Stephen V. Faraone, MD, PhD

ADHD, criminality, pharmacotherapy, and substance abuse typically meet one another in media stories decrying the overuse of drug therapy for ADHD. In a welcome contrast to that popular tale, an elegant research project by 

 tells a new story using the same characters. But in this story, stimulant therapy prevents criminal behavior; keeps ADHD patients out of prison; and leads to better outcomes for the patients, their families, and society.

I call the research elegant because it uses a large Swedish population registry to track verified prescriptions of stimulant medications for ADHD along with verified evidence of criminal activity. Because the large sample deflects criticisms of low power, the population sample provides a representative sample and the use of reg­istries deals with possible investigator biases in making diagnoses. And in Sweden, findings indicate that the prevalence of treated ADHD is only 0.7%

; thus, it is highly likely that the patients in the Swedish registry truly had ADHD. We cannot accuse the Swedes of 

Elegance and simplicity often travel together. That they traveled to Sweden is seen in the simple statement of the main result: “Among patients with ADHD, rates of criminality were lower during periods when they were receiving ADHD medication.”

 Among 25,656 patients with ADHD, pharmacotherapy for the disorder reduced criminality by 32% for men and by 41% for women.

The reduction in criminality afforded by ADHD medications was equally high for stimulant and nonstimulant medications and for patients with and without a history of conduct dis­order. The probability of committing a crime increased when ADHD patients moved from a treatment period to a nontreatment period and decreased when they moved from a nontreatment period to a treatment period. These simple results are easy to explain and difficult to refute.

Although the work by Lichtenstein and colleagues does not explain why ADHD pharmacotherapy re­duces criminality, earlier work offers reasonable explanations. 

 have well-documented, strong, short-term effects on reducing ADHD symptoms and both overt and covert aggression.

 Although long-term data are limited, Fredriksen and colleagues

 found persistent therapeutic effects of these medications. Data from naturalistic studies show that long-term pharmacotherapy for ADHD reduces substance abuse in adolescence.

 Thus, reductions in the impulsivity of ADHD, the severity of comorbid aggression, and the risk of substance abuse might mediate the link between ADHD medication use and criminality.

Studying the effects of pharmacotherapy for ADHD on crime makes sense. Decades of research show that ADHD is associated with 

 and antisocial personality disorder in adults.

Consequently, the prevalence of ADHD in prisons is very high. Findings from a recent literature review indicate that 10% to 70% of prisoners have ADHD.

 This is not news. ADHD was reported in 25% of prisoners more than 2 decades ago.

 Consistent with the idea that failure to treat ADHD increases the risk of criminal behavior, Ginsberg and colleagues

found that ADHD had been identified in childhood in only 2 of 30 inmates with the disorder. Sadly, the incarceration of ADHD sufferers begins early: prevalence of ADHD among adolescents in juvenile detention is 12% to 19%.

We now know that some criminal activity can be eliminated by pharmacotherapy for ADHD. Should this information influence clinical practice? The short answer is an un­equivocal “yes.” Despite media outcries about the overmedication of youths, ADHD is not routinely managed with pharmacotherapy. In a 2007-2008 

, only two-thirds of children with a parent-reported diagnosis of ADHD were taking a medication for the disorder.

 The undertreatment of ADHD is greater than this suggests because many cases of ADHD are not diagnosed.

 reported that 8.7% of 3082 youths in an epidemiological sample met DSM-IV criteria for ADHD. 

, only 47.9% had a prior diagnosis of ADHD and only 32% had been treated consistently with ADHD med­ications. Poor children were the most likely to meet criteria for ADHD but were the least likely to receive consistent pharmacotherapy. Similarly, 

 report that the majority of adults with ADHD are not treated for the disorder. The results of the Swedish study suggest that increasing the appropriate treatment of ADHD should decrease ADHD-associated criminal behaviors, which would benefit patients and reduce correctional costs to society.

The ability of ADHD medications to reduce criminality should remind clinicians that the goal of ADHD pharmacotherapy is not simply a reduction of ADHD’s core symptoms of inattention, hyperactivity, and impulsivity. As Rostain and colleagues

 discuss, the treatment goals for ADHD should go beyond symptomatic improvement and short-term treatment response. These authors counsel clinicians to set the bar high when defining treatment success by using ADHD treatments to improve the functional status of patients, including non-core symptoms such as aggression, which are known to respond to medication. Although the initial improvements in ADHD symptoms can be dramatic, these should not obscure the need to address outcomes in other areas that may require an increased intensity of pharmacotherapy or the use of ajunct psychosocial 

The ability of ADHD medications to reduce criminality clearly has implications for the treatment of ADHD in prisoners. Some work suggests that the clinical features of ADHD are more severe for prisoners with ADHD than for others with ADHD.

