adhd case study quizlet

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Attention-deficit Hyperactivity Disorder (ADHD): Two Case Studies

• Authors: Authors: Joseph Biederman, MD; Stephen V. Faraone, PhD
• THIS ACTIVITY HAS EXPIRED FOR CREDIT

Target Audience and Goal Statement

This activity has been designed to meet the educational needs of pediatricians, family practitioners, child and adolescent psychiatrists, and general psychiatrists involved in the management of patients with ADHD.

Attention-deficit hyperactivity disorder (ADHD) is a chronic condition that affects 8% to 12% of school-aged children and contributes significantly to academic and social impairment. There is currently broad agreement on evidence-based best practices of ADHD identification and diagnosis, therapeutic approach, and monitoring. However, the increasing rate of diagnosis and treatment in the pediatric population has contributed to the significant public debate and misunderstanding of ADHD. Despite increased awareness, Attention-deficit hyperactivity disorder (ADHD) is a chronic condition that affects 8% to 12% of school-aged children and contributes significantly to academic and social impairment. There is currently broad agreement on evidence-based best practices of ADHD identification and diagnosis, therapeutic approach, and monitoring. However, the increasing rate of diagnosis and treatment in the pediatric population has contributed to the significant public debate and misunderstanding of ADHD. Despite increased awareness, ADHD remains underrecognized and may be undertreated by a factor of 10 to 1 in the US population. In order to educate the public and ensure optimal outcomes for ADHD patients, this continuing education activity has been developed to provide physicians and other healthcare providers with the most current information available on assessing and treating ADHD.

Upon completion of this activity, participants should be able to:

• Discuss the incidence of ADHD in adolescents and adults.
• Identify DSM-IV criteria used to make the diagnosis of ADHD in each age group.
• List important comorbidities of ADHD and identify distinguishing features between ADHD and other psychiatric diagnoses with similar manifestations.
• Describe a pharmacologic approach to ADHD treatment, including treatment goals and choice of medication.
• Enumerate self-management skills to be recommended when coaching ADHD patients on how to get along at school, at work, and at home.

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This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME). The Postgraduate Institute for Medicine is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians.

The Postgraduate Institute for Medicine designates this educational activity for a maximum of 1.0 Category 1 credit toward the AMA Physician's Recognition Award. Each physician should claim only those credits that he/she actually spent in the activity.

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Case 2: ADHD in an Adult

Case history.

A 42-year-old woman, mother of a son in his junior year of high school and a 20-year-old daughter, both living at home, comes seeking help because she feels her marriage is falling apart. This patient is the mother of the adolescent with ADHD in the previous case history. Her speech is rambling and a little impulsive. The physician manages to piece together the following history during her first visit, which was scheduled for 30 minutes but takes an hour because of her long, unfocused answers to the questions.

School had always been relatively hard for the patient, starting in grammar school. Though she had presented no behavior problems, teachers consistently complained of the patient's inattention and disorganization. With the help of summer school and tutors she managed to stay on course until she graduated from high school and even to get accepted to college. She was placed on probation after one semester at the university's business school, taking incompletes or "D's" and "F's" in each of her courses because she missed classes. She turned in assignments late, if at all; what she did hand in was sketchy and sloppy. Her advisor recommended that she switch her major from accounting to marketing, taking advantage of the patient's creative streak. With the help of tutoring and coaching in how to stay organized, the patient managed to earn her degree.

She was married for 6 months immediately after high school, but that marriage ended by mutual consent because, the patient says, "Neither of us had any idea what it meant to be in an adult relationship." The patient met her current husband, a graphic arts major, in a college advertising class. They were married in his senior year. It should have been her senior year too, but it took her an extra 1½ years to graduate. After they started dating they dreamed of developing their own business, combining her expertise in marketing with his in design. This was not to be. Not long after they started living together, her husband found that he could not count on his spouse to arrive at a meeting on time, remember to make an important phone call, or even to keep the checkbook in a consistent place. They decided to start a family together instead of a business. The husband worked in advertising while his wife stayed home with their 2 children.

As the children grew they had their own school problems and, later, social and legal troubles. (See previous case.) Their mother did her best to fulfill her role as stay-at-home caretaker, but it still fell on their father to pack their lunches, get them to the bus stop on time, and help them daily with homework. In spite of the patient's background in business, her husband took care of paying bills, balancing the checkbook, and preparing tax returns. The wife became a good cook. Her meals were quite creative but often served late because she had had to run out to the store, sometimes more than once, to purchase ingredients she had forgotten.

Once the children were in third and sixth grade, the patient found employment outside the home. Her husband took it upon himself to create a chore list for each family member. He was the only one to follow through consistently with his assigned tasks. Their home is no less messy than it was when the patient was at home full-time because even then, she was never organized enough to get ahead on the housework. Thanks to the patient, the home is decorated quite creatively. She rearranges the furniture and art work on the walls every few weeks because, she says, keeping things the same for too long makes her feel restless.

The patient's first job was in the marketing department of a local business. Within a few months she lost that position because of tardiness, absenteeism, unmet deadlines, and a general impression that she was not reliable or competent. She made few friends at work except for some smokers with whom she congregated regularly at the back door of the business.

She smokes 2 packs of cigarettes per day, a habit she has had since high school. She also drinks caffeinated coffee all day. The patient has recently cut down on her alcohol consumption after a near-miss on a second DUI and a confrontation with her husband over her escalating alcohol intake. She had tried other recreational drugs in college but did not continue using them after her marriage.

