Hallucinations, Other Psychotic Symptoms in Children Linked to Use of ADHD Medications
Caroline Cassels
January 28, 2009 — Physicians, patients, and parents should be aware that psychotic symptoms or mania arising in children treated with standard, approved drugs for attention-deficit/hyperactivity disorder (ADHD) may constitute an adverse drug reaction and not necessarily an additional psychiatric disorder, Food and Drug Administration (FDA) research suggests.
An analysis of 49 randomized controlled clinical trials as well as postmarketing surveillance data on ADHD drugs shows some children, including those with no identifiable risk factors, developed drug-related symptoms of psychosis or mania, including hallucinations, at usual doses.
"These drugs seem capable of producing this type of adverse psychiatric reaction. If a child receiving 1 of these medications were to develop such symptoms, strong consideration should be given to the idea that it could be a reaction to the medication rather than a separate psychiatric disorder in and of itself," principal investigator Andrew D. Mosholder, MD, from the US FDA, in Silver Spring, Maryland, told Medscape Psychiatry.
The analysis revealed that a total of 11 psychosis/mania adverse events occurred during 743 person-years of double-blind treatment of ADHD medications. Although the number of cases was small, the investigators point out there were no such events reported in 420 person-years of placebo exposure in the same trials. Dr. Mosholder added that such adverse events can occur across the board with all currently approved ADHD medications.
The study is published in the February issue of Pediatrics.
Tip of the Iceberg?
Further, investigators say that the reported incidence in the analysis may represent only the tip of the iceberg. Clinical-trial subjects undergo careful selection to ensure high likelihood of treatment success and a low probability of intolerance to these medications — a situation that does not generally reflect everyday clinical practice. Therefore, they point out, the findings likely underestimate the incidence of such adverse effects in the general population.
"One of the things we would like to call attention to is that such reactions are probably not rare. The other point is that these drugs are increasingly being used in younger children who, if they do experience hallucinations, may have difficulty understanding what's happening to them or describing it to an adult. So, if a child says 'I don't want to go to bed because it is covered with ants,' there should be consideration given that this may be an adverse drug reaction," study coauthor Kate Gelperin, MD, also from the FDA, told Medscape Psychiatry.
A 2003 survey conducted by the US Centers for Disease Control and Prevention estimated that 7.8% of children in the United States aged 14 to 17 years, or more than 4 million, have received a diagnosis of ADHD. Of these individuals, 4.3% were taking medication for the disorder.
According to Dr. Mosholder, the current analysis was prompted by a 2005 review examining postmarketing surveillance data of 1 of the methylphenidate products, which turned up reports of adverse psychiatric events in children.
Based on these reports, the FDA investigated whether such events were also associated with other ADHD agents used in pediatric populations. In March 2006, the investigators presented the current findings to an FDA pediatric advisory committee.
Subsequently, he said, these findings prompted changes to medication labeling and medication guides for ADHD products. However, he added, the current paper marks the first time the findings have been published in the peer-reviewed medical literature.
Half of Cases in Young Children
The study was 2-pronged and examined data from 49 placebo-controlled clinical trials of various ADHD agents in pediatric development programs for the products as well as postmarketing spontaneous reports of psychosis or mania gleaned from the FDA Adverse Event Reporting System (AERS).
The drugs included in the study included 8 agents that are either approved or proposed for the treatment of ADHD. These included Adderall XR extended-release tablets (amphetamine/dextroamphetamine, Shire US) , Focalin XR extended-release capsules (dexmethylphenidate, Novartis Pharmaceuticals), Concerta extended-release tablets (methylphenidate, ALZA Corp), Metadate CD extended-release capsules (methylphenidate, Celltech Pharmaceuticals), Ritalin LA extended-release capsules (methylphenidate, Novartis Pharmaceuticals), Strattera (atomoxetine, Eli Lilly), Daytrana transdermal system (methylphenidate, Shire US), and Provigil (modafinil, Cephalon), which is not approved for the treatment of ADHD.
Analysis of the data from the clinical trial revealed psychosis/mania events occurred during double-blind treatment with every compound except Adderall XR, although the researchers note there were psychosis/mania events reported with open-label Adderall XR treatment. The rate per 100-person years in the pooled active-drug group was 1.48. No such adverse events were reported in patients in the placebo-treatment groups.
Overall, the postmarketing findings revealed a total of 865 unique postmarketing case reports describing signs and/or symptoms of psychosis or mania. The majority of these were pediatric cases, with nearly half reported in children aged 10 years or younger.
No Identifiable Risk Factors
Resolution of symptoms after stopping the medication was reported in 25% to 59%, depending on the drug. Interestingly, no risk factors were identified that could account for the majority of reports of psychosis- or mania-related events.
