ADHD Appears to Be Associated with Depressed Dopamine Activity in the Brain

CHICAGO, Aug. 6, 2007—Adults with attention-deficit/hyperactivity disorder (ADHD) show a blunted response to the drug methylphenidate (Ritalin), which increases brain dopamine levels, according to a report in the August issue of Archives of General Psychiatry, one of the JAMA/Archives journals. This suggests that dopamine dysfunction may be involved with ADHD symptoms and may contribute to substance abuse that often occurs simultaneously.

ADHD is the most prevalent psychiatric disorder among children, according to background information in the article. “Despite decades of research, the specific neurobiological mechanisms underlying this disorder still remain unclear,” the authors write. “Genetic, clinical and imaging studies point to a disruption of the brain dopamine system, which is corroborated by the clinical effectiveness of stimulant drugs (methylphenidate hydrochloride and amphetamine), which increase extracellular dopamine in the brain.”

Nora D. Volkow, M.D., of the National Institute on Drug Abuse, Bethesda, Md., and colleagues studied 19 adults with ADHD (average age 32) who had never received medication and 24 healthy controls (average age 30). Brain scans were performed using positron emission tomography (PET) and a drug known as raclopride labeled with carbon 11 ([11C]raclopride), which binds with dopamine receptors. Scans were performed twice, after injections of placebo and of methylphenidate; the participants did not know which drug they had received. Participants also were asked to report the severity of their ADHD symptoms, whether they could detect the drug, if they liked or disliked it, and if it made them feel “high,” tired, alert, anxious or restless.

In individuals with ADHD, methylphenidate caused less of a decrease in the amount of [11C]raclopride that bound to dopamine receptors in areas of the brain associated with attention than it did in those without ADHD. Since levels of methylphenidate in the blood were the same in both groups, this suggests that those with ADHD released less dopamine in response to the drug than controls. This blunted response was associated with symptoms of inattention. Exploratory analyses also found evidence of reduced [11C]raclopride binding in the hippocampus and amygdala in those with ADHD. These areas of the brain are part of the limbic system, involved in emotional responses as well as consolidating and retrieving memories.

“The findings of reduced dopamine release in subjects with ADHD are consistent with the notion that the ability of stimulant medications to enhance extracellular dopamine underlies their therapeutic effects in ADHD,” the authors write.

Individuals with ADHD also reported liking methylphenidate more than individuals without ADHD, the authors note. “The reinforcing responses to methylphenidate were negatively correlated with the dopamine increases, suggesting that decreased dopaminergic activity may also be involved in modulating the magnitude of the reinforcing effects of methylphenidate,” they continue. “This suggests that dopamine dysfunction is involved with symptoms of inattention but may also contribute to substance abuse comorbidity in ADHD.”
(Arch Gen Psychiatry. 2007;64(8):932-940. Available to the media pre-embargo at www.jamamedia.org).

Editor's Note: This research was supported in part by the Intramural Research Program of the National Institutes of Health, a contract from the Department of Energy, and by a grant from the National Institute of Mental Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations@jama-archives.org .

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EMBARGOED FOR RELEASE UNTIL 3 P.M. (CT), MONDAY August 6, 2007, 2007
Media Advisory: To contact Philip Shaw, M.D., Ph.D., call Jules Asher at 301-443-4536.

GENE VARIANT IS ASSOCIATED WITH BRAIN ANATOMY, CLINICAL COURSE OF ADHD

CHICAGO—A variant of the dopamine receptor gene may be associated with attention-deficit/hyperactivity disorder (ADHD) and with thinner tissue in areas of the brain that handle attention, but also appears associated with better clinical outcomes among individuals with the disorder, according to a report in the August issue of Archives of General Psychiatry, one of the JAMA/Archives journals.

ADHD is among the most heritable of neuropsychiatric disorders, according to background information in the article. Several genes have been identified as possibly associated with the condition. One of the most frequently cited is a polymorphism or different type of the dopamine D4 receptor gene (DRD4) known as the 7-repeat form. “Previous studies have suggested that carriers of the risk allele [alternate form of a gene] may also have a unique neuropsychological, clinical and pharmacological profile, although there remains considerable debate over the exact nature of this phenotype [characteristic],” the authors write.

Philip Shaw, M.D., Ph.D., of the National Institute of Mental Health, Bethesda, Md., and colleagues compared 105 children with ADHD (average age 10.1) to 103 healthy controls, using both magnetic resonance imaging (MRI) and DNA testing. Sixty-seven (64 percent) of the children with ADHD also had a follow-up clinical evaluation an average of six years later.

Among all participants, both with and without ADHD, having the 7-repeat form of DRD4 was associated with thinner tissue in areas of the brain known to control attention—the right orbitofrontal/inferior prefrontal and posterior parietal cortex. Similar regions were also generally thinner in participants with ADHD than those without. “As a result of the overlapping main effects of genotype and diagnosis, there was a stepwise increment in cortical thickness in these regions, with subjects with ADHD with the DRD4 7-repeat allele having the thinnest cortex, followed by subjects with ADHD lacking the 7-repeat allele, healthy 7-repeat allele carriers and finally by healthy non-carriers,” the authors write.

Analyses of the children who participated in the follow-up revealed that the differences between the brain anatomy of those with and without the DRD4 7-repeat allele were most pronounced in early development and disappeared by late adolescence. Individuals with ADHD who carried the DRD4 7-repeat allele had better clinical outcomes and regained thickness in their right parietal cortex—a sign previously linked to better outcomes and that parallels ADHD’s natural history of improvement with age.

“Cross-sectional studies have found regional increases in cortical thickness to correlate with cognitive function, including enhanced verbal declarative and extinction memory, and with ‘fluid’ intelligence in older, healthy subjects,” the authors write. “In children, gains in verbal knowledge are mirrored by change in the cortical thickness of speech areas. While our current study demonstrates changes in cortical thickness and symptoms occurring in tandem, a future goal is to refine further our appreciation of cortical thickness by examining the links between this neuroanatomical variable and putative cognitive endophenotypes [invisible but measurable components on a disease pathway] for ADHD, such as response inhibition and working memory.”
(Arch Gen Psychiatry. 2007;64(8):921-931. Available to the media pre-embargo at www.jamamedia.org).

Editor's Note: This study was supported by the Intramural Research Program of the National Institutes of Health. Please see the article for additional information, including other authors, author contributions and affiliations, financial disclosures, funding and support, etc.

For more information, contact JAMA/Archives media relations at 312/464-JAMA (5262) or e-mail mediarelations@jama-archives.org .

Posted: August 2007


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