatrics at the University of North Carolina-Chapel Hill, said babies exposed to the drugs tended to be locked in one "sleep state," and showed "fewer of the smooth and predictable changes in heart rate that normally occur in newborn infants," and that the results were alarming and demanded a follow-up.
"What we've found, Dr Zeskind said, "is that SSRIs disrupt the neurological systems of children, and that this is more than just a possibility, and we're talking about hundreds of thousands of babies being exposed to these drugs during pregnancy."
"These babies," he said in the February 22, 2004, Sunday Telegraph "are bathed in serotonin during a key period of their development and we really don't know what it's doing to them or what the long-term effects might be."
"It could be that they go 'cold turkey' when they are born," he advised, "or the serotonin could be having an effect on their brains, or it could be a bit of both."
In June 2004, a few months after the Pediatrics article appeared, a study published in Prescrire International, also found that newborns exposed to SSRIs toward the end of pregnancy showed signs of agitation, altered muscle tone, and breathing and suction problems, with an estimated 20% to 30% of the infants in the study affected.
And the adverse events were reported with the use of all SSRIs.
Many researchers say they are unable to determine for certain whether infants with SSRI-associated problems at birth, are suffering from drug withdrawal or whether SSRIs are having a toxic effect on their systems. "The symptoms," the Prescrire research said, "are variously attributed to withdrawal or to the drug itself."
"In practice," the researchers advised, "doctors should be aware of this risk when considering antidepressant treatment for women in the third trimester of pregnancy."
On June 9, 2004, Web MD reported that the FDA was concerned because the "agency has received hundreds of preliminary reports of adverse effects in newborns over the last decade."
Adverse effects were wide-ranging, but the most common included trouble eating, irritability, body rigidity, and respiratory trouble, according to Kathleen Phelan, a safety evaluator in the FDA's division of drug risk evaluation.
The reports suggest, Web MD noted, that infants whose mothers take SSRIs can experience withdrawal symptoms or toxicity after delivery.
The FDA also recorded 19 adverse events in pregnant women who took Effexor, an antidepressant closely related to SSRIs, including seizures, jitteriness, and jaundice.
The following month in July 2004, the adverse event reports prompted the FDA to change the labeling for all SSRIs, warning that newborns exposed to SSRIs have developed problems requiring prolonged hospitalizations, respiratory support, and tube feeding.
In October 2004, researchers from Columbia University published a study in the journal, Science, suggesting that exposure to Prozac in the womb and in early childhood may permanently alter the brain's circuitry and disrupt neural development, leading to serious emotional disorders later in life.
In February 2005, Spanish researchers reported the use of SSRIs was associated with neonatal withdrawal syndrome, in the medical journal, Lancet.
The study by a team at the University of La Laguna in Spain found symptoms of the withdrawal syndrome to include convulsions, irritability, abnormal crying and tremor.
For this study, researchers reviewed the World Health Organization database of adverse reactions for neonatal convulsions and neonatal withdrawal syndrome associated with the use of SSRIs from 72 coutries. By November 2003, they found there were a total of 93 reported cases of SSRI use associated with either neonatal convulsions or withdrawal syndrome.
Of these cases, 64 involved Paxil,
In the September 2005, Journal of Psychopharmacology, Vol 19, No 5, 554-557 (2005), researchers discussed the uncertainty of whether the symptoms found with infants at birth represent Paxil (paroxetine) toxicity or a discontinuation syndrome.
"Serotonin toxicity due to paroxetine seems the most likely mechanism," the Journal wrote, "though an important differential diagnosis is a paroxetine discontinuation (withdrawal) syndrome."
The infant's symptoms began on the first day after birth and persisted for 10 days even though levels of paroxetine were undetectable on day 6, the study found. "Differentiating between these two syndromes," they said, "in the neonate presents a dilemma for clinicians."
Irrespective of the mechanism, the authors of the study said that all infants exposed to SSRIs during the last trimester should be followed closely for adverse symptoms in the first 10 days after birth and the possibility of such symptoms should be discussed with women who are considering starting or continuing SSRI treatment in pregnancy.
In September 2005, Glaxo sent out a "Dear Doctor" letter advising health care professionals of a Paxil label change that, according to data obtained from the National Birth Defects Prevention Study of infants, women who took an SSRIs were more likely to have an infant with omphalocele (abnormality in which the infant's intestine or other abdominal organs protrude from the navel).