Losing that job as a marketer was the first of a succession of job losses. Subsequent reasons included the undependability shown at her first job, but she also impulsively quit when frustrated with working conditions and blurted out harsh criticism of the boss. Each new job brought lower pay and lower status than the previous one. The patient berates herself for her poor job performance, but though intelligent and educated enough, she can't seem to do any better. At the time of this interview she is working as the person on duty at 2 different laundromats for a 60+-hour work week. She likes how busy and active she is at this job; between servicing customers and machines she rarely sits down.

The home environment is messier and more chaotic than ever. It seems to her family that they are all perpetually being sent about the house in search of her glasses, keys, or wallet.

The patient has little energy for anything but her job. According to records received, her previous primary care doctor thought she might be depressed and tried a selective serotonin reuptake inhibitor, with little relief. The patient's answer to a direct question about whether she had taken the medication regularly is vague. It is not clear whether she did not trust the diagnosis of depression or could not remember to take her pills regularly, but the physician suspects that the patient did not have an adequate therapeutic trial of antidepressants. Progress notes in the previous doctor's record confirm the suspicion of noncompliance. That physician also tried clonidine, Vitamin B 6 , and various other measures without success to alleviate the severe PMS symptoms that had escalated over recent years. Still, she sleeps well and maintains a good appetite.

The patient describes herself as unpredictably irritable. She admits to picking fights with her husband and says she has completely lost interest in sex. Now, with concerns looming about both of their children compounded by the patient's being away from home so much of the time, her husband has threatened to leave. She feels like a failure in all realms: as a mother, a spouse, a homemaker, and a breadwinner.

A 5-Question Quiz on ADHD

Do you know the indications for an EEG in a child with ADHD? Or which psychotherapy approaches for ADHD demonstrate evidence-based effectiveness? Answer these questions and more.

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The Multimodal Treatment of Attention Deficit Hyperactivity Disorder Study (MTA):Questions and Answers

Revised november 2009.

Attention deficit hyperactivity disorder (ADHD) is the most common psychiatric disorder in childhood. Several interventions are effective in treating children with ADHD, including medications and behavior therapy. To examine how intensive treatment with medications compares with intensive behavior therapy, or with the combination of the two, NIMH sponsored the Multimodal Treatment of ADHD (MTA) study . The main findings from this study were published in December 1999, and are discussed below.

Q. What is the MTA?

A. The MTA was a multisite study designed to evaluate the leading treatments for ADHD, including behavior therapy, medications, and the combination of the two. The study included nearly 600 children, ages 7-9, who were randomly assigned to one of four treatment modes:

• intensive medication management alone;
• intensive behavioral treatment alone;
• a combination of both; or
• routine community care (the control group).

Q. Why is the MTA important?

A. While previous studies have examined the safety and compared the effectiveness of medication and behavior therapy for ADHD, they generally were short-term—no more than four months. The MTA study examined for the first time the safety and relative effectiveness of these two treatments—alone and in combination for a time period of up to 14 months, and compared these treatments to routine community care.

Q. What are the major findings of the MTA?

A. The MTA primary results were published in December 1999 in the Archives of General Psychiatry . Combination treatment and medication management alone were both significantly superior to intensive behavioral treatment alone and to routine community care in reducing ADHD symptoms. The study also showed that these benefits last for as long as 14 months.

In other areas of functioning (e.g., anxiety symptoms, academic performance, parent-child relations, and social skills), combination treatment was consistently superior to routine community care, whereas medication alone or behavioral treatment alone were not. The children in the combination treatment also ended up taking lower doses of medication than the children in the medication-alone group. These findings were consistent across all six research sites, despite substantial differences among sites in the children's sociodemographic characteristics. Therefore, the study's overall results can apply to a wide range of children and families in need of treatment services for ADHD.

Q. What did the MTA tell us about the safety of stimulant medication?

A. Of the 289 children randomized to medication, 4 percent had adverse effects severe enough to prompt them to discontinue the medication. Adverse effects included loss of appetite, sleep problems, crying spells, and repetitive movements. Medication also slowed the physical growth of children during the 14 months of treatment. The children who received intensive medication treatment (seven days a week) grew 4.25 cm on average and gained 1.64 kg on average, while the children who received behavior therapy only (no medication) grew 6.19 cm on average and gained 4.53 kg on average. 1 Over time, these growth effects may persist if medication is continued. 2  However, 88 percent of the children were successfully treated for the full duration of the study.

Q. What is the role of behavioral therapy in treating ADHD?

A. Research has shown that behavioral therapies are very effective in treating children with ADHD. However, the MTA study demonstrated that, on average, carefully monitored medication with monthly follow-up is more effective than intensive behavioral treatment alone, for up to 14 months.

All children improved over the course of the study, but they differed in the relative amount of improvement. The children receiving medication management, either alone or in combination with behavior therapy, generally showed the greatest improvement. However, children's responses varied enormously, and some children did very well in each of the treatment groups.

For some types of functioning, such as academic performance and family relations, the combination of behavioral therapy and medication was superior to the other treatment groups. Therefore, medication alone is not necessarily the best treatment for every child, and families often need to pursue other treatments, either alone or in combination with medication.

Q. Which treatment is right for my child?

A. Parents must consult with their child's doctor to determine the best course of treatment for their child. No single treatment is best for all children with ADHD. Families should consider side effects of medications, or other circumstances that might render certain treatments inappropriate for their child.

Children with coexisting conditions such as anxiety or external stressors such as high levels of family conflict may do best with a combination of treatments. When determining a suitable treatment, a child's needs, personal and medical history, and other relevant factors need to be carefully considered.

