Attention Deficit Hyperactivity Disorder and Its Treatment

CHAPTER 17 Attention Deficit Hyperactivity Disorder and Its Treatment Symptoms and circuits: ADHD as a disorder of the prefrontal cortex States o...
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CHAPTER

17

Attention Deficit Hyperactivity Disorder and Its Treatment

Symptoms

and circuits: ADHD as a disorder of the prefrontal cortex

States of deficient

and excessive arousal in ADHD

Deficient arousal and ADHD '" Excessive arousal and ADHD Stress, comorbidities,

and simultaneous

ADHD and comorbidity:

deficient

and excessive arousal in ADHD

What should be treated first?

ADHD in children versus adults Stimulant

treatment

Noradrenergic

of ADHD

treatment

of ADHD

Atomoxetine Alpha 2A adrenergic agonists The ADHD pharmacy Summary

that is changing rapidly. A myriad of new drugs, especially in new drug-delivery

Attention deficitishyperactivity disorder (ADHD) psychopharmacology technologies, entering clinical practice. ADHDis anis area also of increasingly being seen not just as a disorder of attention, nor just as a disorder of children. Paradigm shifts are altering the landscape for treatment options across the full range of ADHD symptoms, now reaching into treatment of comorbidities and being refined for the important differences involved in treating adults. This chapter provides a brief overview of the psychopharmacology of ADHD. This includes a short discussion of the symptoms and treatments for ADHD, but information on the full clinical descriptions and formal criteria for how to diagnose and rate ADHD and its symptoms should be obtained by consulting standard reference sources. The discussion here emphasizes the links between various brain circuits and their neurotransmitters with the various symptoms and comorbidities of ADHD. The goal of this chapter is to acquaint the reader with ideas about the clinical and biological aspects of attention, impulsivity, hyperactivity, underarousal, overarousal, and stress. This chapter also covers some of the special aspects involved in treating adults, such as the impact of the frequent comorbidities of Attention Deficit Hyperactivity Disorder and Its Treatment

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anxiety, substance abuse, and mood disorders. Emphasis is on the biological basis of symptoms and their reliefby psychopharmacological agents as well as the mechanism of action of drugs that treat ADHD in children and adults. For details of doses, side effects, drug interactions, and other issues relevant to the prescribing of these drugs in clinical practice, the reader should consult standard drug handbooks (such as the Essential Psychopharmacology: Prescriber's Guide). Symptoms and circuits: ADHD as a disorder of the prefrontal cortex

ADHD is noted for a trio of symptoms: inattention, hyperactivity, and impulsivity (Figure 17-1). It is currently hypothesized that all these symptoms arise in part from abnormalities in various parts of the prefrontal cortex. Specifically, symptoms of selective inattention are hypothetically linked to inefficient information processing in the anterior cingulate cortex (ACC); symptoms of executive dysfunction, particularly the inability to sustain attention and thus the inability to solve problems, are hypothetically linked to inefficient information processing in another part of the prefrontal cortex, the dorsolateral prefrontal cortex (DLPFC) (Figure 17-2). Hyperactive symptoms in ADHD are linked to the supplementary motor cortex/prefrontal motor cortex, whereas impulsive symptoms are hypothetically related to the orbital frontal cortex (Figure 17-2). Not all patients have all of these symptoms or have them all with the same severity, suggesting a topographical distribution of different prefrontal cortex abnormalities in different patients with different symptom profiles. Each area of prefrontal cortex is linked to other brain areas via cortical circuits that connect one area of prefrontal cortex to another (see discussion in Chapter 7 and Figures 7-3,7-14, and 7-15) and via cortico-striatal-thalamic-cortical (CSTC) loops that connect

ADHD: Deconstruct the Syndrome into DSM-IV Diagnostic Symptoms

FIGURE 17-1 DSM-IV symptoms of ADHD. There are three major categories of symptoms associated with attention deficit hyperactivity disorder (ADHD): inattention, hyperactivity, and impulsivity. Inattention itself can be divided into difficulty with selective attention and difficulty with sustained attention and problem solving.

