GlaxoSmithKline to face class action over anti-depressant used on children
A Sydney law firm has launched a class action on behalf of people who as children and adolescents were prescribed the anti-depressant drug Paroxetine.
Drayton Sher Lawyers has called for expressions of interest from people who were prescribed the drug, commonly known as Aropax in Australia, when they were 18 or younger.
Solicitor Tony Nikolic said hundreds of people had indicated they would join the class action, which he expects to file in the Federal Court at the end of May.
Paroxetine was a commonly-prescribed anti-depressant more than a decade ago and for a time was the most commonly used antidepressant in Australia.
In 2001, GlaxoSmithKline (then SmithKline Beecham) funded a randomised trial of the drug that showed Paroxetine was safe for use in adolescents.
But concerns about its use persisted. In 2004 the Therapeutic Goods Administration's Adverse Drug Reactions Advisory Committee said there was international concern about the risk of increased suicidal ideation and self-harm among children and adolescents using Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants.
"It should be noted that none of the SSRIs is approved for the treatment of MDD [major depressive disorder] in children or adolescents in Australia, but these drugs are being used for this purpose."
A team led by the University of Adelaide's Professor Jon Jureidini re-examined the GlaxoSmithKline research last year and found there were "quite striking" rises in the suicidal thoughts experienced by those taking the drug compared with those taking a placebo.
The review team found that 11 people who took the drug in 2001 experienced experienced suicidal thoughts or behaviours, compared with one person who took the placebo.
Mr Nikolic said one person joining the class action had been prescribed Paroxetine as a six-year-old, and soon began having suicidal thoughts.
"Now, if someone is assisted by this, fine. But they know that these things have suicidal thoughts or ideations attached to them."
Mr Nikolic is calling for anyone who was, as a minor, prescribed Paroxetine - which also traded under a number of generic names including Chemmart Paroxetine, Extine, GenRx Paroxetine, Paroxetine Actavis and Terry White Chemists Paroxetine - to come forward if they experienced side effects.
These side effects could include suicidal feelings, attempted suicide, and causing others an injury.
Fairfax contacted GlaxoSmithKline for comment.
Source LaLeva (March 2016)
Examination of Antidepressant Use in Late Pregnancy and Newborn Respiratory Disorder
An analysis of approximately 3.8 million pregnancies finds that use of antidepressants late in pregnancy may be associated with an increased risk of persistent pulmonary hypertension of the newborn (PPHN), according to a study in the June 2 issue of JAMA. However, the absolute risk was small and the risk increase appears more modest than suggested in previous studies. PPHN is a rare but life-threatening condition that occurs when a newborn's circulation system doesn't adapt to breathing outside the womb.
Persistent pulmonary hypertension of the newborn is associated with substantial illness and death: 10 percent to 20 percent of affected infants will not survive, and infants who survive face serious long-term consequences, including chronic lung disease, seizures, and neurodevelopmental problems. An association between selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and risk of PPHN has been controversial since the U.S. Food and Drug Administration issued a public health advisory in 2006. Studies that found no increased risk tended to be small, raising the possibility that they had insufficient power to detect an increased risk, according to background information in the article.
Krista F. Huybrechts, M.S., Ph.D., of Brigham and Women's Hospital, Boston, and colleagues examined the risk of PPHN associated with both SSRI and non-SSRI antidepressants among 3,789,330 pregnant women enrolled in Medicaid (from 46 U.S. states and Washington, D.C.; data from 2000-2010).
Of the study population, 128,950 women (3.4 percent) used an antidepressant during the 90 days before delivery: 102,179 (2.7 percent) were exposed to an SSRI and 26,771 (0.7 percent) to a non-SSRI antidepressant. Overall, 20.8 per 10,000 infants not exposed to antidepressants during the last 90 days of pregnancy had PPHN compared with 31.0 per 10,000 infants exposed to antidepressants. This higher risk among exposed infants was observed for both SSRI (31.5 per 10,000 infants) and non-SSRI (29.1 per 10,000 infants) antidepressants.
Associations between antidepressant use and PPHN were decreased with adjustment for confounders (factors that can influence outcomes that may improperly skew the results).
“Evidence from this large study of publicly insured pregnant women may be consistent with a potential increased risk of PPHN associated with maternal use of SSRIs in late pregnancy. However the absolute risk was small, and the risk increase appears more modest than suggested in previous studies,” the authors write.
“The findings in the largest cohort studied to date, using advanced epidemiologic methods to mitigate confounding by the underlying psychiatric illness and its associated conditions and behaviors, suggest that the risk of PPHN associated with late pregnancy exposure to SSRI antidepressants—if present—is smaller than previous studies have reported. Clinicians and patients need to balance the potential small increase in the risk of PPHN, along with other risks that have been attributed to SSRI use during pregnancy, with the benefits attributable to these drugs in improving maternal health and well-being.”
Source : Newswise (June 2015)
Cumulative Use of Strong Anticholinergics and Incident Dementia
Shelly L. Gray, PharmD, MS1; Melissa L. Anderson, MS2; Sascha Dublin, MD, PhD2,3; Joseph T. Hanlon, PharmD, MS4; Rebecca Hubbard, PhD2,5,6; Rod Walker, MS2; Onchee Yu, MS2; Paul K. Crane, MD, MPH7; Eric B. Larson, MD, MPH2,7
Importance Many medications have anticholinergic effects. In general, anticholinergic-induced cognitive impairment is considered reversible on discontinuation of anticholinergic therapy. However, a few studies suggest that anticholinergics may be associated with an increased risk for dementia.
Objective To examine whether cumulative anticholinergic use is associated with a higher risk for incident dementia.
Design, Setting, and Participants Prospective population-based cohort study using data from the Adult Changes in Thought study in Group Health, an integrated health care delivery system in Seattle, Washington. We included 3434 participants 65 years or older with no dementia at study entry. Initial recruitment occurred from 1994 through 1996 and from 2000 through 2003. Beginning in 2004, continuous replacement for deaths occurred. All participants were followed up every 2 years. Data through September 30, 2012, were included in these analyses.
Exposures Computerized pharmacy dispensing data were used to ascertain cumulative anticholinergic exposure, which was defined as the total standardized daily doses (TSDDs) dispensed in the past 10 years. The most recent 12 months of use was excluded to avoid use related to prodromal symptoms. Cumulative exposure was updated as participants were followed up over time.
Main Outcomes and Measures Incident dementia and Alzheimer disease using standard diagnostic criteria. Statistical analysis used Cox proportional hazards regression models adjusted for demographic characteristics, health behaviors, and health status, including comorbidities.
Results The most common anticholinergic classes used were tricyclic antidepressants, first-generation antihistamines, and bladder antimuscarinics. During a mean follow-up of 7.3 years, 797 participants (23.2%) developed dementia (637 of these [79.9%] developed Alzheimer disease). A 10-year cumulative dose-response relationship was observed for dementia and Alzheimer disease (test for trend, P < .001). For dementia, adjusted hazard ratios for cumulative anticholinergic use compared with nonuse were 0.92 (95% CI, 0.74-1.16) for TSDDs of 1 to 90; 1.19 (95% CI, 0.94-1.51) for TSDDs of 91 to 365; 1.23 (95% CI, 0.94-1.62) for TSDDs of 366 to 1095; and 1.54 (95% CI, 1.21-1.96) for TSDDs greater than 1095. A similar pattern of results was noted for Alzheimer disease. Results were robust in secondary, sensitivity, and post hoc analyses.
Conclusions and Relevance Higher cumulative anticholinergic use is associated with an increased risk for dementia. Efforts to increase awareness among health care professionals and older adults about this potential medication-related risk are important to minimize anticholinergic use over time.
Note: drugs include - antihistamines sold over the counter as sleep aids, such as diphenhydramine (Benadryl, McNeil-PPC Inc), or for allergy relief, such as chlorpheniramine; oxybutynin and tolterodine for overactive bladder; and the tricyclic antidepressants, such as doxepin or amitriptyline, even when used at low doses for migraine prevention or neuropathic pain.
Source : JAMA (Jan 2015)
Did Antidepressant Play a Role in Navy Yard Massacre?
Once again, antidepressants have been linked to an episode of horrific violence. The New York Times reports that Aaron Alexis, who allegedly shot 12 people to death at a Navy facility in Washington, D.C., earlier this week, received a prescription for the antidepressant trazodone in August
When I first researched antidepressants almost 20 years ago, I encountered claims that they sometimes triggered violent episodes—for example, a 1989 incident in which a Kentucky man taking fluoxetine (brand name Prozac) shot to death eight co-workers and then himself. I dismissed the claims, reasoning that, because people prescribed psychiatric drugs are disturbed to begin with, it is not surprising that a tiny fraction hurt themselves and/or others.
By 2004, however, in part because of lawsuits that forced pharmaceutical companies to disclose data on adverse effects, the FDA ordered antidepressant manufacturers to include a warning that antidepressants “increased the risk compared to placebo of suicidal thinking and behavior (suicidality) in children, adolescents, and young adults in short-term studies of major depressive disorder (MDD) and other psychiatric disorders.”
Alexis, who was 34, was reportedly seeking treatment for insomnia when he received his prescription for trazodone. Originally marketed as an antidepressant after its approval by the FDA in 1981, trazodone is also prescribed for anxiety and insomnia. Trazodone was a precursor of the extremely popular selective serotonin reuptake inhibitors (SSRIs); like the SSRIs, trazodone boosts levels of the neurotransmitter serotonin.
A website maintained by the National Institutes of Health states that trazodone and other antidepressants have been associated with “new or worsening depression; thinking about harming or killing yourself, or planning or trying to do so; extreme worry; agitation; panic attacks; difficulty falling asleep or staying asleep; aggressive behavior; irritability; acting without thinking; severe restlessness; and frenzied abnormal excitement.”
Could trazodone have played some role in the Navy Yard rampage? I put this question to David Healy, a professor of psychiatry at Cardiff University in England and an authority on side effects of psychiatric medications.* He has testified in numerous court cases involving suicides and homicides whose perpetrators were ingesting antidepressants. Healy is not opposed to psychiatric medications–he prescribes them to his own patients—but he has long been active in pointing out medications’ risks. *[Healy and other health-care experts have founded an organization called RxISK to gather data on side effects of drugs. See Postscript.]
Healy responded by email that he “would need to know much more details” to judge whether trazodone might have contributed to this week’s massacre. Indeed, as the Times reported, Alexis had displayed signs of mental illness and acted violently well before being prescribed trazodone. In 2004 he fired bullets into a car in Seattle, during what he described later as a “black out” episode. So far, moreover, there are no reports that he had trazodone in his system during his Navy Yard rampage.
But Healy said that, although data on antidepressants and violence are much more scarce than data on suicide, there is evidence that “you can put healthy volunteers on these drugs and some will become violent.” A study by the Drug Safety Research Unit in Southampton of paroxetine (Paxil) and fluoxetine (Prozac) involving more than 25,000 subjects showed that one out of every 250 subjects were involved in “a violent episode,” including 31 assaults and one homicide, Healy said.
Another study involving more than 9,000 subjects taking the antidepressant paroxetine (Paxil) for depression and other disorders showed that subjects experienced more than twice as many “hostility events” as subjects taking a placebo. Healy added: “I have had clinical experience of at least one older man, with no prior history of violence, who became homicidal after a week on citalopram where the problem cleared up once treatment had stopped.”
