FDA Drug Safety Communication: FDA review of study sheds light on two deaths associated with the injectable schizophrenia drug Zyprexa Relprevv (olanzapine pamoate)
The U.S. Food and Drug Administration (FDA) has concluded a review of a study undertaken to determine the cause of elevated levels of the injectable schizophrenia drug Zyprexa Relprevv (olanzapine pamoate) in two patients who died. The study results were inconclusive. We are unable to exclude the possibility that the deaths were caused by rapid, but delayed, entry of the drug into the bloodstream following intramuscular injection. The study suggested that much of the drug level increase could have occurred after death, a finding that could explain the extremely high blood levels found in the two patients who died 3 to 4 days after receiving injections of appropriate doses of Zyprexa Relprevv. On the basis of all of the information reviewed, we are not recommending any changes to the current prescribing or use of Zyprexa Relprevv injection at this time. Patients should not stop receiving treatment without first talking to their health care professionals.
Treatment with Zyprexa Relprevv may help improve the symptoms of schizophrenia, which include hearing voices, seeing things that are not there, and being suspicious or withdrawn. The labeling for Zyprexa Relprevv carries a boxed warning, FDA’s most serious type of warning, for post-injection delirium sedation (PDSS). PDSS is a serious condition with signs and symptoms consistent with olanzapine overdose, in particular, sedation (including coma), delirium, or both. In clinical trials, cases of PDSS were observed within 3 hours after giving an intramuscular injection of Zyprexa Relprevv, although no deaths were reported. To reduce the risk of PDSS, there is also a Risk Evaluation and Mitigation Strategy (REMS) for Zyprexa Relprevv to ensure that patients are observed by health care professionals at a certified facility following injection.
Following the deaths of the two patients who received appropriate doses of Zyprexa Relprevv, FDA requested the drug’s manufacturer, Eli Lilly and Company, to conduct an animal study to test whether movement of olanzapine into blood after death could lead to higher-than-expected blood levels of the drug. The study showed that some animals had increases in drug levels in the blood after death, which could account for the higher-than-expected blood levels found in the two patients who died.
Source : FDA (Aril 2015)
New Medicaid Data Show Antipsychotic Use May Increase the Risk for Diabetes in Some Children
Researchers from The Children’s Hospital of Philadelphia’s PolicyLab Say Prescribing Practices Need to Include Thoughtful Risk/Benefit Consideration
Today in JAMA Pediatrics, researchers from The Children’s Hospital of Philadelphia’s (CHOP) PolicyLab published the largest study to date documenting the significant risks to children’s health associated with prescription antipsychotics, a powerful a class of medications used to treat mental and behavioral health disorders. The results suggest that initiating antipsychotics may elevate a child’s risk not only for significant weight gain, but also for Type II diabetes by nearly 50 percent; moreover, among children who are also receiving antidepressants, the risk may double. Previous PolicyLab research showed that one in three youth receiving antidepressants in the Medicaid program were receiving an antipsychotic at the same time.
Traditionally, antipsychotics have been narrowly prescribed to children with a diagnosis of schizophrenia or bipolar disorder, or to those with significant developmental delays who were displaying aggressive behaviors that were potentially injurious to themselves or others. However, in recent years, these medications are increasingly being prescribed in the absence of strong supporting safety and efficacy data to treat healthier children and adolescents with disruptive behaviors, such as those who are diagnosed with attention deficit hyperactivity disorder (ADHD).
The new study, which used national Medicaid data on more than 1.3 million youth ages 10 to 18 with a mental health diagnosis from the Centers for Medicare and Medicaid Services, must be interpreted in the context of emerging evidence that Medicaid-enrolled children are far more likely than privately insured children to be prescribed antipsychotic medications. Overall, over 25 percent of Medicaid-enrolled children receiving prescription medications for behavioral problems were prescribed antipsychotics by 2008, largely for less severe disorders.
“With such vast numbers of children being exposed to these medications, the implications for potential long-lasting harm can be jarring,” said David Rubin, MD, MSCE, the study’s lead author and co-director of PolicyLab at CHOP. Nevertheless, Rubin and his co-authors remain cautious in over-reacting to these findings. The baseline risk for diabetes among youth who were not exposed to antipsychotics in the study was only 1 in 400, rising to 1 in 260 among those initiating antipsychotics, and at most to 1 in 200 among those who initiated antipsychotics while they were simultaneously receiving antidepressants.
“Although these findings should certainly give us pause,” Dr. Rubin added, “we should not reflexively over-react to them. Rather, we need to incorporate these new revelations about the risk for diabetes into a more thoughtful consideration of the true risks and benefits of prescribing an antipsychotic to a child. Yes, we should try, by all means possible, to minimize the numbers of children and adolescents exposed to these powerful medications. But for some children in immediate crisis, we must also concede that the benefit of the antipsychotic for acute management may still outweigh the risk.”
The study’s authors recommend that clinicians and families who are making medication decisions periodically revisit the treatment strategy to address challenging behaviors. For example, when planning to prescribe antipsychotics to a child, professional organizations recommend beginning cautiously with the lowest dose possible, while strictly monitoring for early evidence of weight gain or abnormal lab tests that often predict later onset of diabetes. Dr. Rubin, who is also an attending pediatrician at CHOP, notes, “Once a child is on the antipsychotic drug, a plan should be agreed upon and periodically revisited to see whether or not an evidence-based counseling service, such as trauma-focused cognitive therapy, could address underlying emotional trauma, which is often the root cause for the behavior. That same periodic review would also seek to transition the child off the antipsychotic as soon as possible, once these problems are more suitably addressed. “
Ultimately, say Rubin and his co-authors, the prescription of antipsychotics to children and adolescents is likely to continue, reflecting a growing demand to address very challenging behaviors in children “At the end of the day, the approach to the individual child who is in crisis is still a case-by-case decision between a family and the treating provider,” said Dr. Rubin. “We can only hope that those decisions are made in full recognition of our findings, and that for some children, alternatives to these powerful medications—such as counseling or other supportive services, will be considered first.”
Source : Newswise (April 2015).
Huge Prescriber of Risky Antipsychotic Drug to Plead Guilty to Taking Kickbacks
Dr. Michael Reinstein has been the subject of two ProPublica investigations. For years, even while under federal investigation, he prescribed more of the drug clozapine than any other doctor in the United States.
A former Chicago psychiatrist who was the nation's top prescriber of the most powerful and riskiest antipsychotic drug intends to plead guilty to a federal felony charge of taking kickbacks from its manufacturer in exchange for prescriptions, court records show.
The U.S. Attorney for the Northern District of Illinois filed a single felony charge against Dr. Michael Reinstein this week for taking $2,000 in November 2009 from drugmaker Teva "in return for Reinstein's referrals of patients" for clozapine prescriptions.
