ADHD

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Designer drugs are rapidly making inroads with young people, primar­ily because of easier access, lower overall cost, and nebulous legality. These drugs are made as variants of illicit drugs or new formulations and sold as “research chemicals” and labeled as “not for human consumption,” which allows them to fall outside existing laws. The ingredients typi­cally are not detected in a urine drug screen.

Notoriously addictive, these designer drugs, such as bath salts, are known to incorporate synthetic cathinones—namely, methylone, mephedrone or methylenedioxypyrovalerone (MDPV). The stimu­lant, amphetamine-like effects of bath salts make the drug attractive to adolescents with attention-deficit/hyperactivity disorder (ADHD).

Why do teens gravitate toward bath salts?
Adolescents with undiagnosed ADHD might self-medicate with drugs that are suited for addressing restlessness, intra­psychic turmoil, and other symptoms of ADHD. In 2 case studies, using the self-medication hypothesis, people with ADHD were more likely to seek cocaine by means of “self-selection.”¹ These drug-seeking behaviors often led to cocaine dependence, even when other substances, such as alco­hol or Cannabis, were available.

Methylphenidate and other ADHD phar­macotherapies influence the nucleus accum­bens in a manner similar to that of cocaine. These findings suggest that adolescents with ADHD and cocaine dependence might respond to therapeutic interventions that substitute cocaine with psychostimulants.¹

Bath salts fall within the same spectrum of psychostimulant agents as methylpheni­date and cocaine. MDPV approximates the effect of methylphenidate at low doses, and cocaine at higher doses. It often is marketed under the name “Ivory Wave” and could be confused with cocaine. Self-administration of MDPV can induce psychoactive effects that help alleviate ADHD symptoms; adolescents might continue to experience enhanced concentration and overall per­formance.² Also, because of the low cost of “legal” bath salts, they are an appealing alternative to cocaine for self-medication.

Managing the sequelae of bath salt intoxication
Bath salts may produce sympathomimetic effects greater than cocaine, which require a proactive approach to symptom manage­ment. A medley of unknown ingredients in bath salt preparations makes it difficult for clinicians to gauge the pharmacological impact on individual patients; therefore, therapeutic interventions are on a case-by-case basis. However, emergencies con­cerning amphetamines and amphetamine analogues and derivatives often have simi­lar presentations.

Cardiovascular effects. MDPV-specific urine and blood tests conducted on patients admitted to the emergency room showed a 10-fold increase in overall dopamine levels compared with those who took cocaine. As a sympathomimetic, high doses of dopamine are responsible for raising blood pressure and could lead to the development of pro­nounced cardiovascular effects.^3,4

Agitation. Clinicians generally are advised to treat agitation before providing a more comprehensive assessment of symptoms. Endotracheal intubation often is a required for adequate control of agitation. Bath salt-induced agitation often is treated with IV benzodiazepines.^4,5 Monitor patients for excessive sedation or new-onset “paradoxi­cal agitation” as a function of ongoing benzo-diazepine therapy. Clinicians also may choose to co-administer an antipsychotic with benzodiazepines, although the practice is not uni­versally encouraged for agitation control.

Mephedrone produces a delirious state in conjunction with psychotic symptoms. Antipsychotic therapy has been suggested for addressing ongoing agitation.⁶ 

Tachycardia. Symptomatic treatment of tachycardia involves beta blockers, such as labetalol. Nitroglycerine has evidence of effi­cacy for chest pain associated with cocaine intoxication; however, it is unclear whether it is effective for similar drugs of abuse.⁴

Multi-organ collapse caused by MDPV necessitates aggressive intervention, includ­ing prompt dialysis. Carefully evaluate the patient for the presence of organ-specific insults and initiate supportive measures accordingly. Pronounced agitation with hyperthermia might portend severely com­promised renal, hepatic, and/or cardiac function in MDPV users.⁷ Those who present with MDPV intoxication and concomitant renal injury seem to benefit from hemodi­alysis.⁸ Repeat intoxication events may yield a presentation of acute renal injury replete with metabolic derangements, including metabolic acidosis, hyperuricemia, and rhab­domyolysis.⁹ Thorough patient assessments and interventions are useful in determining long-term outcomes, including issues per­taining to mortality.

Confronting an epidemic
Adolescents are quickly adopting designer drugs as a readily accessible form of recre­ational “legal highs.”¹⁰ Public awareness and educational initiatives can bring to light the dangers of these substