Hallucinations, Other Psychotic Symptoms in Children Linked to Use of ADHD Medications

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