Clozapine, also known as Clozaril and FazaClo, is approved to treat schizophrenia patients who don't respond to other medications. But it can have dangerous side effects, including seizures, inflammation of the heart muscle, and a drop in white blood cells. The drug is considered particularly risky for elderly patients.
A note in court records says that Reinstein intends to plead guilty at his arraignment next Friday. The action was first reported by the Chicago Tribune.
Reinstein's prescribing patterns have been detailed in two ProPublica reports.
In 2009, ProPublica and the Chicago Tribune reported how in one year Reinsteinprescribed more of the antipsychotic clozapine to patients in Medicaid's Illinois program than all doctors in the Medicaid programs of Texas, Florida and North Carolina combined. Autopsy and court records showed that at least three patients under Reinstein's care had died of clozapine intoxication. At that time, Reinstein defended his prescription record, arguing that clozapine is effective and underprescribed.
Then, in 2013, as part of a ProPublica investigation into Medicare's failure to monitor problem prescribers, we reported that Reinstein prescribed even more clozapine in Medicare's prescription drug program for seniors and the disabled. Medicare continued to let him prescribe in the program even after the U.S. Department of Justice accused him of fraud and Illinois' Medicaid program suspended payments to him.
The U.S. Attorney's office declined to discuss Reinstein's upcoming plea. Reinstein's attorney, Terence Campbell, did not immediately return a phone call from ProPublica seeking comment. He told the Tribune on Thursday that Reinstein was "working toward resolving the issues raised by the government and hopes to put this episode behind him soon."
The Tribune reached Reinstein, as well, yesterday. He would not discuss the criminal case but denied any payments from Teva, clozapine's manufacturer, were for prescribing the drug. The doctor instead said the money was for lectures he gave.
In November 2012, the federal government filed a civil fraud lawsuit against Reinstein, saying he "received illegal kickbacks from pharmaceutical companies and submitted at least 140,000 false claims to Medicare and Medicaid for antipsychotic medications he prescribed for thousands of mentally ill patients in area nursing homes."
Last August, Illinois medical regulators indefinitely suspended Reinstein's medical license after determining that Reinstein received " illegal direct and indirect remuneration" from the maker of generic clozapine, did not consider alternative treatments for his patients, and disregarded patients' well-being. In response to the medical board's accusations, Reinstein's lawyers invoked his right against self-incrimination.
Early last year, Teva Pharmaceutical Industries Ltd., the maker of generic clozapine, agreed to pay more than $27.6 million to settle state and federal allegations that it induced Reinstein to prescribe the drug.
Reinstein's prescribing of clozapine appears to have declined after our 2009 articles about him. From 2007 to 2009, he wrote an average of 20,000 Medicare prescriptions annually for clozapine and the brand-name version, FazaClo. That figure dropped to about 8,000 in 2012, according to data obtained by ProPublica.
Check out how your doctor's prescribing within Medicare compares to others in his or her specialty in your state. Visit our Prescriber Checkup tool.
Source : ProPublica (Feb 2015)
Ex-FDA Chief Says J&J Knew Drug Linked to Male Breast Growth
Johnson & Johnson, which paid more than $2 billion to resolve a criminal probe over its antipsychotic drug Risperdal, knew as early as 2001 that the medication caused boys to grow breasts, a former government regulator said in the first case over the treatment set to be decided by a jury.
Officials of J&J’s Janssen unit funded a 2001 study that showed 3.8 percent of boys given Risperdal during the clinical trial developed breasts that were either “probably or very likely” caused by the drug, David Kessler, the former head of the U.S. Food and Drug Administration, testified Wednesday in state court in Philadelphia.
The study “certainly was a red flag to me,” Kessler told jurors in the trial of a lawsuit brought by a 20-year-old Alabama man who blames the drug for his 100-pound weight gain and his development of female breasts. The man alleges Janssen executives hid the risk that Risperdal could create abnormal breast development in boys.
J&J, based in New Brunswick, New Jersey, faces more than 1,000 cases over the Risperdal side effect in state court in Philadelphia. In 2012, he company settled the first case to go to trial over claims the drug caused gynecomastia, or abnormal breast development, in boys.
Janssen officials said Wednesday the company properly warned patients and their doctors about Risperdal’s risks and didn’t mishandle marketing of the drug.
‘Improved Lives’Risperdal “has improved the lives of countless children and adults throughout the world who suffer from debilitating mental illnesses, and it continues to improve patients’ quality of life today,” Robyn Frenze, a Janssen spokeswoman, said in an e-mailed statement.
In 2013, J&J agreed to pay $2.2 billion to resolve criminal and civil probes into claims that it illegally marketed the drug to children and the elderly. The settlement, which also includes marketing claims about two other J&J drugs, was one of the largest U.S. health-fraud penalties in history.
The accord resolved probes by federal officials and attorneys general in 45 states into allegations the company marketed the drug for unapproved uses. While doctors may prescribe an approved drug for any reason, companies can market them only for purposes authorized by the FDA.
Risperdal also has been linked to excessive weight gain and diabetes. The drug, once J&J’s biggest seller, generated worldwide sales of $24.2 billion from 2003 to 2010, reaching $4.5 billion in 2007. After that, J&J lost patent protection and sales declined.
Safety WarningKessler, testifying as an expert for the man suing J&J over Risperdal, described for jurors his September 2012 review of the drugmaker’s handling of the medication. A pediatrician, Kessler served as head of the FDA for six years starting in 1991. He now works as a medical professor in California.
The former regulator concluded that while J&J knew as early as 2001 that the drug could cause breast development, it didn’t include a warning on the safety label until 2006, the year it received approval to sell the medication to children.
In the years leading to that approval, the company pushed doctors to prescribe the medication through “off-label” marketing, Kessler added.
To fuel such sales, J&J officials provided doctors with trinkets such as children’s Lego-like blocks in bright colors adorned with the Risperdal logo, Kessler said in his report.
Lawyers for the Alabama man who developed breasts after taking Risperdal for five years contend that J&J encouraged doctors to prescribe Risperdal off label for treating childhood disorders such as attention deficit and disruptive behavior, according to court filings.
The case is PP v. Ortho-McNeil Janssen Pharmaceuticals, 120401997, Court of Common Pleas Philadelphia County (Philadelphia)
Source : Bloomberg (Feb 2015)
Antipsychotics in Pregnancy Up Diabetes Risk
Women who took antipsychotic drugs during pregnancy -- including those drugs thought to have less potential for unwanted metabolic effects -- were at increased risk for developing diabetes and giving birth to small infants, researchers said.
Analysis of Swedish national birth and health registry data showed that, relative to mothers-to-be not taking antipsychotic drugs, the risk of gestational diabetes was nearly doubled, according to Robert Bodén, MD, PhD, of Uppsala University in Uppsala, Sweden, and colleagues.