Q. Why do many social skills improve with medication?

A. Previously, it was thought that children with ADHD could only learn new social skills if they were explicitly taught. However, the MTA study findings suggest that many children can acquire these skills on their own when given the opportunity. Children treated with medication management (either alone or in combination with intensive behavioral therapy) showed more improved social skills and peer relations than children in the community comparison group after 14 months. This finding suggests that symptoms of ADHD may interfere with a child's ability to learn specific social skills. Medication may help them learn these skills by diminishing symptoms that had previously inhibited the child's social development.

Q. Why were the MTA medication treatments more effective than community treatments that also usually included medication?

A. There were substantial differences in quality and intensity between the study-provided medication treatments and those provided in the community care group. During the first month of treatment, the MTA doctors worked hard to find the best dose of medication for each child receiving the MTA medication treatment. After this period, the children saw their MTA doctor monthly.

During the treatment visits, the doctor spoke with the parent, met with the child, and worked to determine any concerns that the family might have regarding the medication or the child's ADHD. If the child was experiencing any difficulties, the MTA doctor could adjust the child's medication, In contrast, the community treatment doctors generally saw the children face-to-face only one or two times per year.

Careful monitoring also allowed for early detection and response to any side effects from the medication, which probably helped the children stay on the medication. In addition, the MTA doctors consulted with each child's teacher on a monthly basis, and used this information to make any necessary adjustments in the child's treatment. In contrast, the community treatment doctors did not interact regularly with the children's teachers.

Finally, the MTA doctors delivering the medication treatments generally prescribed higher doses of stimulant medications per day than the community treatment doctors.

Q. How were children selected for this study?

A. Parents heard about the study through their pediatricians and other health care providers, their children's teachers, or through radio/newspaper announcements. They then contacted the investigators. Study investigators interviewed the children and parents to learn more about the nature of the child's symptoms and medical history, and rule out other conditions or factors that may be causing the child's difficulties. The children needed to meet strict criteria to be eligible for the study.

Q. What are the main limitations of the MTA, and what happened after it concluded?

A. The MTA was designed and conducted in the early 1990s, before the extended release formulations of stimulant medications became widely available. The MTA used immediate release methylphenidate (Ritalin), which was administered three times a day. Currently, most children receiving stimulant treatment for ADHD are given a once-a-day dose of medication in the morning. However, this difference in medication administration does not change the study's main conclusions.

In addition, the MTA treatment lasted for 14 months only, after which the children were referred back to their community providers. Some of them continued treatment. Others discontinued their treatment or changed it, based on their individual situation. All participants, regardless of the treatment they received, were invited to return to the MTA clinics every one to two years for an assessment of their ADHD symptoms and level of functioning.

Because their treatment after the end of the study was not controlled, it is not possible to draw accurate conclusions about the effectiveness of interventions beyond 14 months, or determine if treatment improves long-term functioning. However, the observations collected from these uncontrolled follow-up assessments can provide information about the long-term course of ADHD itself. These data are being analyzed and reported as they become available. 3

Q. Where did this study take place?

A. The study was conducted at the following clinical research sites:

• New York State Psychiatric Institute at Columbia University, New York, NY.
• Mount Sinai Medical Center, New York, NY
• Duke University Medical Center, Durham, NC
• University of Pittsburgh, Pittsburgh, PA
• Long Island Jewish Medical Center, New Hyde Park, NY
• Montreal Children's Hospital, Montreal, Canada
• University of California at Berkeley, CA
• University of California at Irvine, CA

Q. Where can I find more information about the MTA study?

A. In addition to the information available on the NIMH Web site on  MTA the following is a selection of MTA references:

• The MTA Cooperative Group: A 14-Month randomized clinical trial of treatment strategies for attention-deficit/hyperactivity disorder (ADHD)  . Arch Gen Psychiatry 1999;56:1073-1086.
• The MTA Cooperative Group: Moderators and mediators of treatment response for children with attention-deficit/hyperactivity disorder (ADHD). Arch Gen Psychiatry 1999;56:1088-1096.
• Swanson JM, Kraemer HC, Hinshaw SP, Arnold LE, Conners CK, Abikoff HB, Clevenger W, Davies M, Elliott GR, Greenhill LL, Hechtman L, Hoza, B, Jensen PS, March JS, Newcorn JH, Owens EB, Pelham WE, Schiller E, Severe JB, Simpson S, Vitiello B, Wells K, Wigal T, Wu M: Clinical relevance of the primary findings of the MTA: success rate based on severity of ADHD and ODD symptoms at the end of treatment. J Am Acad Child Adolesc Psychiatry 2001; 40:168-179.
• Greenhill LL, Swanson JM, Vitiello B, Davies M, Clevenger W, Wu M, Arnold LE, Abikoff HB, Bukstein OG, Conners CK, Elliott GR, Hechtman L, Hinshaw SP, Hoza B, Jensen PS, Kraemer HC, March JS, Newcorn JH, Severe JB, Wells K, WigalT: Impairment and deportment responses to different methylphenidate doses in children with ADHD: the MTA titration trial. J Am Acad Child Adolesc Psychiatry 2001; 40:180-187.
• Vitiello B, Severe JB, Greenhill LL, Arnold LE, Abikoff HB, Bukstein O, Elliott GR, Hechtman L, Jensen PS, Hinshaw SP, March JS, Newcorn JH, Swanson JM, Cantwell DP: Methylphenidate Dosage for Children with ADHD over Time under Controlled Conditions: Lessons from the MTA. J Am Acad Child Adolesc Psychiatry 2001; 40:188-196.
• Owens EB, Hinshaw SP, Kraemer HC, Arnold LE, Abikoff HB, Cantwell DP, Conners CK, Elliot G, Greenhill LL, Hechtman L, Hoza B, Jensen PS, March JS, Newcorn JH, Pelham WE, Richters JE, Schiller EP, Severe JB, Swanson JM, Vereen D, Vitiello B, Wells KC, Wigal T: What treatment for whom for ADHD: Moderators of treatment response in the MTA. J Consult Clin Psychol 2003;71:540-552.
• MTA Cooperative Group: National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: 24-month outcomes of treatment strategies for attention-deficit/hyperactivity disorder. Pediatrics 2004;113:754-761.
• MTA Cooperative Group: National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004;113:762-769.
• Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein J, Pelham W, Abikoff HB, Newcorn J, Molina B, Hinshaw S, Wells K, Hoza B, Severe JB, Jensen PS, Gibbons R, Hur K, Stehli A, Davies M, March J, Caron M, Volkow ND, Posner MI, for the MTA Cooperative Group: Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007;46:1014-1026.
• Molina BSG, Hinshaw S.P., Swanson J.M., Arnold, L.E., Vitiello B, Jensen PS, Epstein JN, Hoza B, Hechtman L., Abikoff, H.B., Elliott GR, Greenhill LL, Newcorn, JH, Wells KC, Wigal TL, Severe JB, Gibbons RD, Hur K, Houck PR, and the MTA Cooperative Group: The MTA at 8 years: prospective follow-up of children treated for combined type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009;48:484-500.