Healy suspects that the main causal factor behind suicide and violence toward others is increased mental and/or physical agitation, which leads about 5 percent of subjects taking antidepressants to drop out of clinical trials, compared to only 0.5 percent of people on placebos.
In their excellent overview “Antidepressants and Violence: Problems at the Interface of Medicine and Law,” published in PLoS Medicine in 2006, Healy and two co-authors note that “serious violence on antidepressants is likely to be very rare.” But they call for “more clinical trial and epidemiological data to be made available and for good clinical descriptions of the adverse outcomes of treatment.”
They add: “Legal systems are likely to continue to be faced with cases of violence associated with the use of psychotropic drugs, and it may fall to the courts to demand access to currently unavailable data. The problem is international and calls for an international response.”
Antidepressants and other psychiatric drugs clearly help alleviate mental illness in some patients. But as I have written previously, such medications may on balance harm patients more than they help. We need better data on the risks that these medications pose not only to patients but also to others.
*Postscript: David Healy and other health-care experts from around the world have formed an organization called RxISK to gather data on adverse effects of pharmaceutical drugs, including violence. The RxISK website calls it “the first free, independent website where patients, doctors, and pharmacists can research prescription drugs and easily report a drug side effect–identifying problems and possible solutions earlier than is currently happening.” I hope RxISK succeeds, because we badly need it.
Source : Scientific American
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Antidepressants Can Cause Sudden Death
Most antidepressants cause a change in the electrical pulse of the heart, which changes the rhythm of the heart beat. It’s called an extended QT interval—and it can result in sudden death with no warning of any kind: BMJ study.
The antidepressant citalopram—brand names Celexa and Cipramil—has joined a growing list of drugs that can cause sudden death by stopping the heart. The study, published in the BMJ, found that the drug causes lengthening in the QT interval, a part of the heart beat cycle.
Several drugs are noted for this issue. The most famous is methadone, noted for sudden death in some individuals, especially when dosage is increased too rapidly. There are no symptoms indicating a risk. A perfectly normal person will literally drop dead.
The heart beat is regulated by electrical pulses. Certain points of the wave pattern that’s printed out for an electrocardiogram (ECG) are labeled Q, R, S, and T, as illustrated in the graphic to the right. If the time between Q and T is lengthened, it’s referred to as extended, elongated, or long QT syndrome, or QT interval prolongation. The only way to know if it’s happening is through an ECG.There are generally no external clues, so outside of testing, you would have no way of knowing that you’ve been affected.
The Study The study’s authors are quite specific about the risk associated with Celexa. The larger the dose, the greater the risk. They noted that the FDA has said:
Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day.
A quick look at Medscape’s drug reference for citalopram confirms that statement.
The researchers examined 38,397 adults who were taking either an antidepressant or methadone at some point between February 1990 and August 2011, more than two decades. The antidepressants that subjects took were citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), paroxetine (Paxil), sertraline (Zoloft), amitriptyline, bupropion (Zyban), duloxetine (Cymbalta), mirtazapine (Remeron), nortriptyline, and venlafaxine (Effexor).
All study participants received an electrocardiogram (ECG) 14-90 days after they’d taken their prescribed drug. The study found that all antidepressants affect the QT interval to some degree, though methadone was worse by a significant amount.
Interestingly, bupropion (Zyban), had the opposite result of the other drugs. The QT interval was shortened. That, though, doesn’t make it safe, as a shorter QT interval can cause palpitations and fainting, and can also result in sudden cardiac arrest.
The worst of the antidepressants for lengthening the QT interval were citalopram (Celexa), escitalopram (Lexapro), and amitriptyline. However, overall, one in five people taking these drugs experienced abnormal ECGs with extended QT intervals. The authors state that the clinical significance of these findings is unknown.
We do know that an extended QT interval can result in sudden death. In reality, this doesn’t happen often—though no one can quantify the frequency of death. So, it seems that the only ethical approach is to inform people of the potential risk of sudden death by taking these drugs.
But we already know that genuine informed consent almost never happens. People are routinely told that the risk is minimal and the specifics are not stated. Ultimately, though, the only one who lives the the results are the person inside your own skin.
More Complete List of Drugs that Prolong the QT Interval A 2004 article in the New England Journal of Medicine discusses prolongation of the QT interval. It listed the known drugs that can cause it. They were:
- Arsenic trioxide
- Calcium-channel blockers: lidoflazine
- Antiinfectives: clarithromycin, erythromycin, halofantrine, pentamidine, sparfloxacin
- Antiemetics: domperidone, droperidol
- Antipsychotics: chlorpromazine, halperidol, mesoridazine, thioridazine, pimozide
Source : Gaia Health
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Psych meds linked to 90% of school shootings
Expert: Psychiatric drugs likely cause of Lanza's extreme violence
From the moment news emerged Friday that a young man had carried out a horrific massacre of elementary-school children, politicians from local city halls to the White House have been restoking the age-old push for more gun control. While guns have been a common denominator in mass slayings at schools by teens, there’s another familiar element that seems increasingly to be minimized. Some 90 percent of school shootings over more than a decade have been linked to a widely prescribed type of antidepressant called selective serotonin reuptake inhibitors or SSRIs, according to British psychiatrist Dr. David Healy, a founder of RxISK.org, an independent website for researching and reporting on prescription drugs.
Though there has been no definitive confirmation that drugs played a role in the Newtown, Conn., assault, that killed 20 children and six adults, media have cited family members and acquaintances saying suspect Adam Lanza was taking prescription medication to treat “a neurological-development disorder,” possibly Aspergers.
Healy cautioned that the public needs “to wait to find out what Adam Lanza was on, and whether his behavior does fit the template of a treatment-induced problem.”
However, in an email to WND, he said he suspected prescribed psychiatric medications was the cause of Lanza’s violent behavior.
Healy said that while the public waits to learn more about Lanza, there are two general points that can be made.
First, he said, “psychotropic drugs of pretty well any group can trigger violence up to and including homicide.”
“Second, the advocates of treatment claim both that it is the illness and not the drugs that causes violence and that we are leaving huge numbers of people untreated.”
But Healy argued that if this were the case, “we should not find that comfortably over 90 percent of school shootings are linked to medication intake.”
Dr. Peter R. Breggin, a Harvard-trained psychiatrist and former full-time consultant at the National Institute of Mental Health, told WND it’s likely that problems for Lanza began with “getting tangled up” with psychiatric medicine.
Breggin insisted there has been overwhelming scientific evidence for decades correlating psychiatrically prescribed drugs with violence.
Writing in Ethical Human Sciences and Services, a peer-reviewed scholarly journal, in 2003, Breggin concluded SSRI drugs could be a factor in suicide, violence and other forms of extreme abnormal behavior, as evidenced in case reports, controlled clinical trials, and epidemiological studies in children and adults.
Since the 1970s, Breggin has testified in approximately 100 trials, including one in which Judge Robert Heinrichs ruled the adverse effects of taking Prozac drove a 16-year-old in Winnipeg, Canada, to commit an unprovoked murder.
Breggin appeared before the Veterans Affairs Committee of the U.S. House of Representatives in 2010 in support of his 2008 book “Medication Madness: The Role of Psychiatric Drugs in Cases of Violence, Suicide and Crime.”
Breggin testified to Congress that research conducted in the medical science demonstrates a causal relationship between antidepressant drugs and the production of suicide, violence, mania and other behavioral abnormalities.
He warned Congress of the risks of giving these drugs to heavily armed young men and women in the military.
Breggin asserted that establishment media “ignores the scientific evidence linking psychiatric medications and violent behavior because psychiatry is the religion of the mainstream media, and they don’t want to see the dangers of psychiatrically prescribed drugs.”
“Besides, the drug companies also have incredible influence through advertising such that they can call the shots,” he said.
He believes the Lanza case fits the pattern of school shooters in some of the most famous incidents in recent memory, including the 1999 shootings at Columbine High School in Colorado and the massacre at Virginia Tech in 2007.
“Adam Lanza has in common with many of the young men who were shooters that they were outsiders who lived in the shadows, who deal with a lot of shame, humiliation and isolation,” Breggin explained.
He calls the psychiatric diagnoses “worthless.”
“We know exactly who they are,” he said. “They are called ‘geeky’ in the extreme. Not a single one has ever come forward with a close friend. They are alienated from their families, and they have been involved in psychiatry.”
Breggin insists that instead of psychiatric treatment, children of this kind need “more reaching out, more socialization, more caring, more involvement.”
“Our schools, our families, and our communities need to be aware of the kids who are withdrawn and violent, not because they are going to become violent – hardly any of them are going to become violent – but because these are really hurt kids,” he said.
“We can call them evil, we can call them mentally ill, but the pattern is really quite clear,” Breggin continued. “They are highly intelligent and highly withdrawn and they are all involved with psychiatry, so the claim psychiatry is going to do some good is really ridiculous.”
In many school shootings carried out by minors, court documents are sealed and the extent of chemical use is unknown to the public.
But in a number of high-profile cases, the link has been reported:
- Kip Kinkel was withdrawing from Prozac and had been prescribed Ritalin when he murdered his mother and stepfather then shot 22 classmates, killing two, in 1998.
- Christopher Pittman was withdrawing from Luvox and from Paxil when he killed his paternal grandparents in 2001.
- Elizabeth Bush, who fired at fellow students in Williamsport, Pa., in 2001, wounding one, was on Prozac.
- Jason Hoffman, was on Effexor and Celexa when he opened fire at his El Cajon, Calif., high school, wounding five.
- Shawn Cooper of Notus, Idaho, was on antidepressants when he fired a shotgun on students and staff.
- T.J. Solomon, on antidepressants, wounded six at his Conyers, Ga., high school.
- Eric Harris was taking Luvox when he and fellow student Dylan Klebold killed 12 students and a teacher and wounded 24 others before turning their guns on themselves at Columbine High School in Colorado.
- At Virginia Tech in 2007, where 32 were murdered, authorities found “prescription medications related to the treatment of psychological problems had been found among Mr. Cho’s effects,” according to the New York Times.
In the past six years, Healy has authored two best-selling books analyzing the degree to which the pharmaceutical industry has influenced medical doctors to prescribe antidepressant drugs to patients with psychiatric problems: “Let Them Eat Prozac: The Unhealthy Relationship Between the Pharmaceutical Industry and Depression,” in 2006 and “Pharmageddon” in 2012.
Recently, Healy’s RxISK.org added a “violence section” to its website, allowing users to enter the name of a prescription drug to find out the side effects recorded in the more than 4 million adverse drug event reports filed with the FDA since 2004.
Was Lanza on meds?
Writing for Slate.com Monday, Emily Willingham was quick to warn against demonizing Asperger’s syndrome, or autism in general, as the cause of Lanza’s violence. Likewise, in a New York magazine piece titled “Asperger’s is a Red Herring to Explain the Newtown Massacre,” Adam Martin wrote, “As the nation sets out to understand how Friday’s massacre came to pass, some are rightly worried that the high-functioning form of autism will become unfairly stigmatized.”
Nevertheless, credible sources have not withdrawn published claims that Lanza was on prescribed psychiatric medication at the time of the shooting.
