Donepezil May Improve Some Functions in Autism

STANFORD, CALIF. — A preliminary analysis of a randomized, double-blind, placebo-controlled study of donepezil suggests that the Alzheimer's drug may slightly improve some neuropsychologic functions in children with autism, Dr. Antonio Hardan said at a pediatric update sponsored by Stanford University.

At the halfway point in a 20-week trial, improvements were seen in scores on some, but not all, neurocognitive tests in 10 autistic children aged 7–17 years receiving the drug, compared with 10 receiving placebo.

Specifically, children somewhat improved their performance on tests aimed at measuring spatial executive functioning (the Design Fluency Test), selective attention (the Color-Word Interference Test), and the California Verbal Learning Test. No improvement was seen on the Expressive One-Word Vocabulary Test, which measures language skills.

“We didn't see magic improvement or large improvements,” emphasized Dr. Hardan, director of the Autism and Developmental Disabilities Clinic at Lucile Packard Children's Hospital of Stanford (Calif.) University.

The trial is small and incomplete, and the results should be interpreted with caution, he said. “But what is nice about this is it opens up a whole group of medications to study.”

The use of donepezil (Aricept) in autism was first studied by Dr. Hardan at the University of Pittsburgh in an open-label study of eight children, half of whom demonstrated improvement on the Aberrant Behavior Checklist and Clinical Global Impression Scale. Improvements were suggested in irritability and hyperactivity, but not in inappropriate speech, lethargy, or stereotypies, he reported (J. Child Adolesc. Psychopharmacol. 2002;12:237–41).

Another novel study of an existing drug in autism is ongoing at Indiana University, Indianapolis, where a broad-spectrum antibiotic once used to treat tuberculosis led to apparent improvement in social withdrawal in a pilot study. A randomized, double-blind study is currently underway, pitting D-cycloserine, a partial agonist of the N-methyl-D-Aspartate (NMDA) glutamate receptor subtype, against placebo, Dr. Hardan said.

Although these are small studies, it is encouraging to see research into existing drugs to determine whether they might be effective in treating children with autism spectrum disorders, he said.

It took 15 years for risperidone (Risper-dal) to be approved for treatment of autism- related irritability, noted Dr. Hardan, who published an early case study suggesting the drug's efficacy in 1996. “That's why [parents] jump at any opportunity [to use a treatment] that could be potentially hazardous for their child.” He stressed that research must be driven by theories that make scientific sense, followed by proof-of-concept studies to see whether evidence exists that an agent may be helpful.

He pointed to “the [high] price of shortcuts,” citing as an example secretin, which was hailed as a possible treatment based on one uncontrolled observational study that hinted it may have improved behavior in three children undergoing gastrointestinal procedures.

No verification was made to determine whether the children actually met diagnostic criteria for autism, he noted. “Based on this, secretin was unfortunately the most studied medication in autism.”

Fifteen randomized, double-blind studies eventually produced uniformly negative results. “You can't find anything consistent like that in medicine,” he said.

Is Autism Prevalence Rising, or Is the Diagnosis Expanding?

An apparent increase in the prevalence of autism and autistic spectrum disorders may be largely explained by differences in diagnosis, rather than true differences in the number of children with these conditions, Dr. Hardan suggested.

“Is there an increase in incidence versus an increase in recognition?” asked Dr. Hardan. Several observations point to the latter, he said.

Much of the increase in prevalence is among children with mild symptoms: children with high-functioning autism, those with Asperger's syndrome, and children with pervasive developmental disorder, not otherwise specified.

“Fifteen or 20 years ago when somebody was verbal, it was very unlikely people were going to consider this an autism spectrum disorder,” he said.

On the other end of the spectrum, children with moderate to severe mental retardation were given that diagnosis decades ago, whereas today many children receive the autism diagnosis instead.

Traditionally, autism spectrum disorders were exclusively made in school-age children.

“Now people in their 20s and 30s who are struggling in daily living activities come to us and ask: 'Do I have an autism spectrum disorder?' Sometimes, some people do,” said Dr. Hardan, but a diagnosis in adulthood would have been unthinkable years ago.

Another important contributor to the apparently increasingly prevalence of autism is simple misdiagnosis, he maintained. Children with ADHD very often have social deficits, difficulties in developing peer relationships, and what Dr. Hardan described as “poor coherence between visual and verbal behaviors.”

But what may resemble autism or an autistic spectrum disorder, often is not, he said.

Children frequently referred to the clinic at Stanford who are misdiagnosed as autistic include those with severe anxiety symptoms, early onset personality disorders, and reactive attachment disorders.

Children in the latter category, often adopted from overseas, have many features that could lead a clinician to mistakenly diagnose autism, including severe social deficits and stereotypical behaviors, he said.

Methodological factors may also have contributed to apparent increases in autism prevalence, as depicted in a recent article, “The autism epidemic: fact or artifact?” (J. Am. Acad. Child Adolesc. Psychiatry 2007;46:721–30).