1 MTA Cooperative Group: National Institute of Mental Health Multimodal Treatment Study of ADHD follow-up: changes in effectiveness and growth after the end of treatment. Pediatrics 2004;113:762-769.

2 Swanson JM, Elliott GR, Greenhill LL, Wigal T, Arnold LE, Vitiello B, Hechtman L, Epstein J, Pelham W, Abikoff HB, Newcorn J, Molina B, Hinshaw S, Wells K, Hoza B, Severe JB, Jensen PS, Gibbons R, Hur K, Stehli A, Davies M, March J, Caron M, Volkow ND, Posner MI, for the MTA Cooperative Group: Effects of stimulant medication on growth rates across 3 years in the MTA follow-up. J Am Acad Child Adolesc Psychiatry 2007;46:1014-1026.

3 Molina BSG, Hinshaw S.P., Swanson J.M., Arnold, L.E., Vitiello B, Jensen PS, Epstein JN, Hoza B, Hechtman L., Abikoff, H.B., Elliott GR, Greenhill LL, Newcorn, JH, Wells KC, Wigal TL, Severe JB, Gibbons RD, Hur K, Houck PR, and the MTA Cooperative Group: The MTA at 8 years: prospective follow-up of children treated for combined type ADHD in a multisite study. J Am Acad Child Adolesc Psychiatry 2009;48:484-500.

ADHD Case Study

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Genetics of ADHD: What Should the Clinician Know?

Oliver grimm.

Department of Psychiatry, Psychosomatic Medicine and Psychotherapy, University Hospital, Goethe University, Frankfurt, Germany

Thorsten M. Kranz

Andreas reif, purpose of review.

Attention deficit hyperactivity disorder (ADHD) shows high heritability in formal genetic studies. In our review article, we provide an overview on common and rare genetic risk variants for ADHD and their link to clinical practice.

Recent findings

The formal heritability of ADHD is about 80% and therefore higher than most other psychiatric diseases. However, recent studies estimate the proportion of heritability based on singlenucleotide variants (SNPs) at 22%. It is a matter of debate which genetic mechanisms explain this huge difference. While frequent variants in first mega-analyses of genome-wideassociation study data containing several thousand patients give the first genome-wide results, explaining only little variance, the methodologically more difficult analyses of rare variants are still in their infancy. Some rare genetic syndromes show higher prevalence for ADHD indicating a potential role for a small number of patients. In contrast, polygenic risk scores (PRS) could potentially be applied to every patient. We give an overview how PRS explain different behavioral phenotypes in ADHD and how they could be used for diagnosis and therapy prediction.

Knowledge about a patient’s genetic makeup is not yet mandatory for ADHD therapy or diagnosis. PRS however have been introduced successfully in other areas of clinical medicine, and their application in psychiatry will begin within the next years. In order to ensure competent advice for patients, knowledge of the current state of research is useful forpsychiatrists.

Introduction

Attention deficit hyperactivity disorder (ADHD) is a developmental disorder with symptoms of inattentiveness, impulsiveness, and hyperactivity, which leads to impairments in everyday life and manifests before the age of 12. The developmental trajectory shows a typical course of clinical symptoms, e.g., decrease of hyperactivity, occurrence of comorbid disorders, e.g., addiction and depression, as well as economic costs and social impairments [ 1 ]. ADHD has a worldwide prevalence of 5 to 7% of school-age children [ 2 ]. In childhood, impulsiveness and hyperactivity are leading symptoms, but decrease in adulthood, whereas inattentiveness becomes the leading symptom [ 3 ]. The extent to which symptoms completely remit or persist into adulthood is variable. While the cross-sectional prevalence of ADHD in adults was estimated between 2.5 and 3% [ 4 ], the persistence of symptoms with corresponding impairments into adulthood is about 65%.

Early on, clinicians noticed that ADHD-typical behavior occurs frequently in syndromic disorders, e.g., Klinefelter syndrome, Williams syndrome, fragile X syndrome, or tuberous sclerosis [ 5 ]. The high heritability [ 6 ] suggests a significant genetic component (see below). Genetic research can contribute not only to the elucidation of neurobiological mechanisms but also to clinical questions such as the effect of operationalization or the genetic correlation with comorbid disorders. Patients with ADHD show high comorbidity with autism, obesity, bipolar disorder and depression, anxiety, and substance use disorder [ 1 , 7 ]. This suggests common underlying risk gene variants. Genetic correlations provide insights how biologic mechanisms manifest in different but related disorders (pleiotropy). In the following, we focus on general aspects of heredity and the complementary results of the analysis of common and rare variants of the genome.