The researchers also found that certain antipsychotics were associated with unusually large heads in newborns, after adjusting for maternal characteristics such as smoking status, they reported in the July issue of Archives of General Psychiatry.
"Pregnant women treated with antipsychotics should be closely monitored for gestational diabetes and deviating fetal growth," Bodén and colleagues concluded.
In their report, they noted that research on antipsychotics during pregnancy has been "lacking or weak," with little to go on even from observational studies. (In the U.S., antipsychotics are generally in pregnancy class C, indicating adverse fetal effects in animal studies but no solid evidence in human studies.)
But some of the side effects of newer antipsychotics -- including weight gain, insulin resistance, and hyperlipidemia -- would reasonably raise concern about risk of gestational diabetes in pregnant women as well as birth defects, Bodén and colleagues suggested.
They examined registry data on nearly 360,000 Swedish women giving birth from July 2005 to December 2009.
Antipsychotic drug use in pregnancy was uncommon, with only 507 women recorded as having taken them.
Among them were 169 who took the two such drugs most commonly associated with adverse metabolic effects, olanzapine (Zyprexa) and clozapine (Clozaril). The other 338 took other antipsychotics. Outcomes associated with the two groups of agents were analyzed separately.
After adjusting for maternal age, country of origin, smoking, height, cohabitation status, and number of previous pregnancies, antipsychotics in both groups were associated with about double the risk of gestational diabetes compared with no antipsychotic use. Odds ratios were as follows:
- Olanzapine and/or clozapine: 1.94 (95% CI 0.97 to 3.91)
- Other antipsychotics: 1.77 (95% CI 1.04 to 3.03)
Bodén and colleagues also looked for relationships between antipsychotics and birth outcomes.
Newborns considered small for gestational age in weight and length appeared to be more common with both groups of antipsychotics before the maternal adjustments were taken in the statistical analysis, with odds ratios ranging from 1.7 to more than 2.6. But after the maternal adjustments, the associations were attenuated substantially and were no longer significant.
But there was an odd finding with regard to head circumference. In the "other" antipsychotics group, there was a significant association with small head size for gestational age prior to adjustments for maternal factors that remained a strong trend even after the adjustments were taken (OR 1.64, 95% CI 0.97 to 2.77).
Among newborns born to mothers taking olanzapine and/or clozapine, on the other hand, there was an association with oversized heads that remained significant in the adjusted model (OR 3.02, 95% CI 1.60 to 5.71).
Bodén and colleagues explained that babies born large for gestational age have previously been associated with gestational diabetes. Because the fetus is not insulin resistant, the high levels of sugar to which it is exposed prompt high levels of insulin secretion, which, in turn, produces macrosomia and increased fetal size.
The divergent findings on head size between the two groups of antipsychotics suggest that direct pharmacologic effects may also play a role, the researchers suggested. But ultimately they could not explain why olanzapine and clozapine, as opposed to the other group, would produce babies with oversized heads. "We do not know the potential mechanism underlying this observation," they wrote.
They did suggest, however, that maternal smoking probably accounted for much of the apparent pre-adjustment risk of low birth weight and length associated with antipsychotics.
Primary source: Archives of General Pyschiatry
Boden R, et al "Antipsychotics during pregnancy: relation to fetal and maternal metabolic effects" Arch Gen Psychiatry 2012; 69: 715-721.
Source : Medpage Today
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J&J in court over mis-marketing 'dangerous' antipsychotic drug
The state of Arkansas is taking legal proceedings against a subsidiary of 'big pharma' company Johnson and Johnson over the marketing of an antipsychotic drug. The state claims that the drug's side effects were suppressed. A subsidiary company of drugs giant Johnson and Johnson, called Janssen Pharmaceuticals Inc., allegedly improperly marketed an antipsychotic drug and misled doctors about the potential side effects of the medicine, according to a lawyer representing the state of Arkansas. According to ABC News, the state of Arkansas is seeking the drugs company to be fined for each of the 250,000 Risperdal prescriptions issued to the state's Medicaid publicly. If the state is successful the court's award could range from $1.25 billion to $2.5 billion. All money would go into the Medicaid fund. The side effects in question relate to diabetes and hormonal imbalance. The action is being taken under violated Arkansas' Medicaid Fraud False Claims Act. The state claims that not only did the drugs company not publicise the side effects in its marketing information, it also misled doctors in a letter about the drug's risks. Evidence from medical practitioners in Arkansas indicates that the drug caused deaths among elderly users and breast growth and lactation in young boys. Bloomberg quotes the attorney for Arkansas saying "By the time this case is over, we will prove to you that Janssen lied about Risperdal’s dangers just to make money." Janssen, through their legal team, are refuting both claims. James Simpson, a lawyer for Janssen said "The state will not present any evidence that a single person was injured while taking Risperdal,” Simpson said in his opening statement. “There will not be any evidence that the state of Arkansas lost a penny in paying for Risperdal for thousands of Arkansas citizens who needed the drug." However, as PhillyPharma has reported, earlier in March 2012 a Texas judge Tuesday approved a $158 million settlement between Johnson & Johnson and the state of Texas over allegations that J&J's Janssen subsidiary illegally promoted Risperdal through the Medicaid program. Risperdal was introduced in 1994 as a "second-generation" antipsychotic drug and was a successful revenue generating product for Janssen. The drug is is used to treat schizophrenia, bipolar disorder and irritability in autism patients.
Source : Digital Journal
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Saphris (asenapine maleate): Drug Safety Communication: Serious Allergic Reactions
The U.S. Food and Drug Administration (FDA) is warning the public that serious allergic reactions have been reported with the use of the antipsychotic medication Saphris (asenapine maleate). The Contraindications, Warnings and Precautions, Adverse Reactions, and Patient Counseling Information sections of the Saphris drug label have been revised to include information about this risk and to inform healthcare professionals that Saphris should not be used in patients with a known hypersensitivity to the drug.
A search of the FDA's Adverse Event Reporting System (AERS) database identified 52 cases of Type I hypersensitivity reactions (allergic reactions) with Saphris use (see Data Summary below). Hypersensitivity reactions can be classified into four categories (Type I to Type IV). Signs and symptoms of Type I hypersensitivity reactions may include anaphylaxis (a life-threatening allergic reaction), angioedema (swelling of the deeper layers of the skin), low blood pressure, rapid heart rate, swollen tongue, difficulty breathing, wheezing, or rash. These signs and symptoms are consistent with the reactions reported in the 52 cases. Several cases reported multiple hypersensitivity reactions occurring at the same time, with some of these reactions occurring after the first dose of Saphris.