STANFORD, CALIF. — A preliminary analysis of a randomized, double-blind, placebo-controlled study of donepezil suggests that the Alzheimer's drug may slightly improve some neuropsychologic functions in children with autism, Dr. Antonio Hardan said at a pediatric update sponsored by Stanford University.

At the halfway point in a 20-week trial, improvements were seen in scores on some, but not all, neurocognitive tests in 10 autistic children aged 7–17 years receiving the drug, compared with 10 receiving placebo.

Specifically, children somewhat improved their performance on tests aimed at measuring spatial executive functioning (the Design Fluency Test), selective attention (the Color-Word Interference Test), and the California Verbal Learning Test. No improvement was seen on the Expressive One-Word Vocabulary Test, which measures language skills.

“We didn't see magic improvement or large improvements,” emphasized Dr. Hardan, director of the Autism and Developmental Disabilities Clinic at Lucile Packard Children's Hospital of Stanford (Calif.) University.

The trial is small and incomplete, and the results should be interpreted with caution, he said. “But what is nice about this is it opens up a whole group of medications to study.”

The use of donepezil (Aricept) in autism was first studied by Dr. Hardan at the University of Pittsburgh in an open-label study of eight children, half of whom demonstrated improvement on the Aberrant Behavior Checklist and Clinical Global Impression Scale. Improvements were suggested in irritability and hyperactivity, but not in inappropriate speech, lethargy, or stereotypies, he reported (J. Child Adolesc. Psychopharmacol. 2002;12:237–41).

Another novel study of an existing drug in autism is ongoing at Indiana University, Indianapolis, where a broad-spectrum antibiotic once used to treat tuberculosis led to apparent improvement in social withdrawal in a pilot study. A randomized, double-blind study is currently underway, pitting D-cycloserine, a partial agonist of the N-methyl-D-Aspartate (NMDA) glutamate receptor subtype, against placebo, Dr. Hardan said.

Although these are small studies, it is encouraging to see research into existing drugs to determine whether they might be effective in treating children with autism spectrum disorders, he said.

It took 15 years for risperidone (Risper-dal) to be approved for treatment of autism- related irritability, noted Dr. Hardan, who published an early case study suggesting the drug's efficacy in 1996. “That's why [parents] jump at any opportunity [to use a treatment] that could be potentially hazardous for their child.” He stressed that research must be driven by theories that make scientific sense, followed by proof-of-concept studies to see whether evidence exists that an agent may be helpful.

He pointed to “the [high] price of shortcuts,” citing as an example secretin, which was hailed as a possible treatment based on one uncontrolled observational study that hinted it may have improved behavior in three children undergoing gastrointestinal procedures.

No verification was made to determine whether the children actually met diagnostic criteria for autism, he noted. “Based on this, secretin was unfortunately the most studied medication in autism.”

Fifteen randomized, double-blind studies eventually produced uniformly negative results. “You can't find anything consistent like that in medicine,” he said.

Is Autism Prevalence Rising, or Is the Diagnosis Expanding?

An apparent increase in the prevalence of autism and autistic spectrum disorders may be largely explained by differences in diagnosis, rather than true differences in the number of children with these conditions, Dr. Hardan suggested.

“Is there an increase in incidence versus an increase in recognition?” asked Dr. Hardan. Several observations point to the latter, he said.

Much of the increase in prevalence is among children with mild symptoms: children with high-functioning autism, those with Asperger's syndrome, and children with pervasive developmental disorder, not otherwise specified.

“Fifteen or 20 years ago when somebody was verbal, it was very unlikely people were going to consider this an autism spectrum disorder,” he said.

On the other end of the spectrum, children with moderate to severe mental retardation were given that diagnosis decades ago, whereas today many children receive the autism diagnosis instead.

Traditionally, autism spectrum disorders were exclusively made in school-age children.

“Now people in their 20s and 30s who are struggling in daily living activities come to us and ask: 'Do I have an autism spectrum disorder?' Sometimes, some people do,” said Dr. Hardan, but a diagnosis in adulthood would have been unthinkable years ago.

Another important contributor to the apparently increasingly prevalence of autism is simple misdiagnosis, he maintained. Children with ADHD very often have social deficits, difficulties in developing peer relationships, and what Dr. Hardan described as “poor coherence between visual and verbal behaviors.”

But what may resemble autism or an autistic spectrum disorder, often is not, he said.

Children frequently referred to the clinic at Stanford who are misdiagnosed as autistic include those with severe anxiety symptoms, early onset personality disorders, and reactive attachment disorders.

Children in the latter category, often adopted from overseas, have many features that could lead a clinician to mistakenly diagnose autism, including severe social deficits and stereotypical behaviors, he said.

Methodological factors may also have contributed to apparent increases in autism prevalence, as depicted in a recent article, “The autism epidemic: fact or artifact?” (J. Am. Acad. Child Adolesc. Psychiatry 2007;46:721–30).