Heritability in ADHD

There are several ways to investigate the heritability of ADHD. A classical strategy makes use of twin studies, due to the possibility of assessing the genetic effect (heritability) of the disorder. According to a recent meta-analysis of twin studies, the heritability of ADHD is estimated at 77–88% [ 8 ]. The magnitude is therefore similar to that of autism spectrum disorder (about 80%), bipolar disorder (about 75%), and schizophrenia (about 80%) [ 6 ].

By means of genome-wide complex trait analysis (GCTA), thousands of individuals are examined for hundreds of thousands of single-nucleotide polymorphisms (SNPs) and thus provide a measure of heritability, the so-called SNP-based heritability. A recent mega-analysis estimates SNP-based heritability (h 2 snp = 22%) in a range comparable to previous estimates of h 2 snp for ADHD in studies with fewer subjects (h 2 snp, 10–28%) [ 9 ]. The proportion of heritability that explains this gap between approximately 74% in twin studies and 22% in SNP-based heritability is also referred to as “hidden heritability” in reference to the search for dark matter in astronomy. One explanation is the fact that statistical power of the performed genome-wide association studies (GWAS) is too small to reliably predict genetic associations. A core problem is the required number of test persons in order to reliably map a genetic association, preferably one with a high effect size. A higher number of participants, along with other measures such as the refinement of statistical methods, would certainly help to considerably increase the predictive power of GWAS. A stronger effect size of the SNPs, a higher allele frequency of the rare alleles of SNPs, and a higher LD lower the required number of subjects decisively [ 10 , 11 ] which in turn means that, in ADHD, there are either very rare alleles or low effect sizes in action given as the latest and largest GWAS only gave 12 genome-wide significant hits by examining more than 20,000 cases.

In addition to the relationship between the number of subjects and the allele frequency of the SNPs, other DNA variants, such as copy number variations (CNV), may explain the missing heritability. CNVs are sections of DNA that either occur in multiple copies or deletions of certain chromosomal sections. CNVs occur at different frequencies but are quite common in patients with ADHD. Small CNVs of only a few kilobases are not detected with the necessary accuracy by GWAS, yet make up the considerably larger part of the genetic variability in ADHD. Large CNVs (> 500 kb) with a frequency of less than 1% can only be detected using sufficiently large sample sizes. In order to be able to map all possible CNVs, whole-genome sequencing (WGS) would be the method of choice.

Genome-Wide Association Studies (GWAS)

Until the late 2000s, candidate gene studies on small samples were the method of choice for testing genetic associations. Genes coding for components of the monoamine transmitter systems was first investigated in ADHD. However, none of the candidate genes was replicated by larger genome-wide studies. A summary of these studies can be found in authoritative reviews [ 8 , 12 , 13 ]. While GWAS initially identified only a few loci for psychiatric disorders [ 14 ], the most recent collaborations succeeded in discovering a larger number of genome-wide significant loci ( p  ≤ 5 × 10 −8 ) by significantly increasing the number of cases and control numbers (> 10,000).

A study of 909 parent-child trios with ADHD-affected children revealed strong genetic associations of the genes glucose-fructose oxidoreductase domain-containing 1 ( GFOD1 ) and cadherin 13 ( CHD13 ) [ 15 – 17 ] with ADHD. GFOD1 is expressed in the frontal cortex; the exact function of the gene is not yet known [ 18 ]. CDH13 encodes for a calcium-dependent cell-cell adhesion protein that influences neuronal development and synaptic plasticity [ 22 ]. In a knockout mouse model of Cdh13 , mice showed hyperlocomotion and learning deficits [ 19 ]. These findings, together with evidence from other association studies in which CHD13 is associated with, e.g., autism, schizophrenia, bipolar disorder, and depression [ 20 ], make CDH13 an interesting candidate gene for ADHD.

Another ADHD candidate gene found in a large family by linkage analysis and replicated in parallel in a global case-control study ( n  = 2627 ADHD subjects, n  = 2531 controls) is adhesion-G protein-coupled-receptor-L3 ( ADGRL3 , formerly LPHN3 ), a brain-specific G protein-coupled receptor with cell adhesion function [ 23 ]. ADGRL3 was confirmed as an ADHD candidate locus in two other independent case-control studies, by association of one haplotype in ADGRL3 [ 21 ] and single associations of several SNPs [ 22 ]. In the zebrafish model, the loss of adgrl3 leads to a reduction of dopaminergic neurons in the ventral diencephalon and a hyperactive/impulsive phenotype [ 23 ], whereas in Adgrl3 -knockout mice, an increase in reward motivation and activity level as well as other ADHD-analogous behaviors was observed—parallel to dysregulation of the dopamine transporter [ 24 , 25 ]. This suggests that the biological validation of an ADHD candidate gene from a GWAS in an animal model can elucidate potential mechanisms of pathogenesis. On the other side, it must be critically questioned whether behavioral traits such as hyperlocomotion in animals are equivalent ADHD-hyperactivity in humans.