 Among imprisoned youths, higher levels of hyperactive/impulsive symptoms, but not inattentive symptoms, predicted violent and nonviolent breaches of prison discipline.

 The effective treatment of ADHD in prisoners would likely facilitate rehabilitation and decrease recidivism. Given the high rates of recidivism, any method of dealing with this issue should be welcomed by the prison system.

The prison system is, however, over-burdened, and pharmacotherapy for prisoners with ADHD is controversial. 

 raises several concerns about treating prisoners with stimulants, which are typically the first-line treatment for ADHD because of their high degree of efficacy. Many prisoners have had substance use disorders, and they would likely abuse stimulants in the prison environment. Prisoners with ADHD could divert stimulants for use as currency in the prison’s black market, making them available to other inmates.

Although no studies have examined the diversion of stimulants among prisoners, in their review of 21 studies of students, Wilens and colleagues

 reported that the lifetime rates of diversion ranged from 16% to 29% of students. Notably, extended-release preparations were less likely to be diverted than immediate-release preparations, which is probably because of the greater difficulty in transforming extended-release products into a compound with abuse potential.

 also raises other concerns. Prisoners who seek to misuse or abuse stimulants would likely in­timidate or assault prisoners with ADHD who are under treatment. And practical issues must be considered. Prison psychiatric services could be overwhelmed by drug-seeking inmates simulating ADHD, because prison formularies would need to adopt costly storage, inventory, and handling procedures.

Because of these concerns, nonstimulant treatment has been suggested as the first approach to ADHD 

 Three FDA-approved nonstimulants are available (atomoxetine, extended-release guanfacine, and extended-release clonidine). In Appelbaum’s

 prison treatment protocol, stimulants are only used after failed trials of one or more nonstimulants. Patients are required to cooperate with nonpharmacological treatment recommendations. Among the latter, cognitive therapy for ADHD has been demonstrated to improve outcomes for stimulant-treated patients.

 Bupropion, which is used off-label for treating ADHD, is not recommended for prisoners because it has been diverted and abused in prison populations.

Nothing in this commentary, or in the report by Lichtenstein and colleagues,

 should be taken to mean that ADHD medications will prevent crime in people without ADHD or that the appropriate treatment of ADHD will lead to dramatic reductions in the overall crime rate. The causes of criminal behavior are complex and multifactorial. Although 

 may play only a small role in the full range of criminal activity, it is a treatable risk factor for criminal behavior. For physicians who treat patients with ADHD on a regular basis, it is reassuring to know that their careful work has had this unforeseen benefit. For physicians who are reluctant to treat patients with ADHD, especially those with a criminal history, the Swedish data call for a reassessment of clinical priorities.

Dr Faraone is Professor of Psychiatry and of Neuroscience and Physiology and Director of Research at SUNY Upstate Medical University in Syracuse, NY. He reports that in the past year, he received consulting income and/or research support from Shire, Akili Interactive Labs, SynapDx, Vaya Pharma, and Alcobra and research support from the National In­stitutes of Health. His institution is seeking a patent for the use of sodium-hydrogen exchange inhibitors in the treatment of ADHD. In previous years, he received consulting fees or was on Advisory Boards or participated in continuing medical education programs sponsored by Shire, Alcobra, Otsuka, McNeil, Janssen, Novartis, Pfizer, and Eli Lilly. Dr Faraone receives royalties from his books 

Straight Talk About Your Child’s Mental Health

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Hjern A, Weitoft GR, Lindblad F. Social adversity predicts ADHD-medication in school children-a national cohort study. 

 Faraone SV, Glatt SJ. A comparison of the efficacy of medications for adult attention-deficit/hyper­activity disorder using meta-analysis of effect size. 

 Faraone SV, Buitelaar J. Comparing the efficacy of stimulants for ADHD in children and adolescents using meta-analysis. 

Connor DF, Glatt SJ, Lopez ID, et al. Psychopharmacology and aggression. I: a meta-analysis of stimulant effects on overt/covert aggression-related behaviors in ADHD.

Fredriksen M, HalmÃ¸y A, Faraone SV, Haavik J. Long-term efficacy and safety of treatment with stimulants and atomoxetine in adult ADHD: a review of controlled and naturalistic studies. 

 Wilens TE, Faraone SV, Biederman J, Gunawardene S. Does stimulant therapy of attention-deficit/hyperactivity disorder beget later substance abuse? A meta-analytic review of the literature. 

 Biederman J, Petty CR, Dolan C, et al. The long-term longitudinal course of oppositional defiant disorder and conduct disorder in ADHD boys: findings from a controlled 10-year prospective longitudinal follow-up study. 

Barkely RA, Fischer M, Smallish L, Fletcher K. Young adult follow-up of hyperactive children: antisocial activities and drug use. 

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 Eyestone LL, Howell RJ. An epidemiological study of attention-deficit hyperactivity disorder and major depression in a male prison population. 

 Ginsberg Y, Hirvikoski T, Lindefors N. Attention deficit hyperactivity disorder (ADHD) among longer-term prison inmates is a prevalent, persistent and disabling disorder. 

 Fazel S, Doll H, LÃ¥ngstrÃ¶m N. Mental disorders among adolescents in juvenile detention and correctional facilities: a systematic review and meta­regression analysis of 25 surveys. 

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http://www.cdc.gov/ncbddd/adhd/medicated.html

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 Kessler RC, Adler L, Barkley R, et al. The prevalence and correlates of adult ADHD in the United States: results from the National Comorbidity Survey Replication. 

 Rostain A, Jensen PS, Connor DF, et al. Toward quality care in ADHD: defining the goals of treatment. 

 Gordon V, Williams DJ, Donnelly PD. Exploring the relationship between ADHD symptoms and prison breaches of discipline amongst youths in four Scottish prisons. 

 Burns KA. The top ten reasons to limit prescription of controlled substances in prisons. 

Wilens TE, Adler LA, Adams J, et al. Misuse and diversion of stimulants prescribed for ADHD: a systematic review of the literature.

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 Safren SA. Cognitive-behavioral approaches to ADHD treatment in adulthood. 

Articles

Some criminal activity can be eliminated by pharmacotherapy for ADHD. Should this information influence clinical practice? The short answer is an un­equivocal “yes.”

Crime and Therapy: Good News About Pharmacotherapy for ADHD

Although attention-deficit/hyperactivity disorder is frequently misunderstood as caused by normal childhood energy, boring classrooms, or overstressed parents and teachers, several decades of research show ADHD to be a valid disorder with a neurobiological basis (Faraone, in press). Genetic studies have played a leading role in clarifying the biological basis of the disorder. Family studies have documented familial transmission; adoption studies show this transmission occurs through biological, not adoptive relationships; and twin studies show that ADHD is highly heritable such that genes account for about 75% of the disorder's variability in the population (Faraone et al., in press). With a prevalence of 8% to 12% (Faraone et al., 2003), it is among the most common of psychiatric disorders.

Given this strong evidence from epidemiologic studies, molecular genetic studies have begun the search for genes that increase susceptibility to ADHD. Two general approaches have been used. Genome scan linkage studies scan the entire genome in search of regions that might harbor susceptibility genes. They do not require a prior hypothesis about which genes cause the disorder. In contrast, candidate gene studies nominate specific genes based on a biological theory about their putative role. They use the method of association to test these prior hypotheses.

To date, there have been three research groups performing genome linkage scans of ADHD (Arcos-Burgos et al., 2004; Bakker et al., 2003; Fisher et al., 2002; Ogdie et al., 2004, 2003). 

 summarizes their main results and gives their highest LOD scores (a statistic that measures the evidence for linkage). With the exception of chromosome 17p11, genomic regions implicated by these studies do not overlap. Because three of the implicated regions (17p11, 16p13 and 15q15) have also been implicated in studies of autism, these findings may suggest a shared genetic susceptibility for these disorders.

For ADHD, the modest replication across studies completed so far suggests that genes of moderately large effect are unlikely to exist. For this reason, further studies are needed to increase the power of available linkage data. Difficulties in replication may also be due to genetic heterogeneity (i.e., there are different forms of ADHD influenced by different genes).

In contrast to the small number of linkage studies, numerous candidate gene studies have used association to determine if biologically relevant genes influence the susceptibility to ADHD. Much of this work has focused on genes in catecholaminergic systems because the drugs that effectively treat ADHD are either dopamine reuptake inhibitors (e.g., stimulants) or norepinephrine reuptake inhibitors (e.g., tricyclic antidepressants, atomoxetine [Strattera]).

