Neurobiology and Genetics of ADHD in Adults

Thomas J. Spencer, MD

CNS Spectr. 2008;13:9(Suppl 13):5-7

An expert panel review of clinical challenges in psychiatry

Funding for this activity has been provided by an educational

grant from Shire Pharmaceuticals Inc.

Accreditation Statement
This activity has been planned and implemented in accordance with the Essentials and Standards of the Accreditation Council for
Continuing Medical Education (ACCME) through the joint sponsorship of the Mount Sinai School of Medicine and MBL
Communications, Inc. The Mount Sinai School of Medicine is accredited by the ACCME to provide continuing medical education for
physicians.

Credit Designation
The Mount Sinai School of Medicine designates this educational activity for a maximum of 2 AMA PRA Category 1 Credit(s)TM.
Physicians should only claim credit commensurate with the extent of their participation in the activity.

Faculty Disclosure Policy Statement

It is the policy of the Mount Sinai School of Medicine to ensure objectivity, balance, independence, transparency, and scientific rigor in
all CME-sponsored educational activities. All faculty participating in the planning or implementation of a sponsored activity are expected
to disclose to the audience any relevant financial relationships and to assist in resolving any conflict of interest that may arise from the
relationship. Presenters must also make a meaningful disclosure to the audience of their discussions of unlabeled or unapproved drugs or
devices. This information will be available as part of the course material.

This activity has been peer reviewed and approved by Eric Hollander, MD, Chair and Professor of Psychiatry at the Mount Sinai School
of Medicine. Review Date: August 27, 2008.

Statement of Need and Purpose

There are numerous reasons to treat attention-deficit/hyperactivity disorder (ADHD) in adults, including to minimize impairment from
core symptoms, to alter the course of co-morbid disorders, and to prevent neurologic deterioration. Untreated adolescents with ADHD
show smaller cerebral volumes compared to medicated patients, who more closely resemble healthy controls. However, treatment of
adult ADHD is often based on upwardly extended models of child and adolescent care. Adults’ differing patterns of co-morbidity and

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 symptom heterogeneity pose new treatment challenges. Having a large number of therapeutic options available for treating ADHD
represents an opportunity for patients to achieve better outcomes, but it also raises a challenge for the busy clinician who must choose
among many diverse options to tailor a regimen for each individual patient. Psychostimulants remain a viable first-choice strategy, yet
there are idiosyncratic differences in response to the various formulations. Recent developments have made stimulants more effective in
a range of clinical situations through the development of new release and pharmacokinetic technologies. Distinctions can be made among
the long-acting medications with regard to the onset, magnitude, and duration of clinical effects. Recognition of these differences is
important for individualizing patient treatment. Transdermal formulations offer new treatment delivery methods that may increase
compliance and safety. In addition, a norepinephrine reuptake inhibitor was recently approved for ADHD, adding a new mechanism to
the armamentarium. Other nonstimulants, such as venlafaxine, bupropion, and tricyclic antidepressants, have also been used to treat
ADHD. While medications are considered the primary treatment for adults with ADHD, several psychosocial treatments seem to be
helpful, including cognitive-behavioral therapy, psychoeducation, and organizational and time management training.

Target Audience
This activity is designed to meet the educational needs of primary care physicians and psychiatrists.

Learning Objectives
• Review the neurobiology of attention-deficit/hyperactivity disorder (ADHD), including genetic influences and neuroanatomical and
neurochemical factors.
• Describe the current practices and controversies surrounding stimulant therapy in adults with ADHD.
• Discuss the benefits of nonstimulant treatment, psychosocial treatment, and emerging treatment options for adult ADHD.

Faculty Disclosures
Dr. Spencer is associate professor of psychiatry at Harvard Medical School and associate director of the Clinical and Research Program
in Pediatric Psychopharmacology at Massachusetts General Hospital in Boston.

Dr. Spencer is a speaker for Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Ortho-McNeil, and Shire; is on the advisory boards of
Cephalon, Eli Lilly, GlaxoSmithKline, Janssen, Novartis, Ortho-McNeil, Pfizer, and Shire; and receives research support from Cephalon,
Eli Lilly, GlaxoSmithKline, Janssen, National Institute of Mental Health, Novartis, Ortho-McNeil, Pfizer, and Shire.