In the most recent and comprehensive meta-analysis of ADHD GWAS data sets to date (20,183 cases, 35,191 controls), 12 genomic loci with genome-wide significance ( p  < 5 × 10 −8 ) could be identified [ 26 •]. The 12 loci cover 16 genes, of which at least four have a high expression in the human brain; for example, DUSP6 regulates the synaptic transmitter dopamine, while MEF2C is primarily associated with autism and intelligence impairment [ 8 ]. Furthermore, there was a genetic correlation with achieved school and education goals, i.e., people with a higher genetic risk for ADHD have a slightly lower success in school and education, regardless of the diagnosis ADHD. Similarly, an earlier study argued for a high genetic correlation ( r  = 0.64) of ADHD and bipolar disorder [ 27 ].

A recent meta-analysis in more than 17,000 cases showed a high overlap in genetic correlation between children and adults as well as continuous measures as well as categorical ADHD definition [ 28 ]. There, genetic factors influencing ADHD persistence in adults (6532 patients with ADHD and 15,874 healthy controls) and early childhood ADHD (10,617 children with ADHD and 16,537 healthy controls) were compared. A comparison of the data sets showed a high genetic correlation ( r  = 0.81) between early childhood and adult ADHD arguing that these are indeed covering the same clinical phenotype. An additional meta-analysis of ADHD over the entire life span in children and adults revealed nine genes significantly associated with ADHD over the life span. This underscores how GWAS can contribute to clinical questions about differences between childhood and adult manifestations of ADHD.

Rare Variants and genetic Syndromes

The association of genetic syndromes with ADHD in childhood has been known for a while. Chromosomal aberrations have been frequently found in ADHD and other developmental disorders [ 29 ].

Fragile X syndrome (FXS) is one of the most frequent genetic syndromes associated with ADHD. Based on parent or teacher reports, 59% of boys with FXS meet diagnostic behavioral criteria for either ADHD-inattentive type only (31.5%), ADHD-hyperactive type only (7.4%), or ADHD-combined type (14.8%) [ 5 ]. FXS is caused by loss-of-function of the FMR1 gene, which encodes the RNA-binding protein, called fragile X mental retardation protein (FMRP). Exaggerated glutamatergic excitation and reduced GABA-signaling have been discussed as main mechanisms for FXS.

Neurofibromin 1 ( NF1 ) is characterized by different tumors in the eyes, the skin, and the central nervous system. The NF1 locus is situated on chromosome 17q11.2. About one third is accompanied by ADHD symptoms during childhood [ 30 ]. The neurobiological basis of the link between ADHD and NF1 might stem from lesions in the basal ganglia.

Tuberous sclerosis complex (TSC) is an autosomal dominant hereditary disorder associated with brain malformations and tumors, skin lesions, and mostly benign tumors in other organ systems, often clinically characterized by epileptic seizures and cognitive impairment. ADHD prevalence in TSC patients has been ranging from about 30 to 60% [ 31 •].

The sexual aneuploidies Turner syndrome and Klinefelter syndrome have been associated with ADHD as well. In patients suffering from Klinefelter syndrome, the rate of ADHD is as high as 63% [ 32 ]. In our experience, these patients are more often seen by adult psychiatrists than the aforementioned syndromes.

Williams-Beuren syndrome (WBS) is a microdeletion on chromosome 7 and is associated with a typical set of symptoms ranging from special facial features (“elf-like”) to pulmonal and cardiovascular anomalies. On a behavioral level, they are characterized as being “hypersocial.” Almost two thirds of WBS show symptoms of ADHD [ 33 ]. The deletion of Limk1 leads to hyperactivity and impaired spatial learning in knockout mice.

Velo-cardio-facial/DiGeorge syndrome (22q11 deletion syndrome) is associated with cardiovascular abnormalities and a variety of psychiatric disorders [ 34 ]. Previous studies often focused on schizophrenia. However, much more patients suffer from ADHD (about 40%), most of them from the inattentive type [ 35 ]. The hemizygous 22q11 deletion encompasses the COMT gene which is a bottleneck for the catecholamine neurotransmission.

While these syndromes are rare, they should be known to the adult psychiatrist because most patients come into contact with the medical system due to the complex comorbidities, e.g., heart disorder in 22q11. However, there are no studies looking at the behavioral trajectory of these genetic syndromes and associated ADHD in adults. Nevertheless, recent polygenic risk analyses suggest that a significant part of the heredity of ADHD is caused by rare variants [ 36 ]. Rare variants do not show the high penetrance of deleterious variants of syndromic disorders. While it is likely that their effect size or penetrance is much lower, their frequency might be more common than the syndromic disorders mentioned above. Some of the “missing heritability” might be explained by these rare variants as the effects of rare variants can account for up to one quarter of heritability [ 14 , 26 •]. The largest classes of rare variants are single-nucleotide variants (SNVs), i.e., classical although very rare polymorphisms (minor allele frequency < 0.1%) of one base pair, and copy number variants (CNVs). CNVs are duplications or deletions and contain both coding and non-coding DNA. While a single variant is rare by definition (0.3–1% of the total human genome), CNVs represent up to 10% of the human genome. The effects of such copy number polymorphisms (CNPs) on ADHD risk have not yet been investigated in detail, although there is a first study [ 37 ] that shows an association of a specific CNP with ADHD.

A study in more than 2800 children with ADHD found an accumulation of large and rare CNVs in the 15q13.3 locus. Although still rare, the frequency of 0.6% results in a relatively high effect size with an odds ratio of 2.2, which is significantly higher than any single locus in ADHD-GWAS [ 29 ].

Initial studies examining CNVs in ADHD case samples focused on children but not on adults. However, due to the small sample size and evolving methodology, the results are inconsistent. A British and an Icelandic study of children found a disproportionately high level of rare, large CNVs in ADHD patients compared to healthy controls [ 38 , 39 ]. Duplications on chromosome 16p13.11 were observed, as well as loci which occurred in autism and schizophrenia.