Compared with dopaminergic and noradrenergic systems, serotonergic systems have received relatively little attention in ADHD research. This is because measures of serotonin metabolism are minimally related to the clinical efficacy of the medicines that treat ADHD. Nevertheless, molecular genetic studies have examined serotonergic genes due to the well-known role of serotonin in impulsivity, one of the core symptoms of ADHD (Brunner and Hen, 1997).

Another biological pathway to ADHD was discovered through study of coloboma mice, which have a hemizygous deletion of chromosome 2q (Wilson, 2000). This deletion region includes the gene encoding SNAP-25, a neuron-specific protein implicated in exocytotic neurotransmitter release. Coloboma mice show spontaneous hyperactivity, delays in achieving complex neonatal motor abilities and learning deficiencies. These problems are not seen if the mice are given a functioning 

 gene through a transgenic procedure. Treatment with mixed amphetamine salts (Adderall) but not methylphenidate (Concerta, Metadate, Ritalin) reverses the hyperactivity, which is consistent with the mechanism of action of these medications.

Methylphenidate treats ADHD by blocking the dopamine transporter. Mixed amphetamine salts block the dopamine transporter but also facilitates the non-vesicular release of dopamine through reverse transport, which would be expected to reverse the deficits in exocytotic neurotransmitter release caused by the coloboma mutation.

To test genes associated with these biological hypotheses, candidate gene studies have used case-control or family-based designs. Case-control designs compare allele frequencies between patients with ADHD and non-ADHD controls. Alleles that confer risk for ADHD should be more common among patients with ADHD. The family-based design compares the alleles that parents transmit to children with ADHD to alleles parents do not transmit. If an allele increases the risk for ADHD, it should be more common among the transmitted alleles than the nontransmitted alleles. From both study designs, it is possible to derive an odds ratio (OR) that assesses the magnitude of the association between ADHD and the putative risk alleles. An OR of 1.0 indicates no association; >1.0 indicates the allele increases risk for ADHD; and 

Faraone et al. (in press) reviewed the ADHD candidate gene literature and examined pooled ORs for candidate genes that had been examined in at least three case-control or family-based association studies. 

 shows seven genes that provide statistically significant evidence of association with ADHD. Other genes have been studied, showing either negative (catechol O-methyltransferase, norepinephrine transporter) or unclear (D2 and D3 dopamine receptors; tyrosine hydroxylase; noradrenergic receptors ADRA2A, 2C and 1C; monoamine oxidase A; serotonin 2A receptor; the A4 and A7 acetylcholine receptor subunits, and the 2A glutamate) results.

The ORs for the positive associations range from 1.13 to 1.45 (

). These small ORs are consistent with the idea that many genes of small effect mediate the genetic vulnerability to ADHD. Moreover, they suggest one explanation for the frequent failure to replicate initial reports of association: Many individual studies are underpowered to find significant associations if the effects are modest (Lohmueller et al., 2003). These small and sometimes inconsistent effects emphasize the need for future molecular genetic studies to implement strategies that will provide enough statistical power to detect small effects.

To address this project, we and colleagues from multiple sites in Europe conceived the International Multi-site ADHD Genetics (IMAGE) project. The main aim of IMAGE is to generate a clinical and genetic resource of 1,400 sibling pairs and their biological parents. The sibling pair design will enable the use of linkage analysis to identify chromosomal regions containing genes of moderate-to-large effect and association strategies to identify genes of small effect. The IMAGE group uses a novel approach by including ADHD probands and all available siblings in one dataset.

In order to increase confidence in the diagnosis and decrease potential genetic and etiological heterogeneity, probands are recruited from ADHD treatment centers and selected for 

 combined subtype. All siblings of probands are included in the study, whether or not they have ADHD, and continuous rating scale measures of symptoms will be used to map genes.

The use of quantitative measures to map genes for common disorders is known as 

and reflects the view that genetic influences on ADHD are continuously distributed throughout the population (Asherson and IMAGE Consortium, 2004). This means that genes that increase risk for ADHD are also expected to influence individual differences in ADHD symptoms throughout the entire population. Similar approaches have been used for other common traits such as blood pressure (Harrap et al., 2002), cholesterol level (Lin, 2003) and dyslexia (Cardon et al., 1994).