Acknowledgment of Commercial Support

Funding for this activity has been provided by an educational grant from Shire Pharmaceuticals Inc.

Peer Reviewer
Eric Hollander, MD, reports no affiliation with or financial interest in any organization that may pose a conflict of interest.

To Receive Credit for this Activity

Read this Expert Roundtable Supplement, reflect on the information presented, and complete the CME posttest and evaluation on pages
19 and 20. To obtain credit, you should score 70% or better. Early submission of this posttest is encouraged. Please submit this posttest
by September 1, 2010 to be eligible for credit.

Release date: September 1, 2008

Termination date: September 30, 2010

The estimated time to complete this activity is 2 hours.

A related audio CME PsychCastTM will also be available online in October 2008 at: cmepsychcast.mblcommunications.com and via
iTunes.

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 Abstract
Treatment of attention-deficit/hyperactivity disorder (ADHD) may positively impact the neurobiology of adult patients with ADHD.
Treatment may also minimize impairment from core symptoms and may alter the course of co-morbid disorders such as depression and
substance use disorder. However, much of the information on stimulant use in adult ADHD comes from studies conducted in children,
and it remains unclear whether there is a difference between children and adults when it comes to the side effects and tolerability of
ADHD treatments. It is known that clinical presentation differs between adults and children, with adults demonstrating a higher
percentage of mood disorders. Current treatments for adult ADHD include psychosocial therapies and pharmacologic therapies, the
latter of which include the stimulants d-methylphenidate extended release (XR), OROS methylphenidate, lisdexamfetamine, and mixed
amphetamine salts XR; and the nonstimulant atomoxetine, a selective norepinephrine reuptake inhibitor. There is need for additional
study of treatment strategies for adult ADHD. Although all classes of ADHD medications are approved in adults, there are fewer
approved formulations for adults than for children. Efficacy in adults is more subjective than in children, which may affect how efficacy
rates for adult treatments are calculated. Adults also present a greater diversion risk than children. In addition, there are several new
and emerging medication treatments worth considering.

This Expert Roundtable Supplement represents part 2 of a 3-part supplement series on adult ADHD led by Lenard A. Adler, MD. In this
activity, Thomas J. Spencer, MD, discusses the neurobiology and genetics of adult ADHD; Mark A. Stein, PhD, discusses stimulant
therapy; and Jeffrey H. Newcorn, MD, reviews nonstimulants and psychosocial treatments.

Etiology
Attention-deficit/hyperactivity disorder (ADHD) is a heterogeneous neurobehavioral disorder with multiple possible etiologies. As in
most complex neuropsychiatric conditions, ADHD is most likely caused by a complex interplay of factors including genetic influences,
environmental/psychosocial issues, neurobiologic (neuroanatomical and neurochemical) factors, and central nervous system insults (eg,
neonatal hypoxia or exposure to chemicals during pregnancy).

Reinforcing the genetic basis of ADHD, a study1 of pre- and perinatal risk factors for ADHD demonstrated that parental ADHD was by
far the greatest risk factor for the disorder. Psychosocial adversity and low birth weight followed as the second and third most significant
risk factors. The fourth most specific risk factor was cigarette exposure which, surprisingly, surpassed the dangers of alcohol and drug
exposure in this sample (Slide 1).

Because individuals with ADHD have deficits in executive function similar to those of individuals with frontal lobe disorders, ADHD
was historically viewed as a “frontal” disorder. Executive function deficits include problems with planning and organization, cognitive
flexibility, working memory, and response inhibition/impulse control. Although these are problems that can exist in normal individuals as
well as those with ADHD, they are strongly associated with ADHD. Indeed, ADHD patients of all ages show relatively similar findings
of impaired performance on one or more tasks of vigilance, search, and attention; working memory (ability to retain information while
processing new information); response inhibition (ability to juggle competing or distracting tasks); verbal learning (encoding); and delay
aversion (the need to have immediate gratification).

Regarding tasks of attention, it is often assumed that those with behavioral symptoms of inattention tend to forget things. In actuality,
these symptoms of attention often involve encoding new information. Therefore, it is less likely that these individuals have forgotten
what they learned; rather, they have not learned it to begin with. A child with ADHD will frequently be unable to repeat what the teacher
said even just a moment ago.