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Essential Psychopharmacology

ADHD: Core Symptoms Hypothetically Linked to Malfunctioning Prefrontal Cortex

/

DLPFC

sustained attention problem solving

prefrontal motor cortex

orbitalfrontal cortex

FIGURE 17-2 MatchingADHD symptomsto circuits. Problemswith selectiveattentionare believedto be linked to inefficientinformationprocessingin the dorsal anteriorcingulatecortex(ACC),whileproblemswith sustained attentionare linkedto inefficientinformationprocessingin the dorsolateralprefrontalcortex(DLPFC). Hyperactivitymay be modulatedby the prefrontalmotorcortexand impulsivityby the orbitalfrontalcortex(OFC).

specific areas of prefrontal cortex to subcortical brain areas. CSTC loops are introduced in Chapter 7 and illustrated in Figures 7-16 through 7-21. Each area of prefrontal cortex is linked to specific topographical areas in the striatum-nucleus accumbens and in the thalamus (see Figures 7-17 through 7-21 and 17-3 through 17-6). The specific symptoms of ADHD hypothetically linked to each of these prefrontal brain circuits are listed in Figures 17-3 through 17-6. For example, the dorsal ACC can be activated by tests of selective attention, such as the Stroop test (Figure 17-3). Hypothetically, patients who cannot focus their attention have inefficient information processing in this part of the brain, including its CSTC projections, shown in Figure 17-3. ADHD patients may either fail to activate this part of the brain when they should be focusing their attention, or they activate this part of the brain very inefficiently and only with great effort and easy fatigability. Activation of the dorsal ACC by the Stroop test is introduced in Chapter 8 and illustrated in Figures 8-14 and 8-15. The DLPFC can be activated by tests of executive function, such as the n-back test (Figure 17-4). Hypothetically, patients who cannot sustain their attention on a task and who experience difficulties in organizing, following through, and solving problems have inefficient information processing in the DLPFC (Figure 17-5). Activation ofDLPFC by the n-back test is introduced in Chapter 8 and illustrated in Figures 8-8 through 8-10 and 8-18 through 8-20. Problems activating this part of the brain cut across many syndromes that share the symptom of executive dysfunction, from schizophrenia (discussed in Chapter 9 and illustrated in Figures 9-15 through 9-17 and 9-59 through 9-61); to major depression (discussed in Chapter 11 and illustrated in Figures 11-45 and 11-50); to mania (discussed AttentionDeficitHyperactivityDisorderand Its Treatment

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Dorsal ACC Regulates Selective Attention The Stroop Task

Blue Red

Orange Red Green Green

- little attention to detail - careless mistakes - does not listen - loses things - distracted - forgetful

I

normal . baseline overactlvation hypoactivation

FIGURE 17-3 Selective attention circuit. Selective attention is hypothetically modulated by a cortico-striatalthalamic-cortical loop arising from the dorsal anterior cingulate cortex (ACC)and projecting to the bottom of the striatum, then the thalamus, and back to the dorsal ACC. Deficient and/or inefficient activation of this brain region can result in symptoms such as paying little attention to detail, making careless mistakes, not listening, losing things, being distracted, and forgetting things. An example of a task that involves selective attention, and thus should activate the dorsal ACC, is the Stroop test.

in Chapter

11 and illustrated

in Chapter

14 and illustrated

fibromyalgia

and "fibro-fog,"

in Figures discussed

disorders of sleep and wakefulness and 16-31). The

pervasiveness

11-56,

in Figures

with

and 11-64);

and 14-45);

in Chapter

(discussed

of problems

11-61,

14-44

15 and illustrated

in Chapter

attention

to anxiety

to disorders

in Figure

16 and illustrated

and concentration

(discussed

of pain

(e.g.,

15-22);

in Figures

to

16-1

across psychiatric

disorders is so great that it can lead one to ask: What is the difference between attention deficit and attention deficit disorder (see also Table 17-1)? Indeed, what are the differences between

treatments

for attention

deficit in different

psychiatric

syndromes

and those for

ADHD? It turns out that the same DLPFC circuit may be involved in mediating these symptoms of executive dysfunction across many psychiatric disorders (Table 17-1), and the same empiric treatments, discussed in detail in this chapter, may be useful for executive dysfunction and inattention, whether the patient has the attention deficit of a psychiatric

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DLPFC Regulates Sustained Attention and Problem Solving n-back test

-

sustaining attention follow through I finish organizing avoids sustained mental effort

I

normal •.. baseline ': overactivation hypoactivation

FIGURE 17-4 Sustained attention circuit. Sustained attention is hypothetically modulated by a cortico-striatalthalamic-cortical

loop that involves the dorsolateral prefrontal cortex (DLPFC) and the rostral (top) part of the

caudate within the striatal complex. Deficient and/or inefficient activation of the DLPFC can lead to difficulty following through or finishing tasks, disorganization, and trouble sustaining mental effort. Tasks such as the n-back test are used to measure sustained attention and problem solving abilities.