The use of quantitative trait measures for ADHD genetic research is based on findings from numerous population-based twin studies that show high heritability for parent and teacher ratings of ADHD symptoms (Thapar et al., 1999). We know, for example, that correlations for parent- and teacher-rated ADHD symptoms are 70% to 75% for identical (monozygotic [MZ]) twins (who share 100% of their genes) and 30% to 35% for nonidentical (dizygotic [DZ]) twins (who share 50% of their genes).

In order to examine the genetic correlation between ADHD diagnosis and continuous rating scale measures, a method called 

 estimates group heritability from the differential regression of identical and nonidentical co-twin trait scores to the population trait mean where twin probands are selected for extreme scores (DeFries and Fulker, 1988). In one study of 6,000 preschool twins, the group heritability for twins where probands were selected for extreme scores ranged from 0.83 to 0.93 (Price et al., 2001).

Using the IMAGE dataset, we estimated the familial correlation between combined-type ADHD probands and continuous measures of ADHD symptoms among siblings. As expected, both inattentive and hyperactive-impulsive symptoms show familial associations to combined-type ADHD of around 0.2 to 0.3, which is similar to sibling correlations for DZ twins estimated from population samples (

There are several potential advantages to our study design. The collection of DNA from a large sample of ADHD probands allows us to perform powerful tests of association that can identify small genetic effects, such as those seen for candidate genes listed in 

. At the same time, we can investigate whether alleles associated with ADHD correlate with quantitative ratings in siblings and we can increase the power of our analysis by combining within- and between-pair tests of association.

We previously tested the utility of this approach by investigating whether some of the genes associated with ADHD showed QTL associations in a population twin sample with parent ratings of ADHD behavior (Mill et al., 2005). We found significant correlations with previously identified risk alleles from 

. Our analyses found positive correlations using within-pair tests of association that are independent of genetic stratification and are robust to potential stratification effects generated by parent raters who may scale similar behaviors differently. In other words, within-pair differences for behavioral scores are more reliable than across-pair comparisons. This was reflected in the strength of the genetic associations we observed. The QTL linkage also takes advantage of the reliable nature of within-pair differences by looking for correlations between the similarity between siblings and the number of parental chromosomes they share at a particular genetic locus.

The IMAGE dataset contains a subset of affected sibling pairs that can be used for more traditional tests of association and linkage using diagnostic status alone. In our initial set of 608 ADHD combined-type probands, we found a sibling concordance rate for combined-subtype ADHD of 22.1% for males and 5.2% for females. This gives rise to similar sibling risk ratios for the combined subtype for males (9.2%) and females (11.5%) when expressed as a ratio against recent prevalence rates in a European population (2.4% males, 0.4% females).

As we discover more genes, the goal of ADHD genetic research will shift from gene discovery toward gene functionality. Quantitative genetic findings have shifted perception of ADHD toward that of a quantitative trait sharing etiological influences with other developmental, behavioral and cognitive traits. Molecular genetics has confirmed a priori hypotheses of dopamine system dysregulation and promises to identify additional genes in the coming decade. Combining genetic, environmental and neurobiological research has the potential to delineate causal links between ADHD and the developmental course of the disorder, including persistence of ADHD symptoms into adulthood and comorbidity with associated psychiatric disorders/traits.

The IMAGE project is a multi-site, international effort supported by National Institutes of Health grant R01MH62873 to Dr. Faraone. IMAGE Project principal investigators are Philip Asherson, MRCPsych, Ph.D.; Tobias Banaschewski, Ph.D.; Jan Buitelaar, M.D., Ph.D.; Richard P. Ebstein, Ph.D.; Stephen V. Faraone, Ph.D.; Michael Gill, M.D., MRCPsych; Ana Miranda, Ph.D.; Fernando Mulas, Dr.D.; Robert D. Oades, Ph.D.; Herbert Roeyers, Ph.D.; Aribert Rothenberger, M.D.; Joseph Sergeant, Ph.D.; Edmund Sonuga-Barke, Ph.D.; Eric Taylor, M.D., Ph.D.; and Hans-Christoph Steinhausen, M.D., Ph.D.

Dr. Faraone is professor of psychiatry and behavioral sciences at the State University of New York Upstate Medical University in Syracuse. He is also director of medical genetics research and head of child and adolescent psychiatry research at the Center for Neuropsychiatric Genetics at Upstate Medical University.

Dr. Asherson is senior lecturer in molecular psychiatry and honorary consultant psychiatrist in the Institute of Psychiatry at King's College in London.