Further genome-wide studies on ADHD in childhood investigated the overall burden of rare, large CNVs in patients compared to healthy subjects. They provide some evidence of an accumulation of rare variants in childhood ADHD [ 40 – 42 ]. Nevertheless, there is no ADHD-specific CNV, but an increase in the total number of CNVs within ADHD patients (“high CNV burden”) compared to the control group is observed.

In a genome-wide screening for CNVs in a cohort of 99 children and adolescents with severe ADHD, seven syndrome-associated CNVs were identified. The gene coding for neuropeptide Y ( NPY ) had been deleted in a ∼ 3 Mb duplication on chromosome 7p15.2–15.3. Interestingly, this was associated with an increased NPY plasma concentration in affected family members [ 43 ].

In a larger whole-genome CNV study with 1013 cases of ADHD and 4105 healthy children of European descent, CNVs affecting metabotropic glutamate receptor genes were enriched across all cohorts [ 44 ]. The study identified GRM5 (coding for glutamate receptor, metabotropic 5) deletions in ten cases and one control, GRM7 deletions in six cases, and GRM8 deletions in eight cases and no controls.

An innovative approach was used in a linkage analysis of three German ADHD families ( n  = 70), where rare variants in the regions inherited by affected members were tested in a large ( n  > 9000) independent cases and controls sample. This led to the identification of AAED1, which interacts with the protein kinase C-alpha-binding protein ( PICK1 ). PICK1 is a regulator of dopamine transporter trafficking dopaminergic neurons.

Since CNVs are rare, these initial results must be considered with caution. The role of these rare variants in healthy populations is not yet clear, and their frequency and location are currently being finalized and mapped. Depending on the definition, a recent CNV map estimated that 4.8–9.5% of the genome contributes to CNVs. This mapping identified about 100 genes that can be completely deleted without producing an apparent phenotype [ 45 ]. Therefore, caution in interpreting associations between ADHD and CNVs of unknown function is needed.

Another group of genetic variations, the so-called single-nucleotide variants (SNVs), also seems to have a large share in the unexplained genetic variability of ADHD. A recent study with 123 ADHD patients and 82 healthy controls by means of complete exome sequencing shows that within the group of ADHD patients, a strongly increased number of amino acid altering SNVs with rare allelic frequency (< 0.1%) are observed [ 46 ]. Another study compared the results of an ADHD case control study on de novo and rare SNVs with those of autism cohorts. It was found that autism and ADHD patients carry a similarly high SNV load (“SNV burden”), which leads to shortened and potentially functionally altered proteins [ 47 ].

Should the knowledge about these rare variants lead to clinical sequencing tests in ADHD patients? So far, this cannot be recommended as these variants still seem to be rare, and complete genome sequencing is expensive. However it can be considered in patients with comorbid intellectual disability.

Polygenic Risk Scores in ADHD and ADHD-Related Traits

A polygenic risk score (PRS) uses the summary statistics of SNP results from large GWAS to predict clinically significant variables. The idea of the PRS is to provide genetic risk prediction, given the large set of SNPs for each individual, and use it as a predictive tool for a specific trait [ 48 •]. An individual PRS can be calculated by summing all trait-associated SNPs weighted by their effect sizes [ 49 ]. In addition, PRS can be calculated for single phenotypes that are related to ADHD. As this technique has gained some popularity, we will give an overview of its application in ADHD and related psychiatric disorders.

PRS provide interesting insights into the dimensional structure of ADHD: A PRS of ADHD risk variants is correlated with attention deficits in the general population [ 50 ] supporting the notion that ADHD is not a clear-cut categorical disorder but the extreme end of a genetically determined, continuous behavioral trait. In addition to an approach generalizable to non-diseased participants, the impact of PRS on ADHD-related endophenotypes [ 51 ] is supported by neuroimaging studies. Genetic variants related to intelligence and education are positively associated with larger total brain volumes in children. However, genetic variants associated with ADHD were related to smaller caudate volume, a subcortical region of the brain that has been consistently found to be reduced in individuals affected by this disorder [ 52 ].

Apart from these more theoretical insights, PRS can be applied to more clinical questions: ADHD comes with a high burden of comorbid disorders which can be studied in large epidemiological samples like the UK Biobank sample. In more than 135,000 participants, an ADHD PRS was highly linked to depression, anxiety, alcohol intake, risk-taking, and negatively to verbal-numerical reasoning. While this gives general insight into the genetic structure of these traits, it should be kept in mind that ADHD and other disorders are probably underdiagnosed in this large sample [ 53 •].

ADHD in childhood, but in some parts in adulthood, too, is tightly linked to school achievement. In studies looking at the link between ADHD PRS and educational achievement or even intelligence, it is clear that PRS predicts educational achievement [ 26 •]. Interestingly, this link is not restricted to ADHD cases but generalizes to the normal population [ 54 ].

PRS can even contribute to the highly debated question, what defines a “persister” versus a remitter (from childhood ADHD) in patients? A recent population-based cohort correlated an ADHD PRS to ADHD symptom trajectories between ages 4 and 17 [ 55 ]. The ADHD PRS was higher in the persistence group in children, pointing to the effect of genetics in the course of the disorder.

Studies using a PRS from other psychiatric disorders, e.g., a schizophrenia risk PRS, predicted ADHD and oppositional defiant disorder in a large sample of children (ALSPAC) [ 56 ]. PRS scores from multiple psychiatric disorders can be used to enhance the discriminatory power between them. Using PRS for five psychiatric disorders and imaging data on neural connectivity, it was shown that there are shared altered functional connectivity patterns for autism spectrum disorder, bipolar disorder, and schizophrenia versus ADHD [ 57 ].