Healthcare professionals should be aware of the risk of hypersensitivity reactions with Saphris and counsel patients who are receiving the drug about how to recognize the signs and symptoms of a serious allergic reaction. Saphris should not be used in patients with a known hypersensitivity to the drug.
Patients should seek emergency medical attention immediately if they develop any signs and symptoms of a serious allergic reaction while taking Saphris.
Additional Information for Patients
- Serious allergic reactions have been reported in patients treated with Saphris.
- Patients should seek emergency medical attention immediately if they develop any signs and symptoms of a serious allergic reaction such as:
- Difficulty breathing
- Swelling of the face, tongue or throat
- Feeling lightheaded
- Serious side effects from the use of Saphris should be reported to the FDA MedWatch program, using the information in the "Contact Us" box at the bottom of this page.
- Type I hypersensitivity reactions, including anaphylaxis and angioedema, have been observed in patients treated with Saphris. In several cases, these reactions occurred after the first dose.
- The hypersensitivity reactions included: anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash.
- Saphris is contraindicated in patients with a known hypersensitivity to the product.
- Patients should be educated to recognize the signs and symptoms of a serious allergic reaction and advised to contact a healthcare professional immediately if they experience any of these symptoms while taking Saphris.
- Adverse events involving Saphris should be reported to the FDA MedWatch program using the information in the "Contact Us" box at the bottom of this page.
Saphris (asenapine maleate) was FDA-approved on August 13, 2009. A search of the AERS database from approval through September 7, 2010 identified 52 cases that reported Type I hypersensitivity reactions associated with Saphris use. Reported signs and symptoms included anaphylaxis, angioedema, hypotension, tachycardia, swollen tongue, dyspnea, wheezing, and rash. Some of the cases reported the occurrence of more than one hypersensitivity reaction following Saphris use. Eight cases reported hypersensitivity reactions after just one dose of Saphris. The reactions reported following one dose included possible angioedema, respiratory distress, and possible anaphylaxis.
Type I hypersensitivity reactions typically require a history of previous exposure to the drug. However, the absence of a known prior exposure does not exclude the reaction, because sensitization may have occurred to a cross-reactive compound in the past even if the patient showed no signs of allergy to the sensitizing product. To date, no specific drug has shown cross-reactivity with Saphris.
Of the 52 cases, 15 reported a resolution of symptoms following Saphris discontinuation, while two of these cases reported a reappearance of symptoms upon reintroduction of Saphris. Nineteen of the cases resulted in hospitalization or emergency room visits, and therapeutic interventions were reported in seven cases.
Although many of the cases have limited information, the findings from the cases are consistent with hypersensitivity reactions, including anaphylaxis, and support a temporal association between the onset of the reactions and Saphris use.
Facts about Saphris (asenapine maleate)
- In a class of medications called atypical antipsychotics.
- Used to treat symptoms of schizophrenia and bipolar disorder.
- From approval in August 2009 to June 2011, approximately 235,000 prescriptions were dispensed for Saphris and approximately 87,000 patients received a dispensed prescription for Saphris from U.S. outpatient retail pharmacies.1,2
- SDI, Vector One®: National (VONA). August 2009-June 2011. Data extracted August 2011.
- SDI, Vector One®: Total Patient Tracker (TPT). August 2009-June 2011. Data extracted August 2011.
Source : FDA (Sept 2011)
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Antipsychotic drugs: Class Labeling Change - Treatment During Pregnancy and Potential Risk to Newborns
including Haldol, FazaClo, Fanapt, Clozaril, Risperdal, Zyprexa, Seroquel, Abilify, Geodon, Invega, Loxitane, Moban, Navane, Orap, Saphris, Stelazine, Thorazine, Symbyax
AUDIENCE: Psychiatry, OBGYN
ISSUE: FDA notified healthcare professionals that the Pregnancy section of drug labels for the entire class of antipsychotic drugs has been updated. The new drug labels now contain more and consistent information about the potential risk for abnormal muscle movements (extrapyramidal signs or EPS) and withdrawal symptoms in newborns whose mothers were treated with these drugs during the third trimester of pregnancy.
The symptoms of EPS and withdrawal in newborns may include agitation, abnormally increased or decreased muscle tone, tremor, sleepiness, severe difficulty breathing, and difficulty in feeding. In some newborns, the symptoms subside within hours or days and do not require specific treatment; other newborns may require longer hospital stays.
BACKGROUND: Antipsychotic drugs are used to treat symptoms of psychiatric disorders such as schizophrenia and bipolar disorder.
RECOMMENDATION: Healthcare professionals should be aware of the effects of antipsychotic medications on newborns when the medications are used during pregnancy. Patients should not stop taking these medications if they become pregnant without talking to their healthcare professional, as abruptly stopping antipsychotic medications can cause significant complications for treatment.
Source : FDA
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Antipsychotic drugs could shrink patients' brains
Experts say findings should not dramatically change current prescription practices.
Evidence that prescription drugs shrink patients' brains would, one might think, suggest only one course of action: stop prescribing them. But the matter turns out to be much more complicated, according to research published today in Archives of General Psychiatry on the effects of antipsychotic drugs in people with schizophrenia1.
In the past 15 years, research has indicated that people with schizophrenia have smaller cerebral volumes than the general population, and that this reduction is particularly large in 'grey-matter' structures, which contain the cell bodies of neurons. For instance, one meta-analysis points to 5–7% reductions in the size of the amygdala, hippocampus and parahippocampus2, which are all involved in memory storage and retrieval.
But scientists have debated whether the decrease is caused by the disease alone, or whether powerful antipsychotic drugs also have a role. According to the latest findings, the more antipsychotics patients receive, the more likely they are to have a decreased amount of grey matter.
The research was led by Beng Choon Ho, a psychiatrist and neuroscientist at the University of Iowa in Iowa City. His team used magnetic resonance imaging (MRI) to scan the brains of 211 patients, administering on average 3 scans per patient over a 7.2-year period1. They found that treatment length and the type and dose of antipsychotic drugs taken were both relatively good predictors of total brain volume change. Use of antipsychotics explained 6.6% of the change in total brain volume and 1.7% of the change in total grey-matter volume.
The study developed from a previous work in which Ho's team analysed the contribution of a genetic variation to grey-matter volume reduction3. In the latest work, the researchers looked again at those results and added data from more patients. This time, they examined the contribution from the dose of antipsychotics prescribed. They found that the greatest reduction came in those who had been recently diagnosed — and so would have just started taking the medications. "We did not expect to see this," says Ho.
Ho says that the effect is "small but significant". He adds, "We have been looking at the data for five years. We've been very careful to get it right because of the potential implications."