disorder or the attention deficit of ADHD. For adults in particular, comorbidity of ADHD with other psychiatric disorders characterized by executive dysfunction is so pervasive that trying to distinguish the attention deficit of ADHD from the attention deficit of other psychiatric conditions may not be clinically useful (Table 17-1). Other areas of prefrontal cortex that may not be functioning efficiently in ADHD are the supplementary motor area and prefrontal motor cortex, linked to symptoms of motor hyperactivity (Figure 17-5), and orbital frontal cortex, linked to symptoms of impulsivity (Figure 17-6). Orbital frontal cortex is a very important part of prefrontal cortex and has been discussed in relation to a wide variety of symptoms that cut across several psychiatric conditions, from impulsivity in schizophrenia (discussed in Chapter 9 and illustrated in Figure 9-14) to suicidality in depression (discussed in Chapter 11 and illustrated in Figure 11-53) to impulsivity in mania (discussed in Chapter 11 and illustrated in Figures 11-58, 11- 59, and 11-66). Perhaps all of these symptoms of impulsivity are due to defective thalamic Attention Deficit Hyperactivity Disorder and Its Treatment

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Prefrontal Motor Cortex Regulates Motor Hyperactivity

hyperactivity

- fidgets - leaves seat - runs / climbs - on the go / driven - difficulty playing quietly normal . baseline hypoactivation ~•. overactivation FIGURE 17-5 Hyperactivity circuit. Motor activity, such as hyperactivity and psychomotor agitation or retardation, can be modulated by a cortico-striatal-thalamic-corticalloop from the prefrontal motor cortex to the putamen (lateral striatum) to the thalamus and back to the prefrontal motor cortex. Common symptoms of hyperactivity in children with ADHD include fidgeting, leaving one's seat, running/climbing, being constantly on the go, and having trouble playing quietly.

filtering "governor"

of information

in CSTC

of the prefrontal

loops,

allowing

cortex, the DLPFC,

impulsive

can inhibit

action

to occur before

it (see discussions

the

of thalamic

9 and 16 and Figures 9-41, 16-4, and 16-5). The orbital frontal cortex is part of the limbic system and is linked to another important limbic area, known as the nucleus accumbens, via CSTC loops (Figures 7-20 and 17-6).

filters in Chapters

This specific circuit may be responsible for linking an incoming stimulus to emotions and for transforming emotions into actions. The limbic CSTC circuit from orbital frontal cortex seems to do this by responding

to various stimuli that are relevant, interesting,

fascinating,

or

rewarding with the release of neurotransmitters such as dopamine. The features of a stimulus that can provoke dopamine release in the nucleus accumbens are sometimes also described as having "salience." Thus, salient stimuli are powerful motivators, and when received, they have the potential of being immediately transformed into action prior to the application of cognitive

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reflection,

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and judgment.

That

is the essence of impulsivity

and might

-

+ + +++ +++ +++ ++ ++ SW++ MDD/GAD OSA +/+ +++ can overlap +++in many different syndromes TABLE 17-1deprivation The ++ same symptoms Narcolepsy

and disorders

Mood/anxiety Sleep

ADHD = attention deficit hyperactivity disorder; MDD = major depressive disorder; GAD disorder; OSA = obstructive sleep apnea; SW = shift-work sleep disorder. +++Most Common ++Common

_ generalized

anxiety

+Average - None

Orbital Frontal Cortex Regulates Impulsivity

impulsivity

-

I

talks excessively blurts out not waiting turn interrupts / intrudes

normal . baseline .; overactivation hypoactivation

FIGURE 17-6 Impulsivity circuit. Impulsivity is associated

with a cortico-striatal-thalamic-corticalloop

that

involves the orbital frontal cortex (OFC), the bottom of the caudate, and the thalamus. Examples of impulsive symptoms in ADHD include talking excessively, blurting things out, not waiting one's turn, and interrupting.

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Deficit Hyperactivity

Disorder and Its Treatment

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TABLE 17-2

What causes ADHD?

