X hits on this document

PDF document






14 / 20


Neuropsychopharmacology: The Fifth Generation of Progress

studies are correct, they may implicate neighboring genes instead of those targeted by the studies. It seems unlikely that a single ‘‘ADHD gene’’ causes ADHD with certainty. Instead, it seems likely that several genes act together to form the genetic substrate of the disorder.

When the ADHD-related variants of these genes are dis- covered, they will probably be ‘‘normal’’ variants and will most certainly not have the devastating effects seen in knockout mouse models. For example, suppose future work confirms that the 7-repeat allele is a risk factor for ADHD. We would consider this a normal variant because about 20% of people who do not have ADHD carry this version of the DRD4 gene. Most of these people do not develop ADHD despite the blunted dopaminergic transmission as- sociated with that allele, and many patients with ADHD do not carry the allele. Thus, the 7-repeat allele cannot be a necessary or sufficient cause of the disorder. Instead, it acts in concert with other genes and environmental risk factors to bring forth ADHD.

Like genetic studies, studies of environmental risk factors suggest that most of these risks exert small but significant influences on the origin of ADHD. For example, most chil- dren with a history of PDCs do not develop ADHD, and most children with ADHD do not have a history of ADHD. Nevertheless, research suggests that such complications are more common among children with ADHD.

These considerations lead us to conclude that the origin of ADHD is multifactorial. A simple multifactorial model posits ADHD to arise a pool of genetic and environmental variables—each of small effect—that act in concert to pro- duce vulnerability to ADHD. If a person’s cumulative vul- nerability exceeds a certain threshold, he or she will manifest the signs and symptoms of ADHD. According to the multi- factorial model, no single factor is a necessary or sufficient cause for ADHD, and each of the etiologic factors is inter- changeable (i.e., it does not matter which factors one has; only the total number is important). Whether risk factors combine in an additive or interactive manner is unknown.

The mouse models of ADHD we described provide ex- amples of multifactorial causation in a simple system. One model showed that individual differences in the DAT gene could directly produce a hypodopaminergic state; these studies showed that dopamine transporter variants differ in their affinity for neurotoxins. Thus, dopamine transporter abnormalities could interact with environmental toxins to produce hyperactivity. Another line of work shows that cate- cholamines are secreted in response to stress, and catechol- amine administration produces fetal hypoxia. Human stud- ies implicate both stress during pregnancy and fetal hypoxia as risk factors for ADHD.

These simple examples suggest that unraveling the com- plexities of multifactorial causation will be a difficult task for ADHD researchers. However, because technological de- velopments in neuroscience and molecular genetics are mov- ing at a rapid pace, the next decade of work should provide

us with more accurate assessments of the brain along with a complete sequence of the human genome. These advances should set the stage for breakthroughs in our understanding of the neurobiology of ADHD and in our ability to treat affected persons.


Dr. Biederman receives research support from Shire Labora- tories, Gliatec, Cephalon, Novartis Pharmaceuticals, and Eli Lilly & Company. In addition, he serves on speaking bu- reaus for SmithKline Beecham, Eli Lilly & Company, and Pfizer Pharmaceuticals.


  • 1.

    Barkley RA. Attention deficit hyperactivity disorder: a handbook for diagnosis and treatment. New York: Guilford, 1998.

  • 2.

    Spencer T, Biederman J, Wilens T, et al. Is attention deficit hyperactivity disorder in adults a valid disorder? Harvard Rev Psychiatry 1994;1:326–335.

  • 3.

    Hill J, Schoener E. Age-dependent decline of attention deficit hyperactivity disorder. Am J Psychiatry 1996;153:1143–1146.

  • 4.

    Biederman J, Newcorn J, Sprich S. Comorbidity of attention deficit hyperactivity disorder with conduct, depressive, anxiety, and other disorders. Am J Psychiatry 1991;148:564–577.

  • 5.

    Caron C, Rutter M. Comorbidity in child psychopathology: concepts, issues and research strategies. J Child Psychol Psychiatry 1991;32:1063–1080.

  • 6.

    Bird HR, Canino G, Rubio-Stipec M, et al. Estimates of the prevalence of childhood maladjustment in a community survey in Puerto Rico: the use of combined measures. Arch Gen Psychia- try 1988;45:1120–1126.

  • 7.

    Anderson JC, Williams S, McGee R, et al. DSM-III disorders in preadolescent children: prevalence in a large sample from the general population. Arch Gen Psychiatry 1987;44:69–76.

  • 8.

    Spencer TJ, Biederman J, Wilens T, et al. Pharmacotherapy of attention deficit hyperactivity disorder across the lifecycle: a literature review. J Am Acad Child Adolesc Psychiatry 1996;35: 409–432.

  • 9.

    Wilens T, Biederman J, Spencer T, et al. Pharmacotherapy of adult attention deficit/hyperactivity disorder: a review. J Clin Psychopharmacol 1995;15:270–279.

  • 10.

    Prince J, Wilens T, Biederman J, et al. A controlled study of nortriptyline in children and adolescents with attention deficit hyperactivity disorder. In: Scientific proceedings of the annual meeting of the American Academy of Child and Adolescent Psychiatrists XV, Chicago, 1999.

  • 11.

    Casat CD, Pleasants DZ, Van Wyck Fleet J. A double-blind trial of bupropion in children with attention deficit disorder. Psychopharmacol Bull 1987;23:120–122.

  • 12.

    Casat CD, Pleasants DZ, Schroeder DH, et al. Bupropion in children with attention deficit disorder. Psychopharmacol Bull 1989;25:198–201.

  • 13.

    Wender PH, Reimherr FW. Bupropion treatment of attention- deficit hyperactivity disorder in adults. Am J Psychiatry 1990; 147:1018–1020.

  • 14.

    Ernst M, Liebenauer LL, Jons PH, et al. Selegiline in adults with attention deficit hyperactivity disorder: clinical efficacy and safety. Psychopharmacol Bull 1996;32:327–334.

  • 15.

    Spencer T, Wilens TE, Biederman J. A double-blind, crossover comparison of tomoxetine and placebo in adults with ADHD.

Document info
Document views70
Page views70
Page last viewedWed Jan 18 20:14:02 UTC 2017