STANFORD, CALIF. — A preliminary analysis of a randomized, double-blind, placebo-controlled study of donepezil suggests that the Alzheimer's drug may slightly improve some neuropsychologic functions in children with autism, Dr. Antonio Hardan said at a pediatric update sponsored by Stanford University.

At the halfway point in a 20-week trial, improvements were seen in scores on some, but not all, neurocognitive tests in 10 autistic children aged 7–17 years receiving the drug, compared with 10 receiving placebo.

Specifically, children somewhat improved their performance on tests aimed at measuring spatial executive functioning (the Design Fluency Test), selective attention (the Color-Word Interference Test), and the California Verbal Learning Test. No improvement was seen on the Expressive One-Word Vocabulary Test, which measures language skills.

“We didn't see magic improvement or large improvements,” emphasized Dr. Hardan, director of the Autism and Developmental Disabilities Clinic at Lucile Packard Children's Hospital of Stanford (Calif.) University.

The trial is small and incomplete, and the results should be interpreted with caution, he said. “But what is nice about this is it opens up a whole group of medications to study.”

The use of donepezil (Aricept) in autism was first studied by Dr. Hardan at the University of Pittsburgh in an open-label study of eight children, half of whom demonstrated improvement on the Aberrant Behavior Checklist and Clinical Global Impression Scale. Improvements were suggested in irritability and hyperactivity, but not in inappropriate speech, lethargy, or stereotypies, he reported (J. Child Adolesc. Psychopharmacol. 2002;12:237–41).

Another novel study of an existing drug in autism is ongoing at Indiana University, Indianapolis, where a broad-spectrum antibiotic once used to treat tuberculosis led to apparent improvement in social withdrawal in a pilot study. A randomized, double-blind study is currently underway, pitting D-cycloserine, a partial agonist of the N-methyl-D-Aspartate (NMDA) glutamate receptor subtype, against placebo, Dr. Hardan said.

Although these are small studies, it is encouraging to see research into existing drugs to determine whether they might be effective in treating children with autism spectrum disorders, he said.

It took 15 years for risperidone (Risper-dal) to be approved for treatment of autism- related irritability, noted Dr. Hardan, who published an early case study suggesting the drug's efficacy in 1996. “That's why [parents] jump at any opportunity [to use a treatment] that could be potentially hazardous for their child.” He stressed that research must be driven by theories that make scientific sense, followed by proof-of-concept studies to see whether evidence exists that an agent may be helpful.

He pointed to “the [high] price of shortcuts,” citing as an example secretin, which was hailed as a possible treatment based on one uncontrolled observational study that hinted it may have improved behavior in three children undergoing gastrointestinal procedures.

No verification was made to determine whether the children actually met diagnostic criteria for autism, he noted. “Based on this, secretin was unfortunately the most studied medication in autism.”

Fifteen randomized, double-blind studies eventually produced uniformly negative results. “You can't find anything consistent like that in medicine,” he said.

Is Autism Prevalence Rising, or Is the Diagnosis Expanding?

An apparent increase in the prevalence of autism and autistic spectrum disorders may be largely explained by differences in diagnosis, rather than true differences in the number of children with these conditions, Dr. Hardan suggested.

“Is there an increase in incidence versus an increase in recognition?” asked Dr. Hardan. Several observations point to the latter, he said.

Much of the increase in prevalence is among children with mild symptoms: children with high-functioning autism, those with Asperger's syndrome, and children with pervasive developmental disorder, not otherwise specified.

“Fifteen or 20 years ago when somebody was verbal, it was very unlikely people were going to consider this an autism spectrum disorder,” he said.

On the other end of the spectrum, children with moderate to severe mental retardation were given that diagnosis decades ago, whereas today many children receive the autism diagnosis instead.

Traditionally, autism spectrum disorders were exclusively made in school-age children.

“Now people in their 20s and 30s who are struggling in daily living activities come to us and ask: 'Do I have an autism spectrum disorder?' Sometimes, some people do,” said Dr. Hardan, but a diagnosis in adulthood would have been unthinkable years ago.

Another important contributor to the apparently increasingly prevalence of autism is simple misdiagnosis, he maintained. Children with ADHD very often have social deficits, difficulties in developing peer relationships, and what Dr. Hardan described as “poor coherence between visual and verbal behaviors.”

But what may resemble autism or an autistic spectrum disorder, often is not, he said.

Children frequently referred to the clinic at Stanford who are misdiagnosed as autistic include those with severe anxiety symptoms, early onset personality disorders, and reactive attachment disorders.

Children in the latter category, often adopted from overseas, have many features that could lead a clinician to mistakenly diagnose autism, including severe social deficits and stereotypical behaviors, he said.

Methodological factors may also have contributed to apparent increases in autism prevalence, as depicted in a recent article, “The autism epidemic: fact or artifact?” (J. Am. Acad. Child Adolesc. Psychiatry 2007;46:721–30).