Genetics

Environment

~75% of variance As heritable or more so as schizophrenia Genes implicated - DAT (dopamine transporter) - DRD 4 (D4 receptor) - DRD 5 (Ds receptor) - DBH (dopamine beta hydroxylase) - ADRA 2A (alpha 2A receptor) - SNAP 25 (synaptic protein) - 5HTTLPR (long) (5HT transporter) - HTR IB (serotonin IB receptor) - FADS 2 (fatty acid desaturase 2)

Fetal distress (e.g., preterm birth) Maternal smoking Iron deficiency? Lead exposure?

help to explain why impulsive people act in self-destructive ways that are not rational and make no sense. Perhaps their brain circuits are not capable of evaluating powerful salient stimuli before they spring into action; such brain circuits may not have the ability to inhibit the expression of feelings and forestall overt behavior. Not surprisingly, the orbital frontal cortex is also implicated in substance abuse, so it is no wonder that there is considerable abuse of nicotine, alcohol, stimulants, and other drugs in patients with ADHD. The role of the orbital frontal cortex circuits in disorders other than ADHD but that are similarly characterized by impulsivity is discussed in further detail in Chapter 19, on drug abuse. What causes these problems in the prefrontal cortex? Currently, genetic factors are thought to be the major cause of neurodevelopmental abnormalities in the prefrontal cortex in ADHD (Table 17-2). In fact, genes that code for subtle molecular abnormalities are thought to be just as important to the etiology of ADHD as they are to the etiology of schizophrenia. Many of the ideas about the neurodevelopmental basis of schizophrenia, such as abnormal synapse formation and abnormal synaptic neurotransmission, serve as a conceptual framework and neurobiological model for ADHD. The genetic factors linked to schizophrenia are discussed extensively in Chapter 9 and illustrated in Figures 9-52 through 9-58. The major genes implicated in ADHD are those linked to the neurotransmitter dopamine (Table 17-2), although links to the genes for the alpha 2A adrenergic receptor, serotonin receptors, and some other proteins are also under intense investigation (Table 17-2). Environmental factors inevitably contribute to ADHD, as they do to so many other psychiatric disorders (Table 17-2). This includes factors such as preterm birth, maternal smoking during pregnancy, and others (Table 17-2). The stress diathesis hypothesis integrating genetics and environment to the etiology of mental illnesses is introduced in Chapter 6 and illustrated in Figures 6-7 through 6-17. States of deficient and excessive arousal in ADHD Deficient arousal and ADHD

ADHD is linked to the neurobiology of arousal mechanisms. Hyperactive children often seem "wired" and overstimulated. From this perspective it can seem counterintuitive that ADHD would be treated with stimulants, whieh actually cause normal individuals to become wired and overstimulated. As discussed above, however, we now know that defective inhibitory influences of a neurodevelopmentally 870

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compromised

prefrontal cortex can

Arousal Spectrum of Cognitive Dysfunction in ADHD with Deficient Arousal

deficient arousal

excessive arousal

normal baseline ~ hypoactivation overactivation

NElDA firing

low tonic firing FIGURE 17-7 Arousal spectrum of cognitive dysfunction in ADHD: deficient arousal. The spectrum of arousal is shown here. Individuals in a state of hypoarousal during the day (depicted here as the prefrontal cortex being blue) may experience inattentiveness, cognitive dysfunction, and sleepiness, with impulsivity particularly associated with hypoactivation of the orbital frontal cortex. In addition, hyperactivity in ADHD patients may result from an effort to combat the state of hypoarousal that these patients are in. Hypoarousal during the day may be associated with low tonic dopamine and norepinephrine firing.

contribute to inefficient information processing, resulting in the ADHD symptoms of inattention, hyperactivity, and impulsivity (Figures 17-3 through 17-6). Specifically, this inefficient information processing is often thought to be the product of deficiencies in arousal networks (Figure 17-7 on the left). Therefore agents that increase the drive of the arousal network by enhancing the synaptic actions of dopamine (DA) and norepinephrine Attention Deficit Hyperactivity Disorder and Its Treatment

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Treating ADHD by Enhancing Arousal in Prefrontal Cortex awake alert creative problem solving

stimulants atomoxetine guanfacine ER modafinil

deficient arousal

normal baseline hypoactivation I. . overactivation

excessive arousal

NElDA firing faster tonic firing

FIGURE 17-8 Treating ADHD by enhancing arousal in prefrontal cortex. Agents that increase the drive of the arousal network by enhancing arousal neurotransmitters such as dopamine and norepinephrine (and thus amplifying tonic firing rates) can increase the efficiency of information processing in prefrontal cortex and thus improve symptoms of inattention, impulsivity, and hyperactivity. Such agents include the stimulants, atomoxetine, guanfacine ER, and modafinil.