Missing control The scale of the study is impressive, says Andreas Meyer-Lindenberg, a neuroscientist at the University of Heidelberg in Mannheim, Germany. "It's by far the largest sample studied longitudinally. And there was a great follow-up and retention rate," he says. Stefan Borgwardt, a neuropsychiatrist at the University of Basel, Switzerland, says that the study "will definitely have a great impact, not only on the field of schizophrenia research but also on clinical practice".
Animal studies support the link. David Lewis, a neuroscientist and psychiatrist at the University of Pittsburgh, Pennsylvania, found that healthy non-human primates, given doses of antipsychotics similar to those given to humans, showed brain volume reductions of around 10%, mostly attributable to loss of the glial cells that support and protect neurons4,5.
But Lewis, who has written an editorial to accompany Ho's study6, warns that his own, Ho's and other studies are "convergent but still circumstantial". It is impossible to distinguish the effect of the disease from that of the drug, he says, because "both are changing over time".
Ho acknowledges that his study is marred by the lack of a placebo control group — for ethical reasons, patients cannot be deprived of the medications they need — and the lack of 'within individual' studies in which the same patient either uses or does not uses the drugs. "It's not the ideal study design, but as good as we could ever get with something like this," says Ho.
Meyer-Lindenberg warns against over-interpreting MRI data, which can be affected by confounding factors including lifestyle, smoking and socioeconomic differences. "Although it does address them as far as possible statistically, this study cannot exclude them," he says. Meyer-Lindberg himself published a study last year showing that antipsychotics cause quickly reversible changes in brain volume that do not reflect permanent loss of neurons (see 'Antipsychotic deflates the brain')7.
Bigger and better? The idea that decreased brain volumes are necessarily bad is also controversial. Borgwardt says that small cerebral volumes are generally thought to lead to worse brain function, and some studies show that the greater the decrease, the worse the illness outcome. Antipsychotics have long been known to have side effects — notably uncontrolled tremors (parkinsonism) and restless leg syndrome (akathisia) — that might be explained by reduction in brain volume.
But decreasing brain volume could also be responsible for the beneficial effects of the drugs. Lewis points out that the reduction is greatest in patients who stay on the drugs the longest — meaning, presumably, that they are getting the best benefit and suffering relatively few side effects.
In the brains of adolescents, volume loss has been shown to reflect maturation through the elimination of superfluous synapses, says Meyer-Lindenberg.
Borgwardt has begun to scan the brains of people at high risk of developing schizophrenia and track the cerebral volume of those who go on to be treated8, a strategy that, on a larger scale, could help to clarify the controversy. An alternative route could be to study people with depression and bipolar disorder, says Lewis. Comparing changes in the brain volume of such patients who use antipsychotics with those that do not would help to tease out the relative contribution of the drugs.
In the meantime, Ho's study and others should strengthen doctors' commitments to use antipsychotic drugs sparingly, say all the researchers contacted by Nature. "We stated as clearly as possible that we are not advocating that people stop taking medications. A large body of evidence shows the drugs relieve symptoms and prevent relapse," says Ho. "But this will reinforce what I have always tried to do with my patients — work with them in finding the lowest effective dose."
- Ho, B.-C., Andreasen, N. C., Ziebell, S., Pierson, R. & Magnotta, V. Arch. Gen. Psychiatry 68, 128-137 (2011). | Article
- Wright, I. C. et al. Am. J. Psychiatry 157, 16-25 (2000). | ISI |
- Ho, B.-C., Andreasen, N. C., Dawson, J. D. & Wassink T. H. Am. J. Psychiatry 164, 1890-1899 (2007). | Article | ISI
- Dorph-Peterson, K.-A. et al. Neuropsychopharmacology 30, 1649-1661 (2005). | Article | ChemPort |
- Konopaske, G. T., et al. Biol. Psychiatry 63, 759-765 (2008). | Article | ISI | ChemPort |
- Lewis, D. A. Arch. Gen. Psychiatry 68, 126-127 (2011). | Article
- Tost, H. et al. Nature Neurosci. 13, 920-922 (2010).
- Borgwardt, S. J. et al. Biol. Psychiatry 61, 1148-1156 (2007). | Article | ISI
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Psychiatric Drugging of Infants and Toddlers in the US - Part I
April 19, 2010
By Evelyn Pringle
The United States has become the psychiatric drugging capital of the world for kids with children being medicated at a younger and younger age. Medicaid records in some states show infants less than a year old on drugs for mental disorders.
The use of powerful antipsychotics with privately insured children, aged 2 through 5 in the US, doubled between 1999 and 2007, according to a study of data on more than one million children with private health insurance in the January, 2010, "Journal of the American Academy of Child & Adolescent Psychiatry."
The number of children in this age group diagnosed with bipolar disorder also doubled over the last decade, Reuters reported.
Of antipsychotic-treated children in the 2007 study sample, the most common diagnoses were pervasive developmental disorder or mental retardation (28.2%), ADHD (23.7%), and disruptive behavior disorder (12.9%).
The study reported that fewer than half of drug treated children received a mental health assessment (40.8%), a psychotherapy visit (41.4%), or a visit with a psychiatrist (42.6%) during the year of antipsychotic use.
"Antipsychotics, which are being widely and irresponsibly prescribed for American children--mostly as chemical restraints--are shown to be causing irreparable harm," warned Vera Hassner Sharav, president of the Alliance for Human Research Protection, in a February 26, 2010 InfoMail.
"These drugs have measurable severe hazardous effects on vital biological systems, including: cardiovascular adverse effects that result in shortening lives; metabolic adverse effects that induce diabetes and the metabolic syndrome," she wrote. "Long-term use of antipsychotics has been shown to result in metabolic syndrome in 40% to 50% of patients."
The lead researcher on the study above, Columbia University psychiatry professor Mark Olfson, told Reuters that about 1.5% of all privately insured children between the ages of 2 and 5, or one in 70, received some type of psychiatric drug in 2007, be it an antipsychotic, a mood stabilizer, a stimulant or an antidepressant.
Psychiatric drugs bathe the brains of growing children with agents that threaten the normal development of the brain, according to Dr Peter Breggin, founder of the International Center for the Study of Psychiatry and Psychology (ICSPP), and author of about 20 books, including "Medication Madness."
The drugs themselves are causing severe disorders in millions of children in the US, he warns. "Substances like antidepressants, stimulants, mood stabilizers, and antipsychotic drugs cause severe, and potentially permanent, biochemical imbalances."
A number of presentations at the annual meeting of the American Psychiatric Association in May 2009, addressed the diagnosis of bipolar disorder, including one titled, "Pediatric Bipolar Disorder: A Critical Look at an American Phenomenon," at which Dr Peter Parry, a consultant child & adolescent psychiatrist, and senior lecturer at Flinders University in Australia, presented a survey on, "Australian and New Zealand's Child and Adolescent Psychiatrists' Views on Bipolar Disorder Prevalence and on Rates of Pediatric Bipolar Disorder in the USA."