"It was surprising to us is that in the postmarketing spontaneous reports we were not able to identify a clear risk factor that predicted the occurrence of the hallucinations or other psychotic events. Going into this analysis, I thought that we would have found more situations where there was a very high dose of the drug or overdose or drug-abuse situation or other psychiatric illness, but this was not the case," said Dr. Gelperin.
It is important, say the investigators, that clinicians, patients, and parents, particularly those with very young children, are aware of the possibility of such adverse reactions.
Prescribers need to sit down with the patient and/or the parents if the patient is a young child and let them know what the safety profile of the ADHD medication is before starting treatment, said Dr. Gelperin.
Second, if a hallucination or other type of adverse psychiatric event does occur, as a first step the drug should be stopped or the dose reduced before any other medication is added or diagnosis made.
"If symptoms of psychosis or mania are overlooked as a drug reaction, the worst-case scenario is that the child is given an additional new diagnosis and an additional new medication, which would be very unfortunate," said Dr. Gelperin.
The authors report no conflicts of interest.
Pediatrics. 2009;123:611-616. Abstract
Wednesday, January 28, 2009
Mercury in High-Fructose Corn Syrup?
Mercury in High-Fructose Corn Syrup?
Miranda Hitti
January 27, 2009 — Some foods and drinks rich in high-fructose corn syrup may contain detectable levels of mercury, a new report shows.
The report, published on the web site of the Minneapolis-based nonprofit Institute for Agriculture and Trade Policy (IATP), shows detectable levels of mercury in 17 out of 55 tested products rich in high-fructose corn syrup.
But the researchers aren't telling people to avoid those products or other items containing high-fructose corn syrup, and they aren't sure what form of mercury those products contained.
The Corn Refiners Association stands by high-fructose corn syrup, calling it "safe."
Mercury and High-Fructose Corn Syrup
The new report comes from researchers including David Wallinga, MD, director of the IATP's food and health program. They bought 55 products that list high-fructose corn syrup first or second on their list of ingredients, which means high-fructose corn syrup was a leading ingredient in those products.
Wallinga's team sent samples of those products to a commercial lab, which checked the levels of total mercury in each sample.
"Overall, we found detectable mercury in 17 of 55 samples, or around 31%," write Wallinga and colleagues.
Here is the list of those products:
Quaker Oatmeal to Go bars
Jack Daniel's Barbecue Sauce
Hershey's Chocolate Syrup
Kraft Original Barbecue Sauce
Nutri-Grain Strawberry Cereal Bars
Manwich Gold Sloppy Joe
Market Pantry Grape Jelly
Smucker's Strawberry Jelly
Pop-Tarts Frosted Blueberry
Hunt's Tomato Ketchup
Wish-Bone Western Sweet & Smooth Dressing
Coca-Cola Classic: no mercury found on a second test
Yoplait Strawberry Yogurt
Minute Maid Berry Punch
Yoo-hoo Chocolate Drink
Nesquik Chocolate Milk
Kemps Fat Free Chocolate Milk
Wallinga and colleagues caution that their list was "just a snapshot in time; we only tested one sample of each product. That clearly is not sufficient grounds to give definitive advice to consumers."
Mercury exposure at high levels can harm the brain, heart, kidneys, lungs, and immune system. A form of mercury called methylmercury is particularly risky to a baby's developing brain and nervous system, according to background information from the Environmental Protection Agency (EPA).
Wallinga points out that the lab only tested for total mercury levels, not methylmercury or other types of mercury. He also notes that the EPA has a "reference dose," or upper limit, for methylmercury intake but not for other forms of mercury.
Where Did the Mercury Come From?
Wallinga's report doesn't prove that the mercury in the tested products came from high-fructose corn syrup, but "I'm hard pressed to say where else it would come from," Wallinga tells WebMD.
Wallinga explains that mercury can be used to make caustic soda, which is one of the products used to make high-fructose corn syrup. That's outdated technology; mercury isn't needed to make caustic soda, notes Audrae Erickson, president of the Corn Refiners Association, in a statement emailed to WebMD.
Erickson didn't comment specifically on Wallinga's study. Instead, her statement focuses on a new study published online in Environmental Health, which shows mercury in some samples of commercial high-fructose corn syrup tested in 2005.
"This study appears to be based on outdated information of dubious significance," Erickson states. "Our industry has used mercury-free versions of the two re-agents mentioned in the study, hydrochloric acid and caustic soda, for several years."
Wallinga agrees about the technological shift away from mercury. "If you just look within the confines of the U.S., yes, about 90% of production now is not using mercury," says Wallinga. "The problem is that we don't actually know where our companies are buying their high-fructose corn syrup from ... it's a global industry."
"For me, the take-home message is really that this is a totally avoidable, unnecessary exposure to mercury," says Wallinga. "We've got a safer, more efficient technology for making these chemicals that are part of the ingredients used to manufacture high-fructose corn syrup."
Mercury's Form Unknown
Like Wallinga's report, the study published in Environmental Health doesn't specify the form of mercury present in the high-fructose corn syrup.
"I would imagine that a good majority of the mercury that is detected would have been in the form of elemental mercury," not methylmercury, toxicologist Carl Winter, PhD, tells WebMD. Winter, who directs the FoodSafe Program at the University of California, Davis, says that methylmercury is "by far the most toxic form of mercury" because methylmercury is better absorbed by the body than other forms of mercury.
"We have a principle in toxicology, which is the dose makes the poison," says Winter. "It's the amount of a chemical, not its presence or absence, that determines the potential for harm, and frankly, I don't see based on their findings that they've made much of a case that this is something that consumers need to worry about." Besides his academic work, Winter is a volunteer spokesman for the Institute of Food Technologists, a nonprofit scientific society that includes food science and technology professionals in industry, academia, and government. Winter says his work has never been funded by food or chemical industries.
Companies Respond
WebMD contacted the makers of all 17 products that tested positive for mercury in Wallinga's report.
ConAgra Foods, which makes Manwich Bold Sloppy Joe and Hunt's Tomato Ketchup, is "absolutely confident in the safety of our products," ConAgra Foods spokeswoman Stephanie Childs tells WebMD.
Childs notes that "the levels of mercury reported in our ketchup are well below the EPA's safe exposure level. In fact, we estimate that you'd have to eat more than 100 pounds of ketchup per day to even come anywhere near the EPA's safe exposure level in terms of mercury.
A spokeswoman for Kraft Foods, Adrienne Dimopoulos, tells WebMD that Kraft has not had time to review the study's findings. However, "Kraft Foods' highest priority is the safety and quality of our products and the safety of our consumers. All of the ingredients we use are approved and deemed safe for food use by regulatory agencies, including the US FDA."
Amy Reilly, a spokeswoman for Target, which makes Market Pantry Grape Jelly, tells WebMD that Target is carefully evaluating the information and that "Target looks to the Food and Drug Administration to provide guidance on the safety of food additives and ingredients."
An FDA spokesperson wasn't immediately available to comment on Wallinga's report or the study published in Environmental Health.
SOURCES:
Dufault, R. Environmental Health, Jan. 26, 2009; online edition.
Wallinga, D. "Not So Sweet: Missing Mercury and High Fructose Corn Syrup."
David Wallinga, MD, director, Food and Health Program, Institute for Agriculture and Trade Policy.
Statement from Audrae Erickson, president, Corn Refiners Association.
Carl Winter, PhD, director, FoodSafe Program and Extension Food Toxicologist, department of food science and technology, University of California, Davis.
Adrienne Dimopoulos, spokeswoman, Kraft Foods.
Amy Reilly, spokeswoman, Target.
Miranda Hitti
January 27, 2009 — Some foods and drinks rich in high-fructose corn syrup may contain detectable levels of mercury, a new report shows.
The report, published on the web site of the Minneapolis-based nonprofit Institute for Agriculture and Trade Policy (IATP), shows detectable levels of mercury in 17 out of 55 tested products rich in high-fructose corn syrup.
But the researchers aren't telling people to avoid those products or other items containing high-fructose corn syrup, and they aren't sure what form of mercury those products contained.
The Corn Refiners Association stands by high-fructose corn syrup, calling it "safe."
Mercury and High-Fructose Corn Syrup
The new report comes from researchers including David Wallinga, MD, director of the IATP's food and health program. They bought 55 products that list high-fructose corn syrup first or second on their list of ingredients, which means high-fructose corn syrup was a leading ingredient in those products.
Wallinga's team sent samples of those products to a commercial lab, which checked the levels of total mercury in each sample.
"Overall, we found detectable mercury in 17 of 55 samples, or around 31%," write Wallinga and colleagues.
Here is the list of those products:
Quaker Oatmeal to Go bars
Jack Daniel's Barbecue Sauce
Hershey's Chocolate Syrup
Kraft Original Barbecue Sauce
Nutri-Grain Strawberry Cereal Bars
Manwich Gold Sloppy Joe
Market Pantry Grape Jelly
Smucker's Strawberry Jelly
Pop-Tarts Frosted Blueberry
Hunt's Tomato Ketchup
Wish-Bone Western Sweet & Smooth Dressing
Coca-Cola Classic: no mercury found on a second test
Yoplait Strawberry Yogurt
Minute Maid Berry Punch
Yoo-hoo Chocolate Drink
Nesquik Chocolate Milk
Kemps Fat Free Chocolate Milk
Wallinga and colleagues caution that their list was "just a snapshot in time; we only tested one sample of each product. That clearly is not sufficient grounds to give definitive advice to consumers."