(NE) can improve the efficiency of information processing in prefrontal circuits and thus, somewhat paradoxically, improve the symptoms of inattention, impulsivity, and hyperactivity in ADHD (see Figure 17-8, moving arousal from deficient on the left in Figure 17-7 to normal in the middle of Figure 17-8). Note that the hypoactivated brain in Figure 17-7, associated with ADHD symptoms on the left, is also associated with a decreased frequency of tonic firing of dopamine and

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norepinephrine neurons, shown at the bottom of the figure. Deficient arousal mechanisms, as shown in the brain in Figure 17-7, can be increased to normal levels of activation, as shown in the brain in Figure 17-8, following successful treatment with stimulants, with the norepinephrine transporter (NET) inhibitor atomoxetine, with the oral sustained-release formulation of the alpha 2A selective adrenergic agonist guanfacine ER, or with the wakepromoting agent modafinil (Figure 17-8). Changes in brain circuitry in ADHD before and after treatment are also shown in Figure 17-9. ADHD patients generally cannot activate prefrontal cortex areas appropriately in response to cognitive tasks of attention and executive functioning. Some studies show that ADHD patients not only fail to activate the dorsal ACC in response to the Stroop test but also actually recruit brain areas that normally do not participate in this function (shown in purple in Figure 17-9, top), a process that gets the job done, but inefficiently, slowly, and with errors. When treated with agents that increase the activation ofDl dopamine receptors and/or alpha 2A adrenergic receptors in prefrontal cortex, these individuals can now activate the appropriate brain area, and perform the task accurately (Figure 17-9, bottom). A very similar phenomenon is observed in prefrontal cortex of narcolepsy patients after they are given stimulants to improve their cognitive performance (see discussion in Chapter 16 and Figure 16-31). Arousal networks are thus also linked robustly to the neurobiological basis of sleep/wake disorders and their treatments (discussed extensively in Chapter 16 and also illustrated in Figures 16-1 through 16-5). Note in Figure 17-8 that after treatment, not only are ADHD symptoms relieved but tonic firing rates of dopamine and norepinephrine neurons are increased. Tonic versus phasic firing rates for dopamine neurons is introduced in Chapter 16 and illustrated in Figure 16-32. The normal rate of tonic firing ofDA and NE neurons is hypothetically linked to being normally aroused and having efficient information processing in the prefrontal cortex and thus normal levels of attention, motor activity, and impulse control (see Figure 17-8, bottom). When arousal mechanisms are low, not only are the tonic firing rates low in arousal neurons utilizing NE and DA (Figure 17-7 at the bottom) but pyramidal neurons in the prefrontal cortex are "out of tune" and unable to distinguish important neuronal signals from unimportant "noise" (Figure 17-10 on the left). When prefrontal pyramidal neurons are out of tune in ADHD, patients cannot focus on one thing more than another because all signals are the same; they cannot sustain attention because it is easy to be distracted from one signal to another; they may move or act impulsively, without thought. Increasing prefrontal arousal mechanisms by enhancing the activity of DA and NE can improve signal-to-noise detection in prefrontal cortex (middle of Figure 17-10) and relieve ADHD symptoms. DA acting at Dl receptors may diminish the level of the noise, whereas NE acting at alpha 2A adrenergic receptors may enhance the size of the signal (middle of Figure 17-10). This notion of malfunctioning prefrontal circuits that are "out of tune" rather than too high or too low is introduced in Chapter 7 and illustrated in Figures 7-25 and 7-26. Excessive arousal and ADHD

There is also the possibility of too much of a good thing. Thus, when arousal mechanisms are too high, the signal-to-noise detection deteriorates and is no better than when the arousal mechanisms are too low (compare far right-hand side of the spectrum on Figure 17-10 with the far left-hand side of the spectrum). Correspondingly, some ADHD patients with excessive arousal (Figure 17-11 on the right) can have the same symptoms as other ADHD patients with deficient arousal (Figure 17-7 on the left). In the state of excessive

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Inability to Activate ACC and Aberrant Activation of Attentional Networks in ADHD: Normalization of Information Processing After Treatment untreated ADHD

The Stroop Task

Blue Red

Orange Red Green

Green

act',at'oe

of DI/0

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