Arcos-Burgos M, Castellanos FX, Pineda D et al. (2004), Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11. Am J Hum Genet 75(6):998-1014.

Asherson P, IMAGE Consortium (2004), Attention-deficit hyperactivity disorder in the post-genomic era. Eur Child Adolesc Psychiatry 13(suppl 1):I50-I70.

Bakker SC, van der Meulen EM, Buitelaar JK et al. (2003), A whole-genome scan in 164 Dutch sib pairs with attention-deficit/hyperactivity disorder: suggestive evidence for linkage on chromosomes 7p and 15q. Am J Hum Genet 72(5):1251-1260.

Brunner D, Hen R (1997), Insights into the neurobiology of impulsive behavior from serotonin receptor knockout mice. Ann N Y Acad Sci 836:81-105.

Cardon LR, Smith SD, Fulker DW et al. (1994), Quantitative trait locus for reading disability on chromosome 6. [Published erratum Science 268(5217):1553.] Science 266(5183):276-279 [see comment].

DeFries JC, Fulker DW (1988), Multiple regression analysis of twin data: etiology of deviant scores versus individual differences. Acta Genet Med Gemellol (Roma) 37(3-4):205-216.

Faraone SV (in press), The scientific foundation for understanding attention-deficit/hyperactivity disorder as a valid psychiatric disorder. Eur J Child Adolesc Psychiatry.

Faraone SV, Perlis RH, Doyle AE et al. (in press), Molecular genetics of attention deficit hyperactivity disorder. Biol Psychiatry.

Faraone SV, Sergeant J, Gillberg C, Biederman J (2003), The worldwide prevalence of ADHD: is it an American condition? World Psychiatry 2(2):104-113.

Fisher SE, Francks C, McCracken JT et al. (2002), A genomewide scan for loci involved in attention-deficit/hyperactivity disorder. Am J Hum Genet 70(5):1183-1196.

Harrap SB, Wong ZY, Stebbing M et al. (2002), Blood pressure QTLs identified by genome-wide linkage analysis and dependence on associated phenotypes. Physiol Genomics 8(2):99-105.

Lin JP (2003), Genome-wide scan on plasma triglyceride and high density lipoprotein cholesterol levels, accounting for the effects of correlated quantitative phenotypes. BMC Genet 4(suppl 1):S47.

Lohmueller KE, Pearce CL, Pike M et al. (2003), Meta-analysis of genetic association studies supports a contribution of common variants to susceptibility to common disease. Nat Genet 33(2):177-182.

Mill J, Xu X, Ronald A et al. (2005), Quantitative trait locus analysis of candidate gene alleles associated with attention deficit hyperactivity disorder (ADHD) in five genes: DRD4, DAT1, DRD5, SNAP-25, and 5HT1B. Am J Med Genet B Neuropsychiatr Genet 133(1):68-73.

Ogdie MN, Fisher SE, Yang M et al. (2004), Attention deficit hyperactivity disorder: fine mapping supports linkage to 5p13, 6q12, 16p13, and 17p11. Am J Hum Genet 75(4):661-668.

Ogdie MN, Macphie IL, Minassian SL et al. (2003), A genomewide scan for attention-deficit/hyperactivity disorder in an extended sample: suggestive linkage on 17p11. Am J Hum Genet 72(5):1268-1279.

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Thapar A, Holmes J, Poulton K, Harrington R (1999), Genetic basis of attention deficit and hyperactivity. Br J Psychiatry 174:105-111.

Wilson MC (2000), Coloboma mouse mutant as an animal model of hyperkinesis and attention deficit hyperactivity disorder. Neurosci Biobehav Rev 24(1):51-57.

New research into the genetic basis and possible genetic markers for attention-deficit/hyperactivity disorder may open the door for new treatments. There is a clear concordance between twins who have ADHD, as well as siblings. What can genetic mapping tell us about treating ADHD?

The Molecular Genetics of ADHD: A View From the IMAGE Project

Many people who have family members afflicted by psychiatric disorders wonder if mental illness is inherited. In fact, over the last several decades, research has provided clinicians with information and empirical risk estimates for some psychiatric disorders. Despite the large body of work, clinical implications of psychiatric genetic data have only recently become apparent. This reflects both increased media attention to genetics, as well as the growing sophistication of patients and their families.