On CBS’s “60 Minutes” Sunday, Mark and Louise Tambascio, friends of the shooter’s mother, Nancy Lanza, said Adam Lanza was being medicated for Asperger’s.
“I know [Adam Lanza] was on medication and everything, but she homeschooled him at home cause he couldn’t deal with the school classes sometimes,” Louise Tambascio told CBS reporter Scott Pelley. “So she just homeschooled Adam at that home. And that was her life.”
Her comment followed Mark Tambascio explaining to Scott Pelley that “friends told us that [Asperger's syndrome] did dominate the Lanzas’ lives.”
In addition, the Washington Post reported over the weekend an unnamed former neighbor of Nancy and Adam Lanza in Newtown, Conn., recalled Adam as “a really rambunctious kid” who “was on medication.”
The story became confused when a now discredited source claiming to be Adam Lanza’s “Uncle Jonathan” told several publications, including the Sun in the United Kingdom, that Adam was being treated with the strong anti-psychotic drug Fanapt.
Later reports found no relatives who knew “Uncle Jonathan.”
Separately, law enforcement officers have found evidence Lanza played graphically violent video games, the Hartford Courant reported on Sunday.
The Express in the United Kingdom reported Monday that Lanza had “an unhealthy obsession for violent video games” and that his favorite video game was said to be a “shockingly violent” fantasy war game called Dynasty Warriors, which is “thought to have given him inspiration to act on his darkest thoughts.”
Source : WND
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Use of SSRIs in Pregnancy Puts Baby at Risk
Pregnant women who took antidepressants were at risk for miscarriage and preterm delivery, and their babies were at risk for a number of developmental and health complications, researchers found.
A systematic review of studies looking at the effects of selective serotonin reuptake inhibitors (SSRIs) in pregnant women on infant outcomes showed a significant relationship between SSRI use and preterm birth (OR 1.46, 95% CI 1.31 to 1.63), persistent pulmonary hypertension of the newborn (OR 2.1, 95% CI 1.5 to 3.0), preeclampsia (OR 1.53, 95% CI 1.33 to 1.69), and long-term neurobehavioral effects, according to Alice Domar, PhD, of Beth Israel Deaconess Medical Center in Waltham, Mass., and colleagues.
SSRI use in women also was associated with a higher risk of miscarriage, birth defects, newborn behavioral syndrome, neonatal electrocardiograph changes, and fetal growth effects, they wrote online in Human Reproduction.
"A standard recommendation for women who report the need for medication to treat symptoms of depression during their pregnancy has been that the benefit of antidepressant use outweighs the risk of depression during the gestational and postpartum period," Domar and colleagues said.
The researchers reviewed current literature about the efficacy and impact of SSRIs on depression treatment and on fertility and infertility to "challenge the assumption that the risks of SSRIs use are lower than the risks of untreated mild and moderate depression in pregnant women," and to look at the impacts of SSRIs on neonatal health.
They noted that, of 74 FDA-registered studies on antidepressants, 38 had positive results, while 36 had negative or questionable results. Of the negative or questionable studies, 22 were unpublished and 11 were published with a positive spin "that conflicted with the FDA's conclusion."
"Overall, the preponderance of evidence suggests that antidepressants do not provide clinically meaningful benefit for most patients with mild or moderate depression," they wrote.
The authors also noted that SSRI exposure during pregnancy "appears to increase rates of miscarriage," citing a report from the American Psychiatric Association (APA) and the American College of Obstetricians and Gynecologists (ACOG) which said antidepressant use during early pregnancy "increased risk for spontaneous abortion."
Higher Risk of Birth Defects
On birth defects, Domar and colleagues wrote that "there has been a consistent 'signal' implicating SSRI use during pregnancy to various congenital anomalies," but that study results have been mixed. They cited a 2005 warning from the FDA, which changed the pregnancy category of paroxetine (Paxil) from category C to D, indicating that the drug demonstrated a risk of cardiac defects in the fetus.
"Most agents or exposures that are consistently associated with miscarriage are also eventually shown to be associated with birth defects," they added.
With regard to premature birth, an "overwhelming majority" of 30 studies looking at preterm birth rates among mothers taking antidepressants versus those who were not showed an association between drug use and preterm birth "across all classes of antidepressants," including SSRIs, serotonin-norepinephrine reuptake inhibitors (OR 1.98, 95% CI 1.49 to 2.63), and tricyclic antidepressants (OR 2.36, 95% CI 1.89 to 2.94).
In addition to those risks, "it is now well established that newborns who have been exposed to antidepressants in utero have high rates of what has been called the newborn behavioral syndrome," which includes symptoms of persistent crying, jitteriness, and difficulty feeding, as well as more severe symptoms of seizures and difficulty breathing, the authors wrote.
And measures of neonatal electrocardiograph changes showed that infants exposed to SSRIs during pregnancy developed prolonged QT syndrome, with some 10% having "markedly prolonged QT intervals" -- which could lead to a fatal ventricular arrhythmia, they added.
Preeclampsia Also More Common
In terms of respiratory issues, the largest study of persistent pulmonary hypertension of the newborn -- a condition that causes elevated pulmonary blood pressure that can in turn cause neonatal respiratory distress and hypoxemia -- in infants exposed to antidepressants during pregnancy showed that late pregnancy exposure to SSRIs increased risk of the condition by more than twofold (OR 2.1, 95% CI 1.5 to 3.0).
The investigators said that preeclampsia is common in 5% to 10% of pregnancies, but that two studies showed an association between antidepressant use and raised odds of the condition. In one study, early use of antidepressants was tied to 28% greater odds of developing preeclampsia (95% CI 1.19 to 1.37), while late use was tied to 38% greater odds (95% CI 1.25 to 1.53), and early and late use drove up odds by 50% (95% CI 1.33 to 1.69).
A second study from Canada showed SSRI use was tied to 53% greater likelihood of pregnancy-induced hypertension (95% CI 1.01 to 2.33), and that paroxetine, in particular, carried 81% greater odds (95% CI 1.02 to 3.23).
Birthweight in SSRI-exposed infants "was significantly less than that for depression-only exposed infants," and later exposure to SSRIs during pregnancy was tied to a greater risk of low birthweight. The APA and ACOG published a report in 2009 verifying these findings, the researchers added.
Neurobehavioral Effects a Concern
Domar and co-authors also noted a number of long-term infant neurobehavioral effects significantly associated with second- or third-trimester exposure to SSRIs in pregnant women, including:
- Delayed sitting by 15.9 days (95% CI 6.8 to 25.0)
- Delayed walking by 28.9 days (95% CI 15.0 to 42.7)
- Delayed sitting without support (OR 2.1, 95% CI 1.23 to 3.60)
- Inability to occupy self at 19 months (OR 2.1, 95% CI 1.09 to 4.02)
The authors noted that psychotherapy and physical exercise are associated with significant decreases in depressive symptoms "in the general population," and that healthcare professionals treating depressed women who are or may become pregnant may want to consider non-SSRI alternatives to depression treatment, particularly given recent findings that SSRI use was not much more efficacious than placebo, they wrote.
The authors noted two limitations of the review. None of the studies were randomized controlled trials because it was deemed unethical to randomly remove pregnant women from drug treatment. Additionally, they noted that many women stop antidepressant use after discovering they are pregnant, which made it "difficult to characterize the 'exposed' group."
Source : MedPage Today via Human Reproduction Domar AD, et al "The risks of selective serotonin reuptake inhibitor use in infertile women: a review of the impact on fertility, pregnancy, neonatal health, and beyond" Hum Reprod 2012; DOI: 10.1093/humrep/des383.
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SSRIs Linked to Risk of Stroke
Use of the selective serotonin reuptake inhibitors (SSRI) class of antidepressants conferred a small, but statistically significant risk of brain hemorrhage, according to an analysis of multiple epidemiologic studies.
SSRI users had a 40% to 50% increase in the relative risk of intracranial and intracerebral hemorrhage compared with people who had never taken one of the drugs, according to Daniel G. Hackam, MD, PhD, and Marko Mrkobrada, MD, of the University of Western Ontario in Hamilton.
A separate analysis showed that concomitant use of an SSRI and an anticoagulant significantly increased the risk of brain hemorrhage compared with anticoagulant use alone.
Although the analysis yielded statistically significant results, investigators offered a cautious assessment of the implications in an article reported in the Oct. 30 issue of Neurology.
"SSRI exposure is associated with an increased risk of intracerebral and intracranial hemorrhage, yet given the rarity of this event, absolute risks are likely to be very low," they wrote in conclusion.
"While the data we reviewed were not randomized, we believe clinicians might consider alternate classes of antidepressants in patients with intrinsic risk factors for intracerebral hemorrhage, such as those receiving long-term oral anticoagulation, individuals with previous intracranial bleeding, and patients with cerebral amyloid angiopathy or severe alcohol abuse," they added.
SSRIs are the most widely used class of antidepressant drugs. As a class, the drugs inhibit platelet aggregation, posing a known risk of gastrointestinal bleeding, the authors noted in their introduction. Whether SSRI use increases the risk of brain hemorrhage has remained unclear, since the few studies examining the issue produced conflicting results.
In an effort to bring some clarity to the conflicting data, Hackam and Mrkobrada performed a systematic review and meta-analysis of studies evaluating the association between SSRI use and brain hemorrhage, pooling studies according to the type of hemorrhage reported.
A literature search retrieved 2,493 citations, which the authors culled to 16 relevant studies involving a cumulative total of 506,411 patients. Four of the studies had a case-control design, and the rest were cohort investigations. All but three of the studies included univariate and multivariate risk estimates.
The studies were separated into four categories, according to their outcome of interest: intracranial hemorrhage, hemorrhagic stroke, intracerebral hemorrhage, and subarachnoid hemorrhage.
Only two categories yielded statistically significant results. SSRI use was associated with adjusted risk ratios of 1.51 for intracranial hemorrhage (95% CI 1.26 to 1.81) and 1.42 for intracerebral hemorrhage (95% CI 1.23 to 65). Results were similar in fixed-effects and random-effects models.
In a subset of five studies (three looking at intracranial hemorrhage and one each reporting hemorrhagic stroke and intracerebral hemorrhage), SSRI exposure in combination with oral anticoagulants was associated with an increased risk of bleeding compared with oral anticoagulants alone (RR 1.56, 95% CI 1.33 to 1.83).
SSRI use was not associated with hemorrhagic stroke or subarachnoid hemorrhage in either an unadjusted or adjusted analysis.
Seven studies included analysis of effect by duration of exposure to SSRI therapy. Six of the seven found that recent, short-term exposure was more strongly associated with hemorrhagic events than was long-term use.
The authors noted that the finding was consistent with the "reported diminution of platelet function following several weeks of exposure to SSRIs. Platelet function may improve with prolonged exposure, or short-term exposure might deplete susceptible patients from the pool of patients at risk for hemorrhage."
The meta-analysis represents the "best current evidence of an association between SSRI use and the risk of [brain hemorrhage]," the authors of an accompanying editorial wrote of the findings. However, they seconded the cautious conclusions of Hackam and Mrkobrada.