However, the strongest effect was reported with Paxil, which accounted for 36% of all SSRI exposures.
In addition, the "Dear Doctor" letter advised that the authors of the study above also found an association of exposure to SSRIs and giving birth to an infant with craniosynostosis (a congenital defect present at birth, in which the connections between skull bones (sutures), prematurely close during the first year of life, causing an abnormally shaped skull.)
Also in September 2005, studies conducted by Danish and US researchers determined that 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 cardiac defects - which appeared to be 60% more likely when women used SSRIs.
In one study, focusing on 1,054 women who took SSRIs during pregnancy, scientists also found that use of the drugs late in pregnancy was associated with a 40% increased risk of premature birth.
And a second study of 377 cases of persistent pulmonary hypertension in babies found SSRI use late in pregnancy was linked a 5.5-fold increased risk.
The findings of the studies were presented an International Society for Pharmacoepidemiology conference and featured in Pulse magazine.
Three months later, on December 8, 2005, the FDA issued a public safety alert about the results of Paxil studies, suggesting that the drug increases the risk for birth defects, particularly heart defects, when women take it during the first three months of pregnancy.
The advisory was based on the preliminary results of two studies. The first involved an evaluation of US health insurer data that found about 2% of women who took Paxil early in pregnancy gave birth to infants with heart defects, compared to about 1% of all women.
The second study reviewed records on about 6,900 infants in Sweden, and found that 1.5% of women taking Paxil in their first trimester gave birth to infants with heart defects, verses 1% of women who took other antidepressants.
"The early results of two studies," the FDA said, "showed that women who took Paxil during the first three months of pregnancy were about one and a half to two times as likely to have a baby with a heart defect as women who received other antidepressants or women in the general population."
Most of the heart defects reported were atrial and ventricular septal defects or holes in the walls of the chambers of the heart, the FDA advised.
In general, according to the FDA, these types of defects range in severity from those that are minor and may resolve without treatment to those that cause serious symptoms and may need to be repaired surgically.
In light of these findings, the FDA told Glaxo to change the pregnancy warning on Paxil labeling from C to the stronger category D, which means that studies in pregnant women have demonstrated a risk to the fetus.
"FDA is advising health care professionals to discuss the potential risk of birth defects with patients taking Paxil," the agency's advisory said, "who plan to become pregnant or are in their first three months of pregnancy."
"FDA is advising health care professionals not to prescribe Paxil in women who are in the first three months of pregnancy or are planning pregnancy," the advisory warned, "unless other treatment options are not appropriate."
In December 2005, Glaxo also notified healthcare professionals about information added to the labeling of Paxil about the risk of major congenital malformations in infants born to women taking Paxil during the first trimester of pregnancy.
Paxil has long been associated with difficult withdrawal side effects, leaving patients virtually addicted to the drug. But a study in the February 5, 2006, Lancet reported evidence that babies born to mothers who take SSRIs during pregnancy experience symptoms of withdrawal at birth.
The study involved 60 infants whose mothers took SSRIs throughout their pregnancies and a second group of 60 infants who were not exposed to SSRIs in the womb. The researchers determined that about one out of three newborns exposed to SSRIs in the womb showed signs of neonatal drug withdrawal.
The newborns were assessed for signs of withdrawal during the first two hours after birth, and then again at regular intervals if they exhibited initial signs of withdrawal.
The researchers found 18 of the newborns, or about 30%, exhibited signs of withdrawal in the hours after birth, and in eight cases the symptoms were considered severe. The most common symptoms included tremors, sleep disturbances, gastrointestinal problems, muscle tensing, and high-pitched crying.
None of the infants who were not exposed to SSRIs had symptoms.
The researchers concluded that babies born to mothers taking SSRIs should be watched in the hospital setting for at least 48 hours following birth and expectant mothers and their doctors should be warned about the potential risk.
"Because maternal depression during pregnancy also entails a risk to the newborn, the risk-benefit ratio of continuing SSRI treatment should be assessed," Dr Rachel Levinson-Castiel, MD, and colleagues wrote.
Another study, published on February 6, 2006, in the Archives of Pediatrics & Adolescent Medicine, also determined that newborns whose mothers had used SSRIs during pregnancy showed an increased risk of symptoms associated withdrawal such as high-pitched crying, tremors, gastrointestinal problems and disturbed sleep. The study found that 13% of the 60 newborns exposed to SSRIs showed severe withdrawal symptoms.