Another study investigated the relationships of PRS of psychiatric disorders and substance (ab-)use. Using PRS for cross-disorder psychopathology (CROSS) from 2573 European-American participants and information on liability to alcohol, cannabis, cocaine, nicotine, and opioids, the authors identified negative association with cannabis and positive association with nicotine use for ADHD that did not survive after correction for multiple testing; however, in the other psychiatric disorders, statistically relevant patterns between substance and disorder-specific PRS could be identified [ 58 ]. These studies underscore that related but distinct genetic risk contributes to common patterns of developmental psychopathology.

In a study which looked at socioeconomic variables like employment, individual income, and household wealth, an ADHD PRS was associated with more negative outcomes in these variables and increased the likelihood of receiving social security disability benefits, unemployment or worker compensation [ 59 ].

However, application of PRS in clinical practice comes with some drawbacks, e.g., most GWAS concentrate on populations of European ancestry. The application in other areas of clinical medicine led to severe problems in interpretation of results [ 60 •].

While these applications of PRS for understanding ADHD are exciting, it should be kept in mind that PRS typically explain only about 5.5% in variance [ 26 •]. In an exemplary study of height, SNPs in a sample of about one million genotyped participants explained 48% variance of body height [ 61 ]. Nevertheless, the receiver-operator accuracy for correctly predicting height from a PRS was between 55 and 65%. This is much too low for a simple clinical screening test and even more applies to ADHD, as the primary studies are far smaller and underpowered.

The findings of recent years indicate that there is a specific genetic basis for ADHD in children and adults that not only increases the risk of the disorder but also the risk of other independent psychiatric diagnoses and socially relevant measures such as school and learning outcomes [ 26 •]. How can this new knowledge be applied to support treatment and diagnosis? In terms of diagnosis, a first step could be to identify rare variants in adults and children that could help distinguish them from other genetic syndromes or neurological disorders. However, this will require even greater validation of the findings. For most patients, the common variants do not seem to explain enough variance to be used in predicting diagnosis. This may change if gene set analyses or polygenic risk scores allow a substantial explanation of heredity.

A general finding from the last 20 years of ADHD psychiatric genetics is that risk genes involved in the regulation of catecholaminergic genes have not been reliably replicated. Genetic findings show that ADHD is more than a simple “catecholaminergic disorder.” The genome-wide loci affected by ADHD often have a general function in areas such as “neurite outgrowth,” “synaptic plasticity,” or “glutamatergic signal transmission” [ 26 •, 62 , 63 ]. Research over the next few years must show whether the common denominator of these variants is brain expression and regulation of neuronal activity and development or whether there are completely different underlying causes [ 64 ].

Another field that could see an earlier clinical application of genetics is the prediction of pharmacotherapy, the so-called pharmacogenomics. Initial studies on pharmacogenomics in ADHD looked at common candidate genes such as the dopamine transporter [ 65 ]. Since therapy is mainly based on improvement of dopaminergic neurotransmission, it is plausible to expect a stronger effect of genes involved in the mediation of dopaminergic effects. Smaller studies have shown that polymorphisms in genes of catecholaminergic neurotransmission [ 66 ] or the SNARE complex of the synapse can indeed predict the response to stimulant therapy [ 67 ].

The application of genomic methods for differential or primary diagnosis of psychiatric disorders does not play a role in clinical medicine so far. Since the explained variance is still too low, other factors for therapy prediction and diagnosis will play a greater role in individual cases. At present, patient treatment does not focus on genetic testing but on an exact clinical diagnosis. Nevertheless, in the future, psychiatrists will have to deal with the fact that some of their patients are diagnosed with a rare variant (SNV or CNV). Currently, it can be stated that beyond already defined genetic syndromes (e.g., 22q11-DS), there is no proven rare variant that determines or predicts ADHD.

PRS are not yet helpful in differential diagnosis either; however, it is to be expected that this will change in the upcoming years. For example, the PRS for breast cancer has been combined with conventional risk factors to identify 16% of the population who may benefit from an earlier screening (and 32% who may delay screening) [ 68 ]. In coronary heart disease, PRS have identified individuals with a risk who benefit more from early initiation of statin therapy than individuals with a lower genetic risk [ 69 ]. It can be assumed that similar results will also find their way into psychiatry, even though genetic investigations in ADHD are currently of predominantly scientific and not yet clinical significance.

In general, the genetic disposition plays a major role in the pathogenesis of ADHD. On the one hand, knowledge and public discussion about this can counteract stigmatization of patients. Genetic causes are now accepted by many affected patients and their relatives as an explanatory model [ 70 , 71 ]. An increase in knowledge of genetics and neurobiology will not replace the physician’s intuition in diagnosing and treating the individual patient. Psychiatric genetics will not change the art of clinical medicine, i.e., the way physician and patient communicate about mental health, but it will provide a useful tool for a more personalized medicine.

Acknowledgements

Open Access funding provided by Projekt DEAL.

Compliance with Ethics Guidelines

Thorsten M. Kranz declares no potential conflicts of interest.

Oliver Grimm has received personal fees from Medice Arzneimittel GmBH.

Andreas Reif has received personal fees from Medice Arzneimittel Pütter GmbH, Shire PLC, neuraxpharm Arzneimittel GmbH, Janssen-Cilag GmbH, and Servier Deutschland GmbH.

This article does not contain any studies with human or animal subjects performed by any of the authors.

This article is part of the Topical Collection on Genetic Disorders

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