Dr Parry and his colleagues conducted a survey of child and adolescent psychiatrists in Australia and New Zealand. Of the 199 psychiatrists who responded to the survey, 90.5% thought pediatric bipolar disorder was overdiagnosed in the US.
In an October 1, 2009 article titled, "Medicating Our Children," Dr Parry reports that since "the mid-1990s in the USA, some researchers have claimed that Paediatric Bipolar Disorder (PBD) frequently starts prior to puberty."
One of PBD's main proponents, Harvard University's Professor Joseph Biederman, stating onset "is squarely in the preschooler age group," he notes.
Parry explains that "PBD has been created by moving the diagnostic goalposts away from traditional concepts of bipolar disorder."
"In children," he says, "episodes were redefined to last hours instead of days or weeks and, instead of manic elation, severe anger in children sufficed as mania."
"Unlike diagnoses like ADHD or depression, or simply accepting a child has serious emotional and behavioural problems in reaction to various stressors, PBD implies a lifelong severe mental illness requiring of strong psychiatric medication," Parry warns.
"In the USA," he says, "the public is furthermore exposed to direct pharmaceutical advertising that can feed the natural desire parents of distressed and aggressive children have for a quick solution by suggesting a simple medication fix."
"The medicating of America's children has become intensely controversial, highlighted by the tragic case of Rebecca Riley, a four-year-old Boston girl diagnosed at 28 months old with ADHD and PBD," he points out.
On April 7, 2009, the author of the book, "Shyness: How Normal Behavior Became a Sickness," Christopher Lane, featured an interview on his Psychology Today blog, "Side Effects," with journalist, Philip Dawdy, the creator of the popular website, Furious Seasons, and discussed the rising number of children being diagnosed with bipolar disorder.
"As for bipolar disorder in kids (meaning pre-teens and younger), it's simply not an issue in the rest of the world," Dawdy told Lane. "The bipolar child is a purely American phenomenon."
"The pharma companies and the Harvard crew worked hand-in-hand to bring America a generation of ADHD kids and bipolar children, and their profound influence can be seen in the millions of children and teens who now carry lifetime diagnoses and take gobs of psychotropic drugs each day, often to their detriment," he advised.
Lane asked for Dawdy's opinion on a recent report in the St Petersburg Times that found 23 infants less than one-year-old had been prescribed antipsychotics in Florida in 2007, as well as the drug overdose death of 4-year-old Rebecca Riley in Massachusetts. "How is it possible for psychiatrists to continue prescribing to infants in such numbers without more oversight?" Lane asked.
"What's gone on with antipsychotics prescribed to infants and toddlers is simply inexplicable to me," Dawdy said. "The drugs are known to cause huge problems in adults, so why the heck would a doctor give them to little kids, especially infants? It boggles my small mind."
"I'm no fan of bans or restrictions," he told Lane, "but this does strike me as a situation where there needs to be a serious rethinking of what we are doing--and maybe there should be a ban on the use of these drugs in kids under, say, 6 years of age."
An October 2007 report by the University of South Florida found the most common diagnosis for antipsychotic use with children in Florida's Medicaid program, between July and December 2005, was ADHD. Roughly 54%, or 1,372 cases, involved prescriptions for children five and under and the total number of antipsychotic users in this young age group was 2,549, with all disorders combined, according to the report.
Increased Prescribing to Poor Children
Federally funded research published online in December, 2009, revealed that children covered by Medicaid were prescribed antipsychotics at a rate four time higher than children with private insurance. The data showed that more than 4% of children in Medicaid fee-for-service programs received antipsychotics, compared to less than 1% of privately insured youth. The study found Medicaid kids were more likely to receive antipsychotics for unapproved uses such as ADHD and conduct disorders than privately insured children.
The researchers examined records for children in seven states for the years 2001 and 2004, chosen as representative of the US Medicaid population. But more recent data through 2007 indicates that the disparity has remained, said Stephen Crystal, a Rutgers professor who led the study, according to the December 11, 2009, New York Times.
Antipsychotics were the top selling class of drugs in both 2008 and 2009. With sales of $14.6 billion in 2009, they brought in more than the $13.6 billion earned by both heart burn and cholesterol medications. Antidepressants ranked fourth with sales of $9.9 billion, according to data by IMS Health. In 2008, the drug makers took in $11.3 billion from antiseizure drugs and $4.8 billion from ADHD drugs.
In a new book titled, "Anatomy of an Epidemic: Magic Bullets, Psychiatric Drugs, and the Astonishing Rise of Mental Illness in America," Robert Whitaker reports that the number of children on government disability rolls due to severe mental illness has increased more than 35-fold since 1987.
The book explores the question of whether the epidemic rise in people disabled by mental illness, among all age groups in the US over the past 20 years, could have been fueled by a drug-based paradigm of care.
It also explores what is happening to children over the long-term who are placed on psychiatric drugs. "Once again, science tells a very clear story, and, as you might imagine, it is one that -- when you think of the millions of children so affected -- makes you want to weep," Whitaker stated in a March 26, 2010, notice for the book's release on the Beyond Meds Website.
(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)
(This report is one of a series of articles focused on the rising rates of psychiatric drugging in the US and is sponsored by the International Center for the Study of Psychiatry and Psychology)
LINK TO SOURCE
Psychiatric Drugging of Infants and Toddlers in the US - Part II
April 19, 2010
By Evelyn Pringle
Of all the harmful actions of modern psychiatry, "the mass diagnosing and drugging of children is the most appalling with the most serious consequences for the future of individual lives and for society," warns the world-renowned expert, Dr Peter Breggin, often referred to as the "Conscience of Psychiatry."
Dr Nathaniel Lehrman, author of the book, "Coming Off Psychiatric Drugs," believes that giving infants and toddlers "powerful, brain-effecting psychiatric medication is close to criminal activity."
"Giving them these drugs," he says, "has no rationale, and ignores the basic fact that youngsters are very sensitive to their environments, both social and chemical, with the juvenile brain easily damaged by the latter."
During an interview on ABC Radio National in August 2007, Dr David Healy, the noted British pharmacology expert, and author of the book, "Mania: A Short History of Bipolar Disorder," told reporter Jane Shields: "Just to give you a feel for how crazy things have actually got recently, it would appear that clinicians in the US are happy to look at the ultrasounds of children in the womb, and based on the fact that they appear to be more overactive at times, and then possibly less active later, they're prepared to actually consider the possibility that these children could be bipolar."
On April 9, 2009, Christopher Lane, author of the book, "Shyness: How Normal Behavior Became a Sickness," published an interview on his Psychology Today blog with Dr Healy. In the interview, Healy explained the history behind the drastic rise in the sale of anticonvulsants and antipsychotics as "mood stabilizers," and the diagnosis of bipolar disorder.