"A key consideration is that the absolute risk increase associated with SSRIs is very small for the average patient," wrote Emer R. McGrath, MB, and Martin J. O'Donnell, MB, PhD, of the National University of Ireland in Galway. "Therefore, for patients with a clear indication for SSRI use, the absolute increase in risk of [brain hemorrhage] should not deter clinicians from prescribing these agents."
"However, these findings emphasize the importance of appropriate patient selection and avoidance of inappropriate prescribing."
Source MedPage Today
Antidepressant Use and Mortality in the ICU - Antidepressant Use Associated with Increased Mortality among Critically Ill Patients?
Researchers at Beth Israel Deaconess Medical Center, in Boston, and the Massachusetts Institute of Technology in Cambridge, have found that critically ill patients were more likely to die if they were taking the most commonly prescribed antidepressants when they were admitted to the intensive care unit (ICU).
The researchers conducted a retrospective study using the electronic medical records of 10,568 patients to look at in-hospital mortality and mortality a year after being admitted to the ICU.
“We found that mortality was higher overall for patients taking antidepressants prior to admission to the ICU and remained significantly higher a year later,” said Katherine. M. Berg, MD, one of the physicians involved in the study. “We also found that certain subgroups of patients, particularly patients admitted for cardiac problems, appeared to be at even greater risk.”
The study results will be presented at the ATS 2012 International Conference in San Francisco.
Of the 10,568 patient records studied, 1,876 patients were taking either a selective serotonin reuptake inhibitor (SSRI) or a serotonin and norepinephrine reuptake inhibitor (SNRI) prior to admission to an ICU. They were compared to patients admitted to an ICU who were not on one of these medications. After adjusting for age, gender, ICD-9 diagnosis, disease severity and co-morbidities, the researchers found that patients on SSRI/SNRI’s prior to admission to the ICU were 73 percent more likely to die in the hospital (p<0.001), and that the increase in risk persisted at one year.
Among patient groups, risk was highest among patients with acute coronary syndrome and those who had undergone cardiac surgery. For both of these patient groups, the risk of dying in the hospital was more than double if they were taking one of these antidepressants prior to admission (OR 2.41; p<.0020 and 2.08; p<0.001, respectively).
Not all patient groups demonstrated that patients on SSRI/SNRI’s were more likely to die. There was, for example, no increase in mortality among patients admitted with sepsis.
Both classes of antidepressants, which work by increasing the levels of neurotransmitters in the brain, are generally thought to have fewer side effects than previous generations of antidepressants. Recent studies, however, have found that SSRIs may increase a patient’s risk of bleeding, dizziness, falls and stroke.
“Major depression is a common disorder affecting more than 16 percent of adults in the United States, and SSRI’s are the most commonly prescribed medication class for this disease,” added Dr. Berg. “The benefits of SSRI’s for the treatment of depression are well documented. Due to the practical limitations of clinical trials, however, the long-term risks are unknown.”
The researchers acknowledged that this study shows an association, but that the preadmission SSRI/SNRI use may not have been the cause of the increased mortality. The authors attempted to control for other factors that could lead to increased mortality, but were unable to control for some potentially important ones such as smoking and depression itself.
The authors stressed that these results require validation by similar studies utilizing other ICU databases. They stated, however, that this information highlights the need for alternative ways to monitor for potential adverse effects of medications, and the role that large clinical databases may play in this line of investigation.
The study was undertaken using the Multiparameter Intelligent Monitoring in Intensive Care II database (MIMIC II). This public, de-identified database was developed with the support of the National Institute of Biomedical Imaging and Bioengineering.
Source : Newswise
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Evidence Shows That Anti-Depressants Likely Do More Harm Than Good
Commonly prescribed anti-depressants appear to be doing patients more harm than good, say researchers who have published a paper examining the impact of the medications on the entire body.“We need to be much more cautious about the widespread use of these drugs,” says Paul Andrews, an evolutionary biologist at McMaster University and lead author of the article, published today in the online journal Frontiers in Psychology.
“It’s important because millions of people are prescribed anti-depressants each year, and the conventional wisdom about these drugs is that they’re safe and effective.”
Andrews and his colleagues examined previous patient studies into the effects of anti-depressants and determined that the benefits of most anti-depressants, even taken at their best, compare poorly to the risks, which include premature death in elderly patients.
Anti-depressants are designed to relieve the symptoms of depression by increasing the levels of serotonin in the brain, where it regulates mood. The vast majority of serotonin that the body produces, though, is used for other purposes, including digestion, forming blood clots at wound sites, reproduction and development.
What the researchers found is that anti-depressants have negative health effects on all processes normally regulated by serotonin.
The findings include these elevated risks:
- developmental problems in infants
- problems with sexual stimulation and function and sperm development in adults
- digestive problems such as diarrhea, constipation, indigestion and bloating
- abnormal bleeding and stroke in the elderly
The authors reviewed three recent studies showing that elderly anti-depressant users are more likely to die than non-users, even after taking other important variables into account. The higher death rates indicate that the overall effect of these drugs on the body is more harmful than beneficial.
“Serotonin is an ancient chemical. It’s intimately regulating many different processes, and when you interfere with these things you can expect, from an evolutionary perspective, that it’s going to cause some harm,” Andrews says.
Millions of people are prescribed anti-depressants every year, and while the conclusions may seem surprising, Andrews says much of the evidence has long been apparent and available.
“The thing that’s been missing in the debates about anti-depressants is an overall assessment of all these negative effects relative to their potential beneficial effects,” he says. “Most of this evidence has been out there for years and nobody has been looking at this basic issue.”
In previous research, Andrews and his colleagues had questioned the effectiveness of anti-depressants even for their prescribed function, finding that patients were more likely to suffer relapse after going off their medications as their brains worked to re-establish equilibrium.
With even the intended function of anti-depressants in question, Andrews says it is important to look critically at their continuing use.
“It could change the way we think about such major pharmaceutical drugs,” he says. “You’ve got a minimal benefit, a laundry list of negative effects – some small, some rare and some not so rare. The issue is: does the list of negative effects outweigh the minimal benefit?”
Source : Newswise
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FDA Drug Safety Communication: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses
Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide).
Facts about Celexa (citalopram hydrobromide)
- In a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs).
- Thought to work by increasing the amount of serotonin in the brain.
- Available as 10 mg, 20 mg, and 40 mg tablets. Also available as an oral solution (10 mg/5 mL).
- In 2011, a total of approximately 31.5 million prescriptions were dispensed for citalopram from U.S. outpatient retail pharmacies.1
- In 2011, approximately 7.2 million patients received a dispensed prescription for citalopram from U.S. outpatient retail pharmacies.2
- In 2011, according to U.S. office-based physician practices, approximately 89.5% of citalopram drug use was at doses of 40 mg and below and 6% of drug use was at doses above 40 mg per day.3
The U.S. Food and Drug Administration (FDA) is clarifying dosing and warning recommendations for the antidepressant Celexa (citalopram hydrobromide; also available in generic form). In August 2011, FDA issued a Drug Safety Communication (DSC) stating that citalopram should no longer be used at doses greater than 40 mg per day because it could cause potentially dangerous abnormalities in the electrical activity of the heart. Citalopram use at any dose is discouraged in patients with certain conditions because of the risk of QT prolongation, but because it may be important for some of those patients to use citalopram, the drug label has been changed to describe the particular caution that needs to be taken when citalopram is used in such patients. The revised drug label also describes lower doses that should be used in patients over 60 years of age.
Changes in the electrical activity of the heart (specifically, prolongation of the QT interval of the electrocardiogram [ECG]) can lead to a risk of an abnormal heart rhythm called Torsade de Pointes, which can be fatal. Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to having low levels of potassium and magnesium in the blood.
The citalopram drug label was revised on August 12, 2011 and again on March 27, 2012, to include new warnings about the potential for QT interval prolongation and Torsade de Pointes, as well as new drug dosage and usage recommendations. (See Additional Information for Healthcare Professionals).
The following changes have now been made to the citalopram drug label as of 3/27/12:
- Recognition that although citalopram use should be avoided, if possible, in patients with certain conditions because of the risk of QT prolongation, ECG monitoring and/or electrolyte monitoring should be performed if citalopram must be used in such patients.
- Patients with congenital long QT syndrome are at particular risk of Torsade de Pointes, ventricular tachycardia, and sudden death when given drugs that prolong the QT interval. Nevertheless, the labeling recommendation for patients with congenital long QT syndrome has been changed from “contraindicated” to “not recommended,” because it is recognized that there may be some patients with this condition who could benefit from a low dose of citalopram and who lack viable alternatives.
- The maximum recommended dose of citalopram is 20 mg per day for patients older than 60 years of age.
- Citalopram should be discontinued in patients who are found to have persistent QTc measurements greater than 500 ms.
Additional Information for Patients (updated from 8/24/2011)
- Do not stop taking citalopram or change your dose without talking to your healthcare professional. Stopping citalopram suddenly can cause withdrawal effects.
- If you are currently taking a citalopram dose greater than 40 mg per day, talk to your healthcare professional.
- Seek immediate care if you experience an irregular heartbeat, shortness of breath, dizziness, or fainting while taking citalopram.
- If you are taking citalopram, your healthcare professional may occasionally order an electrocardiogram (ECG, EKG) to monitor your heart rate and rhythm.
- Your healthcare professional may also order tests to check levels of potassium and magnesium in your blood.
- Read the Medication Guide for citalopram carefully and discuss any questions you have with your healthcare professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the “Contact FDA” box at the bottom of the page.
- Citalopram causes dose-dependent QT interval prolongation, which can cause Torsades de Pointes, ventricular tachycardia, and sudden death.
- Citalopram is not recommended for use at doses greater than 40 mg per day because such doses cause too large an effect on the QT interval and confer no additional benefit.
- Citalopram is not recommended for use in patients with congenital long QT syndrome, bradycardia, hypokalemia, or hypomagnesemia, recent acute myocardial infarction, or uncompensated heart failure. Citalopram use is also not recommended in patients who are taking other drugs that prolong the QT interval.
- The maximum recommended dose of citalopram is 20 mg per day for patients with hepatic impairment, patients who are older than 60 years of age, patients who are CYP 2C19 poor metabolizers, or patients who are taking concomitant cimetidine (Tagamet®) or another CYP2C19 inhibitor, because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.
- Electrolyte and/or ECG monitoring is recommended in certain circumstances
- Consider more frequent ECG monitoring in patients for whom citalopram use is not recommended, but is, nevertheless, considered essential.
- Patients at risk for significant electrolyte disturbances should have baseline serum potassium and magnesium measurement, with periodic monitoring. Hypokalemia and/or hypomagnesemia may increase the risk of QTc prolongation and arrhythmia and should be corrected prior to initiation of treatment with periodic monitoring.
- Citalopram should be discontinued in patients found to have persistent QTc measurements greater than 500 ms.
- Advise patients on citalopram to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm (e.g., dizziness, palpitations, or syncope). If patients experience symptoms, the prescriber should initiate further evaluation, including cardiac monitoring.
- Report adverse events involving citalopram to the FDA MedWatch program, using the information in the “Contact FDA” box at the bottom of the page.