In this article we will address two clinical applications of genetic information. First, we will discuss genetic counseling, which provides general principles to help clinicians communicate genetic risks to patients and family members. Genetic counseling is a well-established medical subspeciality, typically applicable to many rare non-psychiatric medical disorders. Second, we will discuss the potential adverse consequences and the ethical implications raised by the availability of genetic testing. We will illustrate ethical issues using lessons learned from genetic testing in classical Mendelian diseases and discuss established guidelines that may apply to psychiatric disorders.

There has been explosive growth in the number of disease genes identified over the past several years, giving clinicians more information about the heritability of many diseases. However, new knowledge can-and often does-create confusion. There are still several misconceptions concerning human genetics and psychiatric illness. The primary purpose of genetic counseling, therefore, is to correct misunderstandings about the heritability of psychiatric disorders, such as:

 If a disorder is genetic, it inevitably occurs in those who carry the harmful gene(s).

 The influence of genetic factors in psychiatric disorders is highly variable. More commonly, environmental and genetic interactions influence most psychiatric conditions. Furthermore, genetic and environmental influences are likely to differ between individuals and have variable impacts on each individual. Thus, the expression of a single disorder is not necessarily the same in each affected individual. It is also possible that an individual who carries the susceptible gene will not develop the disorder.

If a disorder is genetic, it is untreatable.

 Although many genetic conditions are currently untreatable (for example, Huntington's disease), most psychiatric disorders respond to some form of treatment. Similarly, while the underlying genetics cannot yet be changed, the expression of those genes can be treated. Individuals with identified psychiatric genetic disorders may mitigate the effects of the disorder through medical treatment, psychotherapeutic intervention and lifestyle changes. In addition, much scientific effort has been invested in gene therapy, with the eventual goal of reversing the effects of the deleterious gene. While this may sound like science fiction, gene therapy may become a reality in the future.3.) 

Genetic counseling is associated with eugenics and genocide. 

In fact, contemporary genetic counseling is non-directive, with an emphasis on individual autonomy and informed decision-making. The goal of genetic counseling is to disseminate current scientific knowledge concerning the disorder at hand and to aid the consultand (the person seeking genetic counseling) in making the best possible decision.As with other medical conditions, some psychiatric disorders are inherited while others are not. Genetic counseling serves to educate consultands and provide them with information concerning the disorder of interest. The Table* outlines the seven stages of genetic counseling. Multiple visits may be necessary to complete all stages. Genetic counseling should be tailored to the specific needs of the individual and their family. Interested readers are referred to the chapter entitled "Clinical Applications of Psychiatric Genetics" in Genetics in Mental Disorders: A Guide for Students, Clinicians, and Researchers (1999; Guilford Press) for additional details.

DNA-based tests are the newest technique in testing for genetic disorders. These techniques require direct examination of the DNA molecule (e.g., determination of the number of repeated DNA sequences in the Huntington's disease gene). Other genetic tests include those that detect gene products (e.g., biochemical tests, such as one that screens for phenylketonuria) and those that detect chromosomal changes by microscopic examination of fluorescent chromosomes (e.g., fluorescent in-situ hybridization techniques to screen for velocardiofacial syndrome). Genetic tests are currently used in a variety of situations, including:

presymptomatic testing for prediction of adult-onset disorders;

presymptomatic testing for estimating the risk of developing adult-onset diseases;

diagnostic testing for symptomatic individuals; 

>, genetic tests are currently available for over 700 diseases. For many at-risk individuals, the availability of genetic tests gives them the opportunity to relieve uncertainty and to appropriately plan for their future.

For treatable disorders, a positive test can result in a higher level of surveillance as well as intervention to reduce risk. Unfortunately, only a few genetic tests are definitive (e.g., the test for Huntington's disease, which is 99% predictive). In other single-gene disorders, although the presence of a mutation is highly predictive of the disorder (as in some forms of familial early-onset Alzheimer's disease [AD], in which age of onset is consistently before the age of 60), genetic testing is more complicated. Testing for mutations in one of the three known causative genes (presenilin 1) is clinically available. Testing is recommended only in individuals with age of onset of AD younger than 60 and who have another affected family member with early-onset AD. Although apparent sporadic cases of early-onset AD exist, there is still the possibility of false paternity or early death of an asymptomatic parent who carried the mutation. Testing is not recommended for people with late-onset AD, both sporadic and familial.