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 A landmark study by Castellanos and colleagues2 compared the brain structures of 152 boys (up to 18 years of age) and girls (up to 15
years of age) with ADHD to 139 control children. Total cerebrum, the cerebellum, and the four cerebral lobes were smaller in the ADHD
patients and did not change over time. Developmental trajectories of these structures paralleled that of the controls from age 5–18, but
did not catch up over time. The caudate was the only brain region in which there were initial differences with some subsequent
normalization by the mid-teens. Of note, ADHD patients who were medicated had larger (more normal) brain volumes than those who
were not.

In a seminal study performed by investigators at the National Institute of Mental Health, Shaw and colleagues3 found a delay in cortical
maturation among ADHD patients. The pattern of brain development, from sensorimotor to associative areas, was similar in children
with and without ADHD. However, the age of peak development was delayed in those with ADHD (Slide 2).3 While some interpreted
this finding to mean that the brain abnormalities associated with ADHD eventually normalized, that conclusion is not justified by these
data. In fact, adult data4 using the same measure of cortical thickness, have shown that cortical thickness is not normalized, and that the
areas of the brain that are affected in children with ADHD remain affected in adulthood. In this study the dorsolateral prefrontal cortex
(DLPFC), parietal areas, and anterior cingulate cortex (ACC) are thinner in cortical thickness in adults with ADHD (Slide 3).4

Structural studies5 have revealed that certain parts of the brain are smaller in adults with ADHD compared to controls. The greatest
differences in brain size were in the DLPFC and the ACC. The DLPFC controls working memory which, as noted above, involves the
ability to retain information while processing new information. These deficits impair the ability to use internalized memories to self
direct or organize behaviors. Children with ADHD tend to be deficient in goal-directed behavior and typically perform well only in
structured settings where they are guided to address specific tasts and ignore specific tasks, and are assisted to stay on task.

The ACC is involved with rapidly choosing between competing or distracting tasks and is thought to be a key region of regulation—
required for executive function—involving the ability to focus on one task and choose between options. A structural study of adults
with ADHD has demonstrated that this population has smaller gray matter overall, larger white matter, smaller DLPFC, and smaller ACC
compared to controls.2 Notably, the nucleus accumbens, which is a key part of the reward motivational system, was somewhat larger in
adults with ADHD compared to controls.

A recent functional magnetic resonance imaging study6 measured the amount of brain activity in response to a cognitive challenge in
parent-child dyads with and without ADHD. A go/no go task was utilized, which evaluated the ability to perform a task in response to a
“go” signal and stop performing the task when given a “no-go” signal. Both youths and adults showed attenuated activity in the

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 frontostriatal regions of the brain that are key for attention and inhibitory control (prefrontal cortex and caudate). In addition, adults with
ADHD appeared to activate non-frontostriatal regions (ACC, parietal areas) more than normals.6 The amount of brain activation
observed correlated closely with the degree of efficiency on the task in both children and adults with ADHD.

A different functional imaging study by Valera and colleagues7 employed a test of working memory in adults with ADHD and controls.
They found that the cerebellum was activated more in adult controls than adults with ADHD during the task. These are striking data, as
the cerebellum was once thought to control automatic motor function, not cognition. There are increasing data indicating that the
cerebellum is key regulator of cognition in normal individuals. There is still no single area of the brain known to be different between
ADHD and controls; rather there are differences in discrete brain systems between normals and those with ADHD.

Casey and Durston8 summarized the control systems that are operant in ADHD, using a top-down, bottom-up approach. They
hypothesized that bottom-up neural systems systems detect the regularities and irregularities in the environment to alert the brain to alter
or adjust behavior. These bottom up neural systems cue frontal systems to adjust. For example this may be salient when an individual is
deciding to continue doing a particular task in the same way or to shift activities because the task has changed. Casey and Durston8
posited that the striatum regulates what to expect (type of task), the cerebellum regulates when to expect it (timing of task), and the
parietal lobe alerts one to novel or newer competing stimuli.