FDA has received post-marketing reports of QT interval prolongation and Torsade de Pointes associated with Celexa (citalopram) and its generic equivalents. FDA evaluated the results of thorough QT studies assessing the effects of doses of citalopram and its active S-isomer escitalopram (Lexapro) on the QT interval in adults. Both studies are randomized, double-blind, placebo-controlled, crossover studies. In the citalopram study, 119 subjects received citalopram 20 mg/day and 60 mg/day, moxifloxacin 400 mg/day, and placebo. In the escitalopram study, 113 subjects received escitalopram 10 mg/day and 30 mg/day, moxifloxacin 400 mg/day, and placebo.
The summary of findings is presented in Table 1. As of March 27, 2012, this table has been updated to provide comparative information for escitalopram. Citalopram is a racemic mixture of S- and R-isomers. Escitalopram is the S-isomer of citalopram. The antidepressant activity of citalopram is limited to the S-isomer; therefore, each row of Table 1 shows equally effective doses of citalopram and escitalopram. The maximum recommended dose of escitalopram is 20 mg once daily.
Table 1: Citalopram and Escitalopram: Dose-dependent Change in Corrected QT Interval (QTc) [revised 3/27/2012 to include escitalopram]
See Table (Press Source)
Although the antidepressant effects of the drugs are known to be limited to the S-isomer, the difference between the effects of citalopram racemate and escitalopram on the QT interval presumably means that the QT effects are not specific to the S-isomer.
These studies show that citalopram causes dose-dependent QT interval prolongation that is clinically significant with the 60 mg daily dose. In addition, clinical trials do not show any added effectiveness of citalopram at 60 mg/day compared to 40 mg/day. Therefore, citalopram should not be used at doses above 40 mg per day. Important safety information about the potential for QT interval prolongation and Torsade de Pointes with updated drug dosage and usage recommendations have been added to the citalopram drug label. Given that these findings were not observed with escitalopram, there are no changes planned for escitalopram at this time.
1. IMS, Vector One®: National (VONA). Year 2011. Extracted February 2012.
2. IMS, Vector One®: Total Patient Tracker (TPT). Year 2011. Extracted February 2012.
3. SDI, Physician Drug and Diagnosis Audit (PDDA). Year 2011. Extracted February 2012.
- FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide)
- FDA Drug Safety Podcast for Healthcare Professionals: Revised recommendations for Celexa (citalopram hydrobromide) related to a potential risk of abnormal heart rhythms with high doses
Source : FDA (April 2012)
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Canadian judge rules SSRI antidepressants like Prozac can cause children to commit murder
The use of antidepressant and psychiatric drugs, particularly among children, is an extremely risky activity that could have fatal consequences for both the individuals that use them, as well as their friends and family. According to the National Post, a Canadian judge recently ruled that the extreme mind-altering effects of the antidepressant drug Prozac were in large part responsible for causing a 15-year-old boy to thrust a nine-inch kitchen knife into one of his closest friends.
Though the Winnipeg boy that committed the heinous crime had allegedly abused prescription drugs and "experimented" with cocaine long prior to the incident, he had never had a violent or aggressive personality about him, according to reports. It was only when he began taking Prozac, the very thing doctors had given him as a so-called "solution" to his previous illicit drug problems, that he began to rapidly go off the deep end.
"He had become irritable, restless, agitated, aggressive and unclear in his thinking," said Justice Robert Heinrichs of the Manitoba Justice Department, who ruled on the case. "It was while in that state he overreacted in an impulsive, explosive and violent way. Now that his body and mind are free and clear of any effects of Prozac, he is simply not the same youth in behavior or character."
What the judge appears to be implying here is that Prozac is directly responsible for altering the brain of a user and causing them to think irrationally, which in turn can cause them to harm themselves or others. In other words, if it were not for the use of this mind-warping drug, the murderer in this case most likely would never have dreamed of slaughtering one of his best friends.
Judge Heinrichs ultimately determined that, because of the drug's involvement, the boy who murdered his friend would not be tried in an adult court. Even though the boy pleaded guilty to second-degree murder, the judge only added a ten-month sentence on top of the two years that the boy had already spent in jail pending the trial -- and there will apparently be no appeal, which is a first in any North American court.
In a similar outcome back in 2001, a Wyoming jury ruled that the antidepressant drug Paxil had caused a man to murder his wife, daughter, and granddaughter, after which he killed himself. And one of the mass-murderers in the infamous Columbine High School shooting, Eric Harris, had allegedly been taking the antidepressant drug Luvox at the time that he participated in the tragedy (http://www.naturalnews.com/019342.html).
Source : Natural News
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FDA Drug Safety Communication: Selective serotonin reuptake inhibitor (SSRI) antidepressant use during pregnancy and reports of a rare heart and lung condition in newborn babies
12-14-2011] The U.S. Food and Drug Administration (FDA) is updating the public on the use of selective serotonin reuptake inhibitor (SSRI) antidepressants by women during pregnancy and the potential risk of a rare heart and lung condition known as persistent pulmonary hypertension of the newborn (PPHN). The initial Public Health Advisory in July 2006 on this potential risk was based on a single published study. Since then, there have been conflicting findings from new studies evaluating this potential risk, making it unclear whether use of SSRIs during pregnancy can cause PPHN.
At this time, FDA advises health care professionals not to alter their current clinical practice of treating depression during pregnancy. Healthcare professionals should report any adverse events involving SSRIs to the FDA MedWatch Program.
FDA has reviewed the additional new study results and has concluded that, given the conflicting results from different studies, it is premature to reach any conclusion about a possible link between SSRI use in pregnancy and PPHN. FDA will update the SSRI drug labels to reflect the new data and the conflicting results. (See Data Summary).
PPHN occurs when a newborn baby does not adapt to breathing outside the womb. Newborns with PPHN may require intensive care support including a mechanical ventilator to increase their oxygen level. If severe, PPHN can result in multiple organ damage, including brain damage, and even death
Additional Information for Patients
- If you are pregnant or plan to become pregnant, talk with your healthcare professional if you are depressed or undergoing treatment for depression to determine your best treatment option during pregnancy.
- Talk to your healthcare professional about the potential benefits and risks of taking an SSRI during pregnancy.
- Do not stop taking an SSRI antidepressant without first talking to your healthcare professional. Stopping an SSRI antidepressant suddenly may cause unwanted side effects or a relapse of depression.
- Report any suspected side effects of SSRI use in pregnancy to your healthcare professional and to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- It is unclear whether SSRI use during pregnancy can cause PPHN, because the available data are conflicting (see Data Summary).
- Healthcare professionals and their patients must weigh the small potential risk of PPHN that may be associated with SSRI use in pregnancy against the substantial risks associated with under-treatment or no treatment of depression during pregnancy.
- Untreated depression during pregnancy may lead to poor birth outcomes, including low birth weight, preterm delivery, lower Apgar Scores, poor prenatal care, failure to recognize or report signs of labor; and an increased risk of fetal abuse, neonaticide or maternal suicide.3,4.
- The published joint 2009 American Psychiatric Association (APA) and American College of Obstetrics and Gynecology (ACOG) guidelines for the management of depression during pregnancy includes treatment paradigms for the appropriate management of depression in pregnancy.2 The guidelines may be found here: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3103063/pdf/nihm
- Report adverse events involving SSRIs to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
It is well documented in the medical literature that SSRIs are used during pregnancy.1,2 In general, most epidemiology studies show that adverse events in pregnant patients are similar to those in non-pregnant patients, and many studies find no major fetal abnormalities in excess of the 1-3% found in the general population.5 Two studies suggest an increased risk for PPHN with SSRI use in pregnancy.3,6 Three other studies do not support this association and the potential risk with SSRI use during pregnancy remains unknown. 5,7,8
PPHN affects between 1 and 2 infants per 1000 live births in the general population, a relatively uncommon event, but one associated with significant infant morbidity and mortality as well as long term sequelae.7,8,9 A neonate with primary PPHN is typically a term or late-preterm infant who presents within hours after birth with severe respiratory failure and who often requires mechanical ventilation. These neonates have no radiographic lung abnormalities and no evidence of parenchymal lung disease. Secondary PPHN may be associated with other problems with the fetus, such as meconium aspiration, neonatal infection or congenital heart malformations.8,9,10
The 2006 study by Chambers et al.found a six-fold increase in PPHN among neonates whose mothers were exposed to an SSRI after 20 weeks of gestation, and provided the rationale for the current SSRI product label warning under Usage in Pregnancy: Nonteratogenic Effects stating, "Infants exposed to SSRIs in late pregnancy may have an increased risk for persistent pulmonary hypertension of the newborn (PPHN)." 3 A more recent study by Källén, et al.also found a statistically significant association between SSRI use and PPHN, although the majority of exposures occur during the first trimester of pregnancy.6 The results of these two studies reporting an increase in risk are interpreted by some to show a strong association between SSRI use in pregnancy and the development of PPHN.
A review of the published literature also identified three studies reporting no increase in risk of PPHN.5,7,8 The 2006 study by Wichman et al. is a retrospective cohort study of obstetric deliveries within a defined geographic area conducted by the Mayo Clinic. The study identified 16 neonates with PPHN and no exposures to an SSRI in utero.5 The 2009 study by Andrade et al. is a well-designed retrospective cohort study from four health plans in an ongoing HMO research network study of birth outcomes. The authors found no association between SSRI exposure during the third trimester of pregnancy and PPHN.7 Lastly, the smaller 2011 retrospective case-control study by Wilson et al.identified 58 neonates with PPHN and no SSRI exposure in utero.8
Design features in each of the above five published studies preclude the demonstration, either individually or collectively, of a definitive association between SSRI use and PPHN. Each study incorporates a different study design, different method of collecting exposure information during gestation, and gives incomplete attention to potentially important factors including Cesarean delivery. FDA recommends caution be used when interpreting results of studies with statistical associations, as statistical significance in an epidemiologic study does not always correlate with clinical significance and good clinical decision making.11,12
At present, FDA does not find sufficient evidence to conclude that SSRI use in pregnancy causes PPHN, and therefore recommends that health care providers treat depression during pregnancy as clinically appropriate. FDA will update the SSRI labels as any new data regarding SSRI use and PPHN become available.
- Cooper WO, Willey ME, Pont SJ, Ray WA. Increasing use of antidepressants in pregnancy. Am L Obstet Gynecol 2007;196:544 e1-544.e5
- Yonkers KA, Wisner KL, Stewart DE, Oberlander TF, Dell DL, Stotland N, Ramin S, Chaudron L, Lockwood C. The management of depression during pregnancy: a report from the American Psychiatric Association and the American College of Obstetricians and Gynecologists. General Hospital Psychiatry 2009;31:403-413.
- Chambers CD, Hernandez-Diaz S, Van Marter LJ, Werler MM, Louik C, Jones KL, Mitchell AA. Selective Serotonin-Reuptake Inhibitors and Risk of Persistent Pulmonary Hypertension of the Newborn. NEJM 2006;354(6):579-587.
- O'Keane V, Marsh SM. Depression during pregnancy. BMJ 2007;334:1003-1005.
- Wichman CL, Morre KM, Lang TR, St. Sauver JL, Heise RH, Watson WJ. Congenital heart disease associated with selective serotonin reuptake inhibitor use during pregnancy. Mayo Clin Proc 2009;84(1):23-27.
- Källén B and Olausson PO. Maternal use of selective serotonin re-uptake inhibitors and persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Safety 2008;17:801-806.