When testing at-risk individuals, an affected family member should be tested first to confirm the molecular diagnosis of the family. In the absence of this information, a negative test could simply indicate that the family has another genetic form of dementia. Testing for mutations in the two other genes (amyloid precursor protein and presenilin 2) is only available on a research basis. Testing for mutations causative for AD is not useful in predicting the age of onset, severity or type of clinical symptoms, or rate of progression of the disease.

The apolipoprotein E4 (APO E4) should not be used in presymptomatic testing. Although 35% to 60% of AD cases have an E4 allele, its presence is not highly diagnostic of AD. Furthermore, epidemiologic data in presymptomatic individuals with longitudinal follow-up are not well-established. In addition, there is consensus that children at risk for adult-onset disorders should not be tested in the absence of clinical symptoms. Additional information on testing guidelines for AD and other genetic disorders is available on GeneClinics' Web site <

In more common diseases, such as adult-onset cancers and coronary artery disease, only age-adjusted risk estimates can be provided. Likewise, most psychiatric disorders are presumed to be multifactorial (e.g., due to multiple genes and gene-environmental interactions). Many uncertainties regarding future presymptomatic testing in psychiatric disorders remain. Testing guidelines for individual disorders depends on who is at risk for specific disorders, the accuracy of risk prediction, the best age to provide test results and how the genetic test results are to be used to improve the lives of those tested.

Informed consent is the guiding principle behind the ethics of clinical practice and genetics research and testing. Consultands who choose to undergo genetic testing for clinical reasons should be thoroughly informed about the risks and benefits of the procedure and should always have the option to terminate the process. The counselor should discuss the potential social consequences of genetic testing with consultands. Unlike other laboratory tests, genetic tests may also reveal information about other family members, who, in turn, may or may not want access to this information. Part of the consent process should routinely describe the confidentiality of the data, although clinicians must inform the consultand that the genetic information is part of their medical records. Since stigmatization may occur as a consequence of test results, consultands should review their life and disability insurance prior to testing, as insurance companies have argued that they should have access to presymptomatic genetic testing results.

To compute the costs of health and life insurance, actuaries take into account many factors known to predict disease and death. Few people can argue with the rationale that smokers should pay higher health insurance premiums than non-smokers. Does a parallel argument justify the use of genetic information? Theoretically, insurance companies should have access to genetic profiles of individuals who apply for insurance. Should those who are at risk for untreatable or chronically debilitating disorders pay higher insurance premiums? Should insurance companies have the right to deny coverage to those individuals?

In the same vein, employers may want access to employee records regarding medical information including risk factors for genetic disorders since potential at-risk employees could eventually become less productive, and they may increase health care costs. Understandably, there is reason for concern that discrimination based on genetic testing could occur. Proponents have argued that employers should have access to genetic test results for disorders that may impair judgment and job performance in occupations involving the safety of the general public (e.g., commercial airline pilots and physicians).

The implications of the Human Genome Project have not escaped the attention of legislators. In the United States, several states have already enacted genetic privacy laws. In general, these laws limit the use of genetic data by insurance companies. However, the idea that genetic data should be treated differently from other clinical data has been hotly debated. Society can anticipate additional ethical and legal debates. Indeed, such debates are likely to intensify as the ability to predict behavioral and personality traits becomes a reality. Society will then have to decide the ethical, legal and social implications of this new knowledge. Much work is ongoing as part of the Ethical, Legal, and Social Implications Program of the Human Genome Project. (For additional information, please visit <

The Human Genome Project will undoubtedly provide an abundance of data to assist researchers in identifying the genes that contribute to human behavioral disorders. With the working draft of the human genome in hand, identification of genes relevant to human behavior continues. The implications of genetic data for diagnosing and treating psychiatric disorders remain speculative. Clinical applications often arise during the mature phases of a scientific discipline. As psychiatric genetics enters into the gene identification era, more clinical applications will be discovered. Although the future of psychiatric genetics will answer many scientific and clinical questions, it will also raise many questions about the legal, ethical and social implications of these answers. Medical and scientific advances may bring many gifts to society in the form of new knowledge; as clinicians and scientists, we should approach this new knowledge with caution, as one of these gifts could be a Pandora's box.

The Human Genome project has provided an abundance of genetic information, including identification of many disease-causing genes. Clinical applications, genetic counseling and the potential ethical issues raised by the availability of genetic testing are all areas of concern in gene research. Will genetic counseling in classical genetic diseases help to provide guidelines for behavioral disorders?

Author | Stephen V. Faraone, MD, PhD

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