Research results published in the February 9, 2006 New England Journal of Medicine found that mothers who took SSRIs, in the second half of their pregnancies were 6 times more likely to give birth to infants with a lung disorder called persistent pulmonary hypertension (PPHN).
The condition occurs when a newborn's circulation system does not adapt to breathing outside the womb and causes high pressure in the blood vessels of the lungs making them unable to get enough oxygen into their bloodstream and can be fatal.
Researchers estimated that one to two infants per 1,000 live births developed PPHN, and between 10% and 20% of infants with PPHN will end up dying even if they receive treatment.
The study compared 377 women whose infants had PPHN with 836 whose infants did not have the condition. Overall, 14 of the infants with PPHN had been exposed to an SSRI after the 20th week of pregnancy, compared to 6 of the infants in the control group.
That means that PPHN "occurred about six times more frequently in women taking SSRIs," said Christina Chambers, lead author of the study and assistant professor of pediatrics at the University of California, San Diego.
The results of the study prompted FDA officials to hold a news conference. "This appears to be a very well-conducted study and we find the results to be very concerning," said Dr Sandra Kweder, deputy director of the office of new drugs at the FDA.
In a related study involving 73 infants who were exposed to an SSRI right up until delivery, and 101 infants who were only exposed during the first trimester of pregnancy, researchers found that babies exposed throughout the entire pregnancy had significantly increased complications like hypotonia, respiratory problems and jitteriness compared to the other infants. Two of the infants in the group of 73 had PPHN, while none of the 101 infants had the disease.
Two months after the results of the PPHN studies came to light, 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 were more likely to have premature and low birth weight babies.
The researchers compared babies born to 972 women taking SSRIs with babies born to mothers who did not take antidepressants and found women using the drugs were twice as likely to have a stillbirth, and nearly twice as likely to have baby with a low birth weight as well.
Almost 20% of women who used SSRIs gave birth prematurely, compared to 12% of mothers who did not use the drugs. Infants born to women using SSRIs were also found to be more likely to have seizures.
In July 2006, the FDA instructed the drug companies to revise the labels on SSRIs to include information about the life-threatening lung problem PPH.
In addition to all the side effects found to be associated with SSRIs, studies have shown the drugs to be ineffective. In fact, in 1998, a meta-analysis of published clinical trials also indicated that 75% of the response to antidepressants was duplicated by placebo (Kirsch & Sapirstein, 1998).
Four years later, an analysis of the efficacy data submitted to the FDA for approval of the 6 most widely prescribed antidepressants approved between 1987 and 1999, determined that approximately 80% of the response to medication was duplicated in placebo control groups, according to the Emperor's New Drugs study, Antidepressants and Placebos: Secrets, Revelations, and Unanswered Questions, published in the journal Prevention & Treatment, Volume 5, Article 23 (2002).
"Improvement at the highest doses of medication," the article said, "was not different from improvement at the lowest doses."
In an article responding to comments on the Emperor's New Drugs study, Kirsch et al stated that "there is now unanimous agreement among commentators that the mean difference between response to antidepressant drugs and response to inert placebo is very small."
"It is so small that," they noted, "despite sample sizes involving hundreds of participants, 57% of the trials funded by the pharmaceutical industry failed to show a significant difference between drug and placebo."
The authors went on to say that the small difference between the drug response and the placebo response has been a "dirty little secret" known to researchers who conduct clinical trials, FDA reviewers, and a small group of critics who analyzed the published data, but until now it was not known to the general public, depressed patients, or even their physicians.
In addition to depression, SSRIs are now being prescribed for a wide variety of conditions including, generalized anxiety disorder, social anxiety disorder, and obsessive-compulsive disorder.
Experts claim the drugs are being prescribed for non-existent disorders that are inventions of the pharmaceutical industry used to justify the sale of these high-priced drugs.
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"The basic tenet of biological psychiatry is that mental illness is an "organic" disease," he explains in the 2004 article, Biology of Mental Illness, "meaning that the patient has too much or too little of a neurotransmitter, too much or too little of a receptor, or an overactive or underactive neuronal circuit," he wrote.
"Never has a theory with so little scientific evidence been so well accepted by the American public," Mr Leo notes, "three of the seven most commonly prescribed drugs are now mood elevators."