- Andrade SE, McPhillips H, Loren D, Raebel MA, lane K, Livingston J, Boudreau DM, Smith DH, Davis RI, Willy ME, Platt R. Antidepressant medication use and risk of persistent pulmonary hypertension of the newborn. Pharmacoepidemiol Drug Safety 2009;18:246-252.
- Wilson KL, Zelig CM, Harvey JP, Cunningham BS, Dolinsky BM, Napolitano PG. Persistent pulmonary hypertension of the newborn is associated with mode of delivery and not with maternal use of selective serotonin reuptake inhibitors. Am J Perinatol 2011;28(1):19-24.
- Hernandez-Diaz S, VanMarter LJ, Werler MM, Louik C, Mitchell AA. Risk Factors for Persistent Pulmonary Hypertension of the Newborn. Pediatrics2007;120:e272-e282.
- Levine, EM, Ghai V, Barton JJ, Storm CM. Mode of delivery and risk of respiratory disease in newborns. Obstetrics and Gynecology 2001;97:3:439-442.
- Chambers C. Selective serotonin reuptake inhibitors and congenital malformations. BMJ 2009;339:b3525.
- Nonacs, R. SSRIs and PPHN: a review of the data [internet]. Boston (MA): Massachusetts General Hospital, Center for Women's Mental Health; posted 2009, Nov 10. Available from: http://www.womensmentalhealth.org/posts/ssris-and-pphn-a-review-of-the-data/
Table 1: Selective Serotonin Reuptake Inhibitor (SSRI) Drugs
Generic name Found in Brand name(s)
Fluoxetine Prozac, Sarafem, Symbyax
Fluvoxamine Luvox, Luvox CR
Paroxetine Paxil, Paxil CR, Pexeva
Facts about Selective Serotonin Reuptake Inhibitors (SSRIs):
- Marketed under various brand and generic drug names (see Table 1).
- Used to treat depression and other psychiatric disorders.
- Are commonly used drugs to treat depression during pregnancy in the United States. 1,2
- There are no adequate and well-controlled studies of SSRIs in pregnant women.
Source : FDA
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60 Minutes: Unhappy pills - Video
Video from New Zealands 60 Minutes News Programme
FDA Drug Safety Communication: Abnormal heart rhythms associated with high doses of Celexa (citalopram hydrobromide)
The U.S. Food and Drug Administration (FDA) is informing healthcare professionals and patients that the antidepressant Celexa (citalopram hydrobromide; also marketed as generics) should no longer be used at doses greater than 40 mg per day because it can cause abnormal changes in the electrical activity of the heart. Studies did not show a benefit in the treatment of depression at doses higher than 40 mg per day.
Previously, the citalopram drug label stated that certain patients may require a dose of 60 mg per day.
Changes in the electrical activity of the heart (prolongation of the QT interval of the electrocardiogram [ECG]) - see Data Summary below - can lead to an abnormal heart rhythm (including Torsade de Pointes), which can be fatal. Patients at particular risk for developing prolongation of the QT interval include those with underlying heart conditions and those who are predisposed to low levels of potassium and magnesium in the blood.
The citalopram drug label has been revised to include the new drug dosage and usage recommendations, as well as information about the potential for QT interval prolongation and Torsade de Pointes. (See Additional Information for Healthcare Professionals)
Additional Information for Patients
- Do not stop taking citalopram or change your dose without talking to your healthcare professional. Stopping citalopram suddenly can cause unwanted side effects.
- If you are currently taking a citalopram dose greater than 40 mg per day, talk to your healthcare professional about changing your dose.
- Seek immediate care if you experience an irregular heartbeat, shortness of breath, dizziness, or fainting while taking citalopram.
- If you are taking citalopram, your healthcare professional may occasionally order an electrocardiogram (ECG, EKG) to monitor your heart rate and rhythm. An ECG is a test that checks for problems with the electrical activity of your heart.
- Read the Medication Guide for citalopram carefully and discuss any questions you have with your healthcare professional.
- Report any side effects you experience to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of the page.
- Citalopram causes dose-dependent QT interval prolongation. Citalopram should no longer be prescribed at doses greater than 40 mg per day.
- Citalopram should not be used in patients with congenital long QT syndrome.
- Patients with congestive heart failure, bradyarrhythmias, or predisposition to hypokalemia or hypomagnesemia because of concomitant illness or drugs, are at higher risk of developing Torsade de Pointes.
- Hypokalemia and hypomagnesemia should be corrected before administering citalopram. Electrolytes should be monitored as clinically indicated.
- Consider more frequent electrocardiogram (ECG) monitoring in patients with congestive heart failure, bradyarrhythmias, or patients on concomitant medications that prolong the QT interval.
- 20 mg per day is the maximum recommended dose for patients with hepatic impairment, who are greater than 60 years of age, who are CYP 2C19 poor metabolizers, or who are taking concomitant cimetidine (Tagamet®), because these factors lead to increased blood levels of citalopram, increasing the risk of QT interval prolongation and Torsade de Pointes.
- No dose adjustment is necessary for patients with mild or moderate renal impairment.
- Advise patients to contact a healthcare professional immediately if they experience signs and symptoms of an abnormal heart rate or rhythm while taking citalopram.
- Report adverse events involving citalopram to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of the page.
FDA has received post-marketing reports of QT interval prolongation and Torsade de Pointes associated with Celexa and its generic equivalents. In addition, FDA has evaluated the results of a thorough QT study assessing the effects of 20-mg and 60-mg doses of citalopram on the QT interval in adults. In this randomized, multi-center, double-blind, placebo-controlled, crossover study, 119 subjects received citalopram 20 mg per day (Day 9), citalopram 60 mg per day (Day 22), and placebo. The overall summary of findings is presented in Table 1
Table 1: Increase in the Corrected QT Interval for Citalopram (FDA Analysis)
Citalopram Dose Increase in QT Interval (ms) 90% Confidence Interval (ms)
20 mg/day 8.5 (6.2, 10.8)
60 mg/day 18.5 (16.0, 21.0)
40 mg/day 12.6* (10.9, 14.3)*
*Estimate based on the relationship between citalopram blood concentration and QT interval.
Compared to placebo, maximum mean prolongations in the individually corrected QT intervals were 8.5 and 18.5 milliseconds (ms) for 20 mg and 60 mg citalopram, respectively. For 40 mg citalopram, prolongation of the corrected QT interval was estimated to be 12.6 ms.
As a result of this thorough QT study, FDA has determined that citalopram causes dose-dependent QT interval prolongation and should no longer be used at doses above 40 mg per day. Important safety information about the potential for QT interval prolongation and Torsade de Pointes with drug dosage and usage recommendations are being added to the package inserts of Celexa and its generic equivalents.
- National Center for Biotechnology Information. U.S. National Library of Medicine. PubMed Drug & Supplements Monograph Citalopram. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a699001.html. Accessed July 20, 2011.
Facts about Celexa (citalopram hydrobromide)
- Is in a class of antidepressants called selective serotonin reuptake inhibitors (SSRIs).
- Thought to work by increasing the amount of serotonin in the brain.1
- Available as 10 mg, 20 mg, and 40 mg tablets. Also available as an oral solution (10 mg/5 mL).
Source : FDA (Aug 2011)
Link to Source
SSRI Stories - Antidepressant Nightmares
Antidepressants have been recognized as potential inducers of mania and psychosis since their introduction in the 1950s. Klein and Fink1 described psychosis as an adverse effect of the older tricyclic antidepressant imipramine. Since the introduction of Prozac in December, 1987, there has been a massive increase in the number of people taking antidepressants. Preda and Bowers2 reported that over 200,000 people a year in the U.S. enter a hospital with antidepressant-associated mania and/or psychosis. The subsequent harm from this prescribing can be seen in these 4,500+ stories.
Before the introduction of Prozac in Dec. 1987, a little less than one percent of the population in the U.S. was diagnosed with bipolar disorder – also known as manic depression. Now, with the widespread prescribing of antidepressants, the percent of the population in the United States that is diagnosed with bipolar disorder (swing from depression to mania or vice versa) has risen to 4.4%3 . This is almost one out of every 23 people in the U.S.
This web site focuses on the Selective Serotonin Reuptake Inhibitors (SSRIs), of which Prozac was the first. Other SSRIs are Zoloft, Paxil (Seroxat), Celexa, Sarafem (Prozac in a pink pill), Lexapro, and Luvox. Other newer antidepressants included in this list are Remeron, Anafranil and the SNRIs Effexor, Serzone, Cymbalta and Pristiq as well as the dopamine reuptake inhibitor antidepressant Wellbutrin (also marketed as Zyban).
Source : SSRI stories
Read more and read the horrifying list (4,500) of violence and death - people on antidepressants
Antidepressants for Children - Prozac – how could it be approved for children in
In December 2003, the British MHRA (Medicines and Healthcare products Regulatory Agency) banned the use of all antidepressants for children and adolescents under 18 years [1,2].There were no proven benefits with the drugs but evidence that they resulted in increased suicidal behaviour. The only antidepressants that MHRA specifically excluded from the ban was Prozac, earlier the same year approved by FDA [3, 4], based on two short studies (more about them later ) .
On 25 April 2005 the European Medicines Agency, EMEA, published warnings for all antidepressants - including Prozac. They should not be given to children and adolescents diagnosed with depression , they increased the risk for suicidal behaviour and hostility. The British Medical Journal (BMJ) wrote: “The European Medicines Agency has ruled that selective serotonin reuptake inhibitors (SSRIs) and selective serotonin and norepinephrine reuptake inhibitors (SNRIs) [newer classes of antidepressants] should not be prescribed for
children and adolescents under the age of 18 [for depression]…” . This created a very special situation. FDA had approved Prozac for children, the British MHRA had not wanted to offend FDA and leading psychiatrists and exempted Prozac from their ban of antidepressants, but now the EMEA issued warnings for all antidepressants –
including Prozac – and “said “should not be given to children and adolescents “ . MHRA's angry reaction to the decision of EMEA told some of the pressure exerted on the agency. A spokeswoman for the agency said:
“There is still time to influence it [the decision]. We back what Emea’s scientific panel is saying but the key difference is that Prozac is the one drug for which there is clinical-trial evidence that it is effective. The profession know they are going to have to prescribe something and it is important they know what the dangers are and the best way of prescribing it. We think it is safe to use so long as it is monitored carefully.”  [Italics here.] There was a strong pressure from the “profession” [psychiatry], which“have to prescribe
something”, and when it was not possible to prescribe Prozac, it became a big problem. The directive from EMEA about Prozac to children went straight against the approval that FDA made in early 2003, in that a majority of experts from European agency now found that Prozac should not be given to children and adolescents. And here is where this story starts. We did not know anything about the game behind
the scenes – we did not know how it could be that the same authority – the European Medicines Agency, EMEA – one year later 6 June 2006 approved Prozac for children. The British Medical Journal then wrote: “The European Medicines Agency has approved the use of fluoxetine (Prozac) for children aged 8 years or more and teenagers who have moderate to severe depression…”  How did the turnaround happen? What new information had emerged in one year? What forces pushed through the change of the decision? None of this has been answered in the past for the simple reason that the records from the medical agencies telling the story have not seen the light.