"The key event in the mid-1990s that led to the change in perspective was the marketing of Depakote by Abbott as a mood stabilizer," Healy tells Lane, and further explains:
"Mood stabilization didn't exist before the mid-1990s. It can't be found in any of the earlier reference books and journals. Since then, however, we now have sections for mood stabilizers in all the books on psychotropic drugs, and over a hundred articles per year featuring mood stabilization in their titles.
"In the same way, Abbott and other companies such as Lilly marketing Zyprexa for bipolar disorder have re-engineered manic-depressive illness. While the term bipolar disorder was there since 1980, manic-depression was the term that was still more commonly used until the mid-1990s when it vanishes and is replaced by bipolar disorder. Nowadays, over 500 articles per year feature bipolar disorder in their titles."
"As of 2008, upwards of a million children in the United States--in many cases preschoolers--are on "mood-stabilizers" for bipolar disorder, even though the condition remains unrecognized in the rest of the world," Healy points out.
"But there is no evidence that the drugs stabilize moods," he says. "In fact, it is not even clear that it makes sense to talk about a mood center in the brain."
"A further piece of mythology aimed at keeping people on the drugs," he reports, "is that these are supposedly neuroprotective--but there's no evidence that this is the case and in fact these drugs can lead to brain damage."
Healy says the FDA's decision to add a black-box warning about suicide to SSRIs likely had little to do with the switch to prescribing antipsychotics as safer for children. What "was quite striking was how quickly companies were able to use the views of the few bipolar-ologists who argued that when children become suicidal on antidepressants it's not the fault of the drug," he points out.
"The problem, they said, stems from a mistaken diagnosis and if we could just get the diagnosis right and put the child on mood stabilizers then there wouldn't be a problem," he explains.
"There is no evidence for this viewpoint, but it was interesting to see how company support could put wind in the sails of such a perspective," he says.
Because having just one label was very limiting, Healy says, child psychiatry "needed another disorder--and for this reason bipolar disorder was welcome."
He reports that the same thing is happening to children labeled with ADHD. "Not all children find stimulants suitable," he advises, "and just as with the SSRIs and bipolar disorder it has become very convenient to say that the stimulants weren't causing the problem the child was experiencing; the child in fact had a different disorder and if we could just get the diagnosis correct, then everything else would fall into place."
A report titled, "Adverse Events Associated with Drug Treatment of ADHD: Review of Postmarketing Safety Data," presented at the FDA's March 22, 2006, Pediatric Advisory Committee meeting bears witness to Healy's explanation by stating in part: "The most important finding of this review is that signs and symptoms of psychosis or mania, particularly hallucinations, can occur in some patients with no identifiable risk factors, at usual doses of any of the drugs currently used to treat ADHD."
Between January 2000, and June 30, 2005, the FDA identified nearly 1,000 cases of psychosis or mania linked to the drugs in its own database and those from the drug makers themselves.
The antipsychotics are just as dangerous as the SSRI antidepressants, Healy says. "Long before the antidepressants were linked with akathisia, the antipsychotics were universally recognized as causing this problem," he explains in the Lane interview. "It was also universally accepted that the akathisia they induce risked precipitating the patient into suicidality or violence."
"They also cause a physical dependence," Healy states. "Zyprexa is among the drugs most likely to cause people to become physically dependent on it."
"In addition," he points out, "these drugs are known to cause a range of neurological syndromes, diabetes, cardiovascular problems, and other problems."
"It's hard to understand how blind clinicians can get to problems like these, especially in youngsters who grow obese and become diabetic right before their eyes," Healy tells Lane.
As for what he calls the "medicalization of childhood," in the radio interview, Healy points out that "children always have been unhappy, they always have been nervous, but that's actually part and parcel of being a child."
"You have to go through these things," he said. "This is how we learn to cope with the problems of life."
Children can best be helped in the safest way, he says, "if they're just seen and if they actually have the opportunity to talk about their problems, and if they get basic and sensible input about how to perhaps help them cope with these problems."
Healy said it's important to remember that severe mental illness is rare in children and that most children with a mental health problem do not need medication. Children are being picked up and put on pills "who really don't need to be on these pills and who are going to be injured by them," he warned.
"I think possibly 10 to 15 years up the road," he told Shields, "we're going to be looking at a generation of children who will have been seriously injured by the treatments that they appear ever-increasingly likely to be put on now."
But the administration of multiple drugs at once complicates the situation so that it may be impossible to determine which drugs are most responsible for the adverse reactions children experience, according to Dr Breggin.
"Because so many doctors and so many drug companies will share the blame for mistreating these children, they will be unable to seek redress against individual perpetrators through the courts when they grow up," he explains.
(Evelyn Pringle is an investigative journalist focused on exposing corruption in government and corporate America)
(This report is one of a series of articles focused on the rising rates of psychiatric drugging in the US and is sponsored by the International Center for the Study of Psychiatry and Psychology)
Author's Bio: Evelyn Pringle is an investigative journalist and researcher focused on exposing corruption in government and corporate America.
LINK TO SOURCE
Drugged Warriors: Sharp Rise in U. S. Military Psychiatric Drug Use and Suicides
By Bruce E. Levine
One in six service members is now taking at least one psychiatric drug, according to the Navy Times, with many soldiers taking "drug cocktail" combinations.
One in six service members is now taking at least one psychiatric drug, according to the Navy Times, with many soldiers taking "drug cocktail" combinations. Soldiers and military healthcare providers told the Military Times that psychiatric drugs are "being prescribed, consumed, shared and traded in combat zones."
The Navy Times reporters Andrew Tilghman and Brendan McGarry also noted that there has been a large increase in military suicides. From 2001 to 2009, the Army's official suicide rate increased from 9 per 100,000 soldiers to 23 per 100,000. During that same period, the Marine Corps suicide rate increased from 16.7 per 100,000 soldiers to 24 per 100,000.
A Military Times investigation of records obtained from the Defense Logistics Agency revealed that the DLA spent $1.1 billion on psychiatric and pain medications from 2001 to 2009, and that there was a 76 percent increase in psychiatric drugs. DLA records show:
• Antipsychotic drugs spiked most dramatically -- orders jumping by more than 200 percent.
• Orders for anti-anxiety drugs and sleeping pills such as Valium and Ambien increased 170 percent.
• Orders for antiepileptic drugs (also known as anticonvulsants) such as Depakote, routinely used as psychiatric medications, increased 70 percent.
• Antidepressants showed a 40 percent increase.
Investigators found that antipsychotic and antiepileptic drugs, approved for bipolar disorder and schizophrenia, are now commonly used to treat post-traumatic stress disorder (PTSD) symptoms such as nightmares, nervousness, and anger outbursts. The use of antipsychotic drugs for non-psychotic conditions such as PTSD is called "off-label" prescribing. The general public is also subject to off-label prescribing, which is considered legal.