Mercury exposure at high levels can harm the brain, heart, kidneys, lungs, and immune system. A form of mercury called methylmercury is particularly risky to a baby's developing brain and nervous system, according to background information from the Environmental Protection Agency (EPA).
Wallinga points out that the lab only tested for total mercury levels, not methylmercury or other types of mercury. He also notes that the EPA has a "reference dose," or upper limit, for methylmercury intake but not for other forms of mercury.
Where Did the Mercury Come From?
Wallinga's report doesn't prove that the mercury in the tested products came from high-fructose corn syrup, but "I'm hard pressed to say where else it would come from," Wallinga tells WebMD.
Wallinga explains that mercury can be used to make caustic soda, which is one of the products used to make high-fructose corn syrup. That's outdated technology; mercury isn't needed to make caustic soda, notes Audrae Erickson, president of the Corn Refiners Association, in a statement emailed to WebMD.
Erickson didn't comment specifically on Wallinga's study. Instead, her statement focuses on a new study published online in Environmental Health, which shows mercury in some samples of commercial high-fructose corn syrup tested in 2005.
"This study appears to be based on outdated information of dubious significance," Erickson states. "Our industry has used mercury-free versions of the two re-agents mentioned in the study, hydrochloric acid and caustic soda, for several years."
Wallinga agrees about the technological shift away from mercury. "If you just look within the confines of the U.S., yes, about 90% of production now is not using mercury," says Wallinga. "The problem is that we don't actually know where our companies are buying their high-fructose corn syrup from ... it's a global industry."
"For me, the take-home message is really that this is a totally avoidable, unnecessary exposure to mercury," says Wallinga. "We've got a safer, more efficient technology for making these chemicals that are part of the ingredients used to manufacture high-fructose corn syrup."
Mercury's Form Unknown
Like Wallinga's report, the study published in Environmental Health doesn't specify the form of mercury present in the high-fructose corn syrup.
"I would imagine that a good majority of the mercury that is detected would have been in the form of elemental mercury," not methylmercury, toxicologist Carl Winter, PhD, tells WebMD. Winter, who directs the FoodSafe Program at the University of California, Davis, says that methylmercury is "by far the most toxic form of mercury" because methylmercury is better absorbed by the body than other forms of mercury.
"We have a principle in toxicology, which is the dose makes the poison," says Winter. "It's the amount of a chemical, not its presence or absence, that determines the potential for harm, and frankly, I don't see based on their findings that they've made much of a case that this is something that consumers need to worry about." Besides his academic work, Winter is a volunteer spokesman for the Institute of Food Technologists, a nonprofit scientific society that includes food science and technology professionals in industry, academia, and government. Winter says his work has never been funded by food or chemical industries.
Companies Respond
WebMD contacted the makers of all 17 products that tested positive for mercury in Wallinga's report.
ConAgra Foods, which makes Manwich Bold Sloppy Joe and Hunt's Tomato Ketchup, is "absolutely confident in the safety of our products," ConAgra Foods spokeswoman Stephanie Childs tells WebMD.
Childs notes that "the levels of mercury reported in our ketchup are well below the EPA's safe exposure level. In fact, we estimate that you'd have to eat more than 100 pounds of ketchup per day to even come anywhere near the EPA's safe exposure level in terms of mercury.
A spokeswoman for Kraft Foods, Adrienne Dimopoulos, tells WebMD that Kraft has not had time to review the study's findings. However, "Kraft Foods' highest priority is the safety and quality of our products and the safety of our consumers. All of the ingredients we use are approved and deemed safe for food use by regulatory agencies, including the US FDA."
Amy Reilly, a spokeswoman for Target, which makes Market Pantry Grape Jelly, tells WebMD that Target is carefully evaluating the information and that "Target looks to the Food and Drug Administration to provide guidance on the safety of food additives and ingredients."
An FDA spokesperson wasn't immediately available to comment on Wallinga's report or the study published in Environmental Health.
SOURCES:
Dufault, R. Environmental Health, Jan. 26, 2009; online edition.
Wallinga, D. "Not So Sweet: Missing Mercury and High Fructose Corn Syrup."
David Wallinga, MD, director, Food and Health Program, Institute for Agriculture and Trade Policy.
Statement from Audrae Erickson, president, Corn Refiners Association.
Carl Winter, PhD, director, FoodSafe Program and Extension Food Toxicologist, department of food science and technology, University of California, Davis.
Adrienne Dimopoulos, spokeswoman, Kraft Foods.
Amy Reilly, spokeswoman, Target.
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