To get an application approved of course first requires an application. And a newspaper article from June 2004  revealed: MHRA had in order to deal with the pressure asked the pharmaceutical company Eli Lilly to submit an application for approval of Prozac in the UK and Europe. A representative of a patient association, who quit the UK expert committee because of lack of transparency, was very upset that MHRA, who should
oversee the pharmaceutical companies, contacted one of them and asked them to apply for an approval. He said: “This raises real issues about their impartiality. They are saying they want an SSRI [this type of antidepressants] to be given to children. It is not their job to decide such a thing. If they are going to do deals with the drug companies, where does it stop?” Well, we already know that it stopped with Prozac being approved for children in Europe two years later. But it can already now be said that Sweden had at least as much to do with the approval decision being pushed through. UK and Sweden – and the psychiatric consultants
that these countries made use of – pushed it through while several other countries strongly argued for not approving Prozac. At the same time as EMEA (25 April 2005) issued warnings on all antidepressants and wrote
“should not be used to treat depression in children and adolescents”, the Swedish Medical Products Agency, MPA, (29 April) submitted it comments to the evaluation done by France and UK about the application submitted by Lilly for the approval of Prozac (France opposed the approval). The Swedish Medical Products Agency (MPA) gave the following amazing assessment  (p. 1): “…the MPA currently supports the overall view of the UK, i.e. that approval may be recommended provided commitments of further studies and appropriate wording of the SPC [Summary of Product Characteristics].” In other words, the Swedish MPA and the UK MHRA at this time supported the approval of Prozac for children. The arguments for giving approval were strange, to say the least, they had little to do with any good scientific evidence that this was an effective and safe medicine for children. This is what the MPA had to say (p. 1): “It is a fact that SSRIs, including fluoxetine [Prozac], are used ’off label’ [without being approved for what it is prescribed for] in children and adolescents, and approving use of fluoxetine allows for providing treatment recommendations, better post marketing surveillance in these populations and possibilities to request further studies.” MHRA had used the absurd argument ”the profession [psychiatry] know they are going to have to prescribe something”, and the reasons given by the MPA were of the same low class. The Swedish agency responsible for making sure that people got safe and effective medicines said they wanted to accept a psychiatric drug for children because doctors already prescribed it! The agency further stated that if Prozac is approved for children now they can later require
further studies about the harmful effects. With this logic one could easily approve all antidepressants to children – not to mention even more toxic psychiatric drugs, as psychiatrists already prescribe also these for children, despite all evidence of harmful effects. Strangely enough the Swedish Medical Products Agency, eight days after EMEA issued directives about all antidepressants, convened its own expert meeting. Among the participants were the officials who signed the above assessment , as well as prominent consultants as
Psychiatry Professor Anne-Liis von Knorring, scientific advisor to the Agency, and Psychiatry Professor Bruno Hägglöf. The result of this meeting was treatment recommendations for antidepressants for children – ”an update of the state of knowledge” . In those it was written that no antidepressants are approved for children, but that “it is well known that pharmacological treatment of children is sometimes deemed necessary and that antidepressants are used” (the same kind of argument that was used in the assessment above). About Prozac it is written: “Among antidepressant drugs fluoxetine has the most convincing clinical documentation ... ” [Italics here.] The risk of suicidal behaviour is mentioned, the risk that together with the absence of positive effect, got EMEA to eight days earlier, for all antidepressants announce: “should not be given to children and adolescents”. The experts in the MPA-meeting however go far to ignore the proven risk of increased
suicidal behaviour (i.e. “not significant increase in risk compared to placebo” ). What is really strange is that the MPA opposes the just issued European warnings and that the Agency issues the positive statements about Prozac (“the most convincing clinical documentation”) when they know that several other medical agencies in Europe have another view on this. In addition, the MPA at this point knows that the investigation of Prozac is
continuing at European level, that a variety of questions about the clinical trials of Prozac and the safety risks of the drug have been submitted to the manufacturer Eli Lilly, and that the answers from the company, when eventually received, will form the basis for a reassessment of the drug. The continued handling of the case at European level was referred to Holland, who, in the role of “Rapporteur ”, should request further answers from the pharmaceutical company Eli Lilly and submit a new evaluation. On 31 October 2005 the evaluation from the Dutch Medicines Evaluation Board (CBG) was issued: Prozac (fluoxetine) - Paediatric Indication, Rapporteurs' Assessment Report. It is an incredible report. It begins with the words: “It is not recommended to grant an indication to fluoxetine for the treatment of depression in children and adolescents because the benefit/risk balance in the claimed indication is deemed negative.” In other words, Prozac should not be approved for depressed children and adolescents; the dangers of the drug are greater than any benefit. Note that this evaluation is made about 10 years after the prescription of Prozac for children in the United States began to rise heavily (although the drug was not approved for children), and nearly three years after FDA (January 2003) approved Prozac for children. Please note that the evaluation is made after the Dutch Medicines Evaluation Board asked for and received answers to a number of follow-up questions from the company Eli Lilly.
The ”unresolved issues” around Prozac, the reasons why different medical agencies in Europe in the end of April 2005 rejected Lilly's application for approval was taken up by the Dutch medical agency: “Overall there were unresolved objections and concerns with respect to the following issues:
- Representativeness of the included patient population.
- The lack of information regarding optimal dose.
- The limited information regarding long-term efficacy.
Safety from clinical studies:
- Higher rates of suicidal related events in the fluoxetine compared to placebo treated patients.
- Concerns about reduced height and weight gain.
- Lack of data concerning effects on maturation, cognition and behavioural development.
- Limited long-term safety data.
- Effects on bone development.
- Effects on sexual development.
- Irreversible testicular toxicity.
- Effects on emotional development.”
It was these questions and others that the Dutch Medicines Evaluation Board (as “Rapporteur”) should give further consideration and on which the agency requested additional information from Eli Lilly.
So what was the reason that the “Rapporteur” in October 2005, after having received the
replies from Eli Lilly, stated that Prozac could not get an approval in Europe? The Board referred to what was already known and said that the answers from Lilly had not diminished worries of damage. They wrote:
“Concerns about safety issues were not resolved, specifically concerns about suicide related behaviours, including suicide attempt and suicidal ideation, and, from non-clinical data, about the effect on growth, sexual maturation, cognitive and emotional development. The limited evidence concerning long-term safety
is a concern as well, especially given these safety signals.” The Board further questioned whether the descriptions of positive effects in the studies submitted had anything to do with the actual effect in clinical activities (more about that later):
“Moderate effects, though somewhat inconsistent across trials, were seen, but there are doubts about the external validity of these results due to the stringent selection procedure.”
The Board further wrote: “In addition to objections that were raised in response to the request, during
the course of this procedure new information concerning safety have become available from preclinical as well as clinical studies. Animal studies have raised concerns with respect to effects of early exposure on growth and sexual maturation. A non-company sponsored clinical study (the Treatment of Adolescents with Depression Study (TADS)) demonstrated that fluoxetine, in common with other SSRls, is associated with increased risk of suicidal behaviours in young persons.”
Comments about the “efficiacy” of Prozac In the report the Dutch agency then assesses the clinical trials that were part of the application, which should show that Prozac was “effective” for children and adolescents, one
of the requirements for the approval of the drug. The Board writes (p. 9) that the evidence of efficiacy is “mixed – a modest effect that reached significance only in some trials…”. But, as they write, “more important is the fact that the patients population that was included in the trials is a highly selected group that is not likely
to be representative of the total depressed patient population”. The Board explains in detail how the various studies of Prozac were done, and compare them with other studies of antidepressants in children. It is explained that Eli Lilly and the researchers who conducted the trials of Prozac had used another method than what had been used in the trials of other antidepressants. For example, all children who would participate in
the Prozac studies, had to undergo “an extensive screening and evaluation procedure” before
they became included in the actual studies, with the result that many were excluded from the
studies. Part of this extensive procedure was (in two of the studies ) that all children before the actual study were given a placebo (sugar pill) for a week. The children who showed improvement when they received placebo were excluded from the study. We know from other trials of antidepressants that a high proportion of those receiving placebo improved just as much as those receiving antidepressants. In other words, when comparing the groups one gets no positive effect of the antidepressant drug, compared to placebo, which in itself shows that the drug does not work, it does not have a positive chemical effect (placebo works just as
well). So the reason they gave all children placebo for a week before they began the actual study
was to be able to exclude children who got better on placebo, and thus it was expected that a
smaller proportion of children who received placebo in the actual study would get a positive
result. The researchers wanted to increase the chance of obtaining a difference between the
active drug (Prozac) and placebo, increasing the chance of obtaining “evidence” that Prozac
It was this approach that the Medicines Evaluation Board was referring to when they wrote
about “a highly selected group ”. The Board also made the comparison to what happened
when researchers in other studies of antidepressants did not from the beginning exclude
children that could worsen the results of the drug versus placebo. A comparison is made with
the studies of paroxetine (Seroxat/Paxil) where a ”lower percentage of patients were excluded”. The Board said: “Comparison of the results indicate that the percent responders in the active arms are similar in the paroxetine and the f1uoxetine trials … while the percent responders to placebo are generally higher in the paroxetine trials.” [Emphasis added.] In studies with paroxetine, the proportion of ”placebo responders” was 55%, 58%, 46%, whereas in studies with fluoxetine it was 32%, 53%, 35%. Exclusion of children in the Prozac studies strongly diminished the proportion who received a positive result on placebo – thus creating a
”positive” difference between the antidepressant and placebo; with this approach Eli Lilly
could argue that Prozac was ”effective” – which the Dutch Medicines Evaluation Board did not agree to.
Conclusions on the “safety” of Prozac The Dutch Medicines Evaluation Board summarizes the safety risks :
“In the face of the limited efficacy results, safety concerns are all the more salient. Increased risk for suicide related behaviours emerged as the most concerning safety finding from the clinical trials. Other safety concerns include effects on growth and sexual maturation including effects on fertility, and effects on cognitive and emotional development.” They note again that Prozac can not be approved (the benefit is not greater than the risk) and write:
“The company should be encouraged to conduct further trials, concerning the dose, the efficacy in a more general population and concerning long-term safety.”
And so Prozac got approved
The above means that in the end of 2005, the medical agency in Europe that had been responsible (as “Rapporeur”) to investigate the matter, considered that Prozac was not acceptable for children. It had raised a number of issues for the pharmaceutical company, but found that the answers the company provided did not change anything in the assessment. Prozac was not approved.
In the additional documents in the case it can be seen in the summary report from 6 February
2006 (Joint Assessment Report)  that several countries (France, Ireland and Denmark) supported Holland's assessment that Prozac cannot be approved for children and adolescents.
The updated assessments from the “Rapporteur”, the Dutch medical agency, shows that at crucial points it is written ”Issue not resolved”, while estimates from the Swedish Medical Products Agency (“Co-Rapporteur”) of these points are ”Issue solved” or ”Issue to be discussed with the company ”.
The Dutch agency expresses its deep disappointment with the pharmaceutical company Eli Lilly and writes (p. 6):
“The responses of the company at this time ... indicates that the company is not intending to carry out any more studies to address the unresolved safety concerns.”
The Board also states:
“The lack of willingness on the part of the company to carry out additional studies that would elucidate safety concerns is disappointing, as the MAH [Marketing Authorization Holder] has a clear responsibility for evaluation of safety in this population.”
And based on this information the European Medicines Agency (EMEA) the 25-27 April 2006, is conducting hearings in London with Eli Lilly. Now they agree, and now it goes fast. On 6 June, an approval is granted for Prozac! It is associated with ”requirements” for a number of follow-up studies – on the very safety issues that should have been resolved before an approval was granted.
The Swedish Medical Products Agency tells on its website : “Fontex/Prozac (fluoxetine)
is approved for treating depression in children and adolescents ”, and says that ”EMEA decided to recommend that Prozac is approved for treating depression in children and adolescents over eight years of age”. It further says: “The Scientific Committee, the CHMP [Committee for Human Medicinal Products, experts in EMEA from the various countries], states that studies in children and adolescents demonstrated that fluoxetine is effective against moderately severe and severe depression.”
The MPA of course says nothing about the story above. There is nothing in the MPA statement about the previously used “scientific arguments” that ”The profession know they are going to have to prescribe something... ” (MHRA)  and that Prozac should be approved because it is already used for children [MPA] .
In its assessment from April 2005  the MPA also told that one of the good grounds on which it would approve Prozac for children was that one then – after the approval – got good chances for “better post marketing surveillance in these populations and possibilities to request further studies”. What happened with this may require a separate article. The wise reader can guess: Did Eli Lilly really in an effective way conduct the required studies, that they previously did not want to do, now when Prozac had been approved? Did the MHRA, MPA and Eli Lilly after the approval start with new effective follow-up actions for the children who received Prozac?
Reporter – investigating psychiatry
Here you can read the full report from Holland: CBG, The Dutch Medical Evaluation
Board, Prozac (fluoxetine) - Paediatric Indication, Rapporteurs' Assessment Report, 31
October 2005, http://jannel.se/Prozac-HollandAR.pdf
 The Independent, Threat of suicide leads to ban of major antidepressants for children,10 December 2003,
 Medical News Today,UK - Major antidepressants banned - Suicide Threat,13 December 2003,
 M2 Press Wire,FDA Approve Prozac for Pediatric use, 6 January 2003,
 FDA, Approval of Prozac for Pediatric Use, FDA Patient Safety News, 14 April 2003,
 EMEA press release,The European Medicines Agency finalis review of antidepressants in children and
adolescents, 25 April 2005 http://www.ema.europa.eu/pdfs/human/press/pr/12891805en.pdf
 BMJ, Regulator restricts use of SSRIs in children, 30 April 2005,
 The Independent, Britain set for clash with Europe over ban on Prozac for under - 18s, 26 April 2005,
 BMJ, European agency approves use of fluoxetine for children and teens, 17 June 2006,
 The Guardian, Safety alert on adult use of antidepressants,14 June 2004,
 MPA, Comments From The Medical Products Agency, On The Final Variation Assessment Reports
(FVARS); 29 April 2005, (Lena Björk, Hans Melander, Ulla Liminga, Eva Gil Berglund ) .
 MPA, Pharmacological treatment of depression in children and adolescents - an update of the state of
knowledge - Treatment Recommendation, May 2005 ; http://www .lakemedelsverket.se / upload / health -
medical care / reading / depressionbarn.pdf
 CBG, The Dutch Medical Evaluation Board, Prozac (fluoxetine) - Paediatric Indication, Rapporteurs'
Assessment Report, 31 October 2005, http://jannel.se/Prozac-HollandAR.pdf
 CBG, The Dutch Medical Evaluation Board, Joint Assessment Report, 6 February 2006.
 MPA, [Swedish] Fontex/Prozac (fluoxetin) godkänns för behandling av depression hos barn och ungdomar,
6 June 2006, http://www.lakemedelsverket.se/Alla-nyheter/NYHETER-2006/FontexProzac-fluoxetin-godkannsfor-behandling-av-depression-hos-barn-och-ungdomar/
LINK TO SOURCE
Antidepressants for Children - Part II
Prozac for children - what happened with the follow-up? By Janne Larsson
Reporter - investigating psychiatry
September 21, 2010
Prozac was approved for children in Europe in 2006. [1, 2] Several countries were strongly opposed, but the UK and Swedish medical agencies pushed to get the drug approved. They thought it was a good idea to first approve Prozac and afterwards do the needed safety studies.
So what happened to the needed studies and the careful monitoring which were a requirement - a condition - for the approval of Prozac for children in Europe?
The Dutch Medicines Evaluation Board (CBG) was in 2005 responsible for the assessment of whether or not Prozac could be approved for children in Europe. The Agency found that Prozac could not be approved and wrote about the effects and harmful effects of the drug:
"In the face of the limited efficacy results, safety concerns are all the more salient. Increased risk for suicide related behaviours emerged as the most concerning safety finding from the clinical trials. Other safety concerns include effects on growth and sexual maturation including effects on fertility, and effects on cognitive and emotional development." 
The Dutch agency expressed its deep disappointment with the pharmaceutical company Eli Lilly and wrote (p. 6):
"The responses of the company at this time... indicates that the company is not intending to carry out any more studies to address the unresolved safety concerns."
The Agency also stated:
"The lack of willingness on the part of the company to carry out additional studies that would elucidate safety concerns is disappointing, as the MAH [Marketing Authorization Holder] has a clear responsibility for evaluation of safety in this population." 
In Part I of this article I let the wise reader guess: Did Eli Lilly really in an effective way conduct the required studies, that they previously did not want to do, now when Prozac had been approved? Did the UK MHRA, the Swedish MPA and Eli Lilly after the approval start with new effective follow-up actions for the children who received Prozac?
The Swedish Medical Products Agency (MPA) had already in the early negotiations about the approval of Prozac for children pushed for such authorization. The Agency was aware of the serious signs of damage that had been presented in the case files, but said that safety issues could be investigated after the pharmaceutical company had got its positive decision:
The Agency wrote:
"...the MPA currently supports the overall view of the UK, i.e. that approval may be recommended provided commitments of further studies and appropriate wording of the SPC [Summary of Product Characteristics]." [Emphasis here.]
"It is a fact that SSRIs, including fluoxetine [Prozac], are used 'off label' [without being approved for what it is prescribed for] in children and adolescents, and approving use of fluoxetine allows for providing treatment recommendations, better post marketing surveillance in these populations and possibilities to request further studies." [Emphasis here.] 
And the English and Swedish Agencies pushed through the approval with these "scientific arguments". Prozac was approved in June 2006 and the pharmaceutical company Eli Lilly agreed to do the studies that had not been made prior to approval, and to ensure that children who received Prozac were closely monitored for effects and harmful effects.
Eli Lilly undertook at the time of approval  to do several things, which included the following:
1. Investigate the effect of Prozac on sexual maturation in children 8-12 years. This would be done in an American study ("TADSjr") under the National Institute of Mental Health (NIMH).
2. Examine if different registers in Europe could be used to obtain data on how Prozac affects the sexual maturation of children.
The company should also in Prozac studies with rats investigate the following:
4. "neurohormonal investigation of sexual maturation".
5. "characterization of testicular pathogenesis".
6. "characterization of effects on specified emotional behavior".
The Company should among other things examine what the Dutch Medicines Board had taken up about Prozac's "effects on growth and sexual maturation including effects on fertility, and effects on cognitive and emotional development".
We take a big step forward to 2010 and look at what happened to the proud commitments - the requirements, the conditions, for the approval of Prozac for children in Europe.
And we can in the UK electronic Medicines Compendium read:
"In addition, only limited evidence is available concerning long-term effect on safety in children and adolescents, including effects on growth, sexual maturation and cognitive, emotional and behavioural developments." 
More than four years after the requirements to closely examine these long-term effects there is still "limited data" available.
So what did Eli Lilly do, and what did the regulatory agencies, who should ensure that Eli Lilly complied to the requriements, do?
Eli Lilly should first investigate the effect of Prozac on sexual maturation in children 8-12 years. This would be done in collaboration with the researchers who had conducted the TADS study, Treatment for Adolescents with Depression Study, the main study that Eli Lilly used to push through the approval of Prozac for children (see Part I).
The researchers who conducted TADS would with funding from the National Institute of Mental Health (NIMH) conduct a follow-up study of children 8-12 years ("TADSjr"). Eli Lilly would "catch on" and as part of this study examine the effects of Prozac on sexual maturation.
In September 2006, Lilly submitted a proposal on how to conduct the study. 
The Assessor at the UK MHRA was not satisfied and wanted several questions answered. On November 16, Lilly responsed. The Assessor from MHRA, who apparently had decided to do a thorough job, was not at all satisfied. In the response to Lilly, on December 12, the often used phrase was "Issue not resolved" and the Assessor concluded by writing that almost none of the questions had received satisfactory answers.  On December 19, other Assessors in Europe commented on the report and a summary assessment report was issued.  On January 31, 2007, Eli Lilly replied to the Evaluators' comments and questions.  On March 1, MHRA answered on Lilly's report.  On March 12, MHRA sent a letter to Lilly to explain what was now required for this study.  And Lilly replied on April 12.  MHRA sent a report to other European regulatory agencies for comments on April 23.  Only Italy responded, and MHRA May 2, sent a new letter to Lilly and requested information.  On May 21, Lilly submitted the information.  After a few short communications Eli Lilly, July 6, submitted the revised design of the study. 
One year had now passed since Prozac was approved for children and the discussions were still about the design of the study that would provide answers to how Prozac affected different important aspects of children's life, including sexual maturation.
On July 19, MHRA issued a new assessment report to the European regulatory authorities. It was now agreed how the study should be done.  What remained was to actually conduct the study for which the design had been discussed over a year.
And this takes us forward to September 9, 2009. Now, MHRA publishes a summary of what has happened with the study that Lilly would conduct.
The Agency writes (p. 3):
"Now the TADS Jr study will not be conducted because of lack of funding by the NIMH, and consequently the exploration of possible effects of fluoxetine [Prozac] treatment on sexual maturation as part of this study will not be feasible."
One of the requirements for the approval of Prozac, in June 2006, was that this study must be conducted. The design of the study was then discussed for a year. And now, three years afterwards, it is said that the study was not even begun - and will not be done!
So how do MHRA and the other regulatory agencies handle this situation?
The MHRA writes:
"The MAH [the manufacturer, Eli Lilly] therefore requests [as this study would not be conducted] that the post-authorisation commitment [the requirements that should be fulfilled after approval of the drug] to clinically evaluate the effect of fluoxetine on sexual maturation be considered fulfilled." 
In other words, Eli Lilly requests that the requirement in this area should be considered fulfilled - even if the company has done nothing. The major concern about the effects of Prozac on children, that got the Dutch Medicines Evaluation Board (CBG) not to grant approval for Prozac, is existing just as much as four years earlier. Despite that Eli Lilly wants to skip all studies of long-term effects of Prozac in this area.
And what does MHRA say about this?
"The RMS [Reference Member State] [in this case UK] agrees that any clinical study to investigate the effects of fluoxetine on sexual maturation would be forbiddingly hard to conduct and difficult to interpret. The RMS therefore recommended accepting the Company's request that the FUM [Follow-Up Measure] to clinically evaluate the effect of fluoxetine on sexual maturation be considered fulfilled."
Abracadabra, the requirement was conjured away. The Swedish MPA, who wanted to approve