In February 2010, Brig. Gen. Loree Sutton, the Army's highest-ranking psychiatrist, reported to Congress that 17 percent of the active-duty force and as much as 6 percent of deployed troops are on antidepressants.
Just how insane is it to prescribe psychiatric drugs to deployed troops? The Navy Times piece tells us about Spc. Mike Kern who enlisted in 2006 and spent a year deployed in 2008 with the 4th Infantry Division as an armor crewman, running patrols out of southwest Baghdad. Suffering from nervousness, sleep problems and depression, Kern was given the antidepressant Paxil. A few days later, while patrolling the streets in the gunner's turret of a Humvee, Kern said he began having serious thoughts of suicide for the first time in his life. Kern said:
I had three weapons: a pistol, my rifle and a machine gun. I started to think, 'I could just do this and then it's over.' That's where my brain was: 'I can just put this gun right here and pull the trigger and I'm done. All my problems will be gone.'
The Food and Drug Administration now requires that antidepressants must be labeled with a warning about increased risk of "suicidality" (which includes suicidal thoughts as well as attempts). This "black-box" warning is a result of research concluding that antidepressants double the risk of suicidality in depressed children, teenagers, and young adults as compared to equally depressed young people who are not taking antidepressants. Given meta-analyses (that I cite in Surviving America's Depression Epidemic ) which show that antidepressants are often no more effective than placebos, the potential risks of giving these drugs to soldiers in a war zone clearly outweigh any potential benefits.
Many of these psychiatric drugs prescribed to service members can also impair motor skills, reduce reaction times, and generally make one more sluggish -- or what soldiers call "stupid." So in addition to antidepressants potentially resulting in increased suicidality, other psychiatric drugs can make deployed soldiers feel less capable of protecting themselves and their buddies. While being slow or "stupid" is not going to cost a general or politician his or her life, it can cost soldiers the vigilance necessary to keep themselves and their fellow soldiers alive.
Bruce E. Levine is a clinical psychologist and his latest book is Surviving America's Depression Epidemic: How to Find Morale, Energy, and Community in a World Gone Crazy (Chelsea Green Publishing, 2007). His Web site is www.brucelevine.net
SOURCE : LALEVA.ORG
LINK TO SOURCE
Atypical Antipsychotics Increase Cardiometabolic Risk in Children
By Kenneth J. Bender, PharmD, MA |
A study of the adverse effects of 4 second-generation antipsychotics in children and adolescents documented substantial weight gain during 11 weeks of treatment with each agent, with the increased abdominal fat that has been associated with development of metabolic syndrome in adults. Metabolic abnormalities emerged with 3 of the 4 agents, differing in type and severity with the agent and, in some cases, with the dose.
In this analysis from the Second-Generation Antipsychotic Treatment Indications, Effectiveness and Tolerability in Youth (SATIETY) study, 10% to 36% of 272 patients between 4 and 19 years of age (mean, 13.9 years) who had not previously received antipsychotic medication became overweight or obese. There was minimal weight change in a comparison group of patients who had refused the agent, or who discontinued it within 4 weeks.1
Christoph Correll, MD, Zucker Hillside Hospital, Glen Oaks, NY, and colleagues conducted this observational cohort study as the largest to date of adverse experiences with second-generation antipsychotics in antipsychotic treatment–naive children. The researchers noted that there has been increasing use of these agents in younger patients for psychotic and bipolar disorders as well as nonpsychotic disorders, despite little available age-specific data on adverse reactions.
“Cardiometabolic adverse effects, such as age-inappropriate weight gain, obesity, hypertension, and lipid and glucose abnormalities are particularly problematic during development,” Correll and colleagues indicate, “because they predict adult obesity, the metabolic syndrome, cardiovascular morbidity, and malignancy.”
In an editorial accompanying the study in JAMA, Christopher Varley, MD, and Jon McClellan, MD, Seattle Children’s Hospital, added: “The development of clinically significant hyperlipidemias and insulin resistance after only 12 weeks of treatment portends severe long-term metabolic and cardiovascular sequelae. These results challenge the widespread use of atypical antipsychotic medications in youth.”2
The SATIETY study monitored treatment with aripiprazole (Abilify), olanzapine (Zyprexa), quetiapine (Seroquel), or risperidone (Risperdal), selected and dosed by clinicians to treat psychotic, mood, or aggressive spectrum disorders in this young cohort. After approximately 11 weeks, there was a mean weight gain of 8.5 kg with olanzapine, 6.1 kg with quetiapine, 5.3 kg with risperidone, and 4.4 kg with aripiprazole.
Adverse changes from baseline in levels of total cholesterol, triglycerides, and non–high-density lipoprotein (HDL) cholesterol and also in the ratio of triglycerides to HDL cholesterol were statistically significant with olanzapine and quetiapine. Risperidone was associated with significantly increased triglyceride levels. Olanzapine in dosages greater than 10 mg/d and risperidone in doses greater than 1.5 mg/d were associated with significantly greater increases in total cholesterol and non-HDL cholesterol. There were no metabolic abnormalities or significant changes from baseline with aripiprazole treatment.
Considering atypical antipsychotics for adolescents
This study was published in October, as the FDA continued to consider recommendations from the June meeting of the Psychopharmacologic Drugs Advisory Committee to approve olanzapine, quetiapine, and ziprasidone (Geodon) for indications in children and adolescents, for which—as of this writing—only risperidone and aripiprazole are approved. Although the advisory panel voted to recommend approval of the drugs for treating young patients, a report in JAMA notes that the votes were split over issues of safety.3
Members of the advisory committee had indicated concern, according to the JAMA report, that approval for specific conditions such as bipolar disorder in children would encourage off-label use in this population, or use for approved indications but without rigorous application of diagnostic criteria. Agency representatives at the meeting agreed with the need for approved labeling to narrowly define indications based on DSM-IV criteria.
Correll and colleagues also express concern and suggest that the cardiometabolic risk of these agents in children should be balanced “through careful assessment of the indication for their use, consideration of lower-risk alternatives, and proactive adverse effect monitoring and management.”
1. Correll CU, Manu P, Olshanskiy V, et al. Cardiometabolic risk of second-generation antipsychotic medications during first-time use in children and adolescents. JAMA. 2009;302:1765-1773.
2. Varley CK, McClellan J. Implications of marked weight gain associated with atypical antipsychotic medications in children and adolescents. JAMA. 2009;302:1811-1812.
3. Kuehn BM. FDA panel OKs 3 antipsychotic drugs for pediatric use, cautions against overuse. JAMA. 2009;302:833-834.
Psychiatric Times December 2009 (Link to Article)