Sonuga-Barke9 described a dual pathway model consisting an executive circuit and a reward circuit (Slide 4).9 The executive circuit is
more cognitive and involves directed attention, the ability to control the attention, the ability to follow innate goals, and the ability to
keep a long-term goal in mind while working on the details of a task. The reward circuit involves maintaining interest in a task (which
affects attention in individuals with and without ADHD), and the ability to tolerate delayed rewards. In concert with these tasks are
different frontosubcortical circuits that regulate executive control; inhibition and emotional regulation; and motivation and reward.10 The
regions of the frontal lobe and striatum that modulate executive control are thought to be the DLPFC, the dorsolateral caudate, the globus
pallidus, and thalamus in a feedback loop. Inhibition and emotional regulation are thought to be modulated by the lateral orbitalfrontal
cortex, in a different, parallel feedback control loop through the caudate, globus pallidus, and thalamus. Finally, motivation and reward
regulation are thought to be modulated by the ACC, the nucleus accumbens, globus pallidus, and thalamus (Slide 5).10

Additionally, specific areas of the brain often serve several functions. For example the ACC measures error detection, reward, and
response inhibition. In a landmark functional study, 11 adults with ADHD showed less activation in the ACC while performing the
Counting Stroop Task, which measures primarily response inhibition.11 Normal individuals were able to perform the task efficiently,
activating the ACC, thought to be the most efficient area of the brain for this task. Adults with ADHD struggled with the task and used
ancillary circuits of the brain to compensate for less activation of the ACC. Bush and colleagues11 recently published a study showing
that 7 weeks of treatment with methylphenidate normalized activation in the ACC. Those receiving medication showed increases in
activation of the ACC and DLPFC at follow-up as compared to baseline and to those receiving placebo treatment. Hence, those areas of
the brain that were underactive in adults without treatment normalized with treatment.

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 The neurobiology of ADHD is strongly influenced by genetic factors. The data come from studies of monozygotic and dizygotic twins.
In a meta-analysis of the various studies, Faraone and colleagues12 reported on the mean heritability of ADHD. Heritability refers to the
amount of genetic influence for a particular condition. A coefficient of 1 indicates an entirely genetically influenced phenomenon, while
a 0 indicates no genetic influence. Asthma, panic disorder, depression, and anxiety had a mean heritability rate below 50%.
Schizophrenia and autism, two of the most biologically driven medical psychiatric conditions, are heritable at ~75%. ADHD falls in this
higher range as well, at a mean heritability rate of 75%.

Pooled odds ratios from meta-analyses of candidate genes reveals that there is not one single gene associated with ADHD.11 Rather, the
disorder is thought to result from a combination of small effects from a number of genes (polygenetic). While there is no one gene for
ADHD, there are a finite number of genes that must interact in order to produce this disorder. The candidate genes that have been
identified thus far relate to synthesis, packaging, release, detection, and recycling of dopamine or catecholamines, and other related
neurotransmitters such as serotonin.

Conclusion
Dysfunction of frontosubcortical networks, which regulate attention, working memory, and inhibitory control, are present in both in
children and adults with ADHD. Dysregulation of several neurotransmitter systems, such as dopaminergic, noradrenergic, and nicotinic
have been observed in ADHD probands as well. Genes of small effect that each confer susceptibility are DRD4, DAT, DRD5, SNAP-25.
There are environmental influences, but many of them are early biologic insults and not necessarily psychosocial. There is multifactorial
causation involved in ADHD, and an additive effect of multiple vulnerability genes.

References
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Behav Pediatr. 2002;23(1):16-22.
2. Castellanos FX, Lee PP, Sharp W, et al. Developmental trajectories of brain volume abnormalities in children and adolescents with
attention-deficit/hyperactivity disorder. JAMA. 2002;288(14):1740-1748.
3. Shaw P, Eckstrand K, Sharp W, et al. Attention-deficit/hyperactivity disorder is characterized by a delay in cortical maturation. Proc
Natl Acad Sci U S A. 2007;104(49):19649-19654.
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attention deficit hyperactivity disorder? Am J Psychiatry. 2006;163(6):957-960.
9. Sonuga-Barke EJ. The dual pathway model of AD/HD: an elaboration of neuro-developmental characteristics. Neurosci Biobehav Rev.
2003;27(7):593-604.
10. Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol. 1993;50(8):873-880.
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fMRI and the Counting Stroop. Biol Psychiatry. 1999;45(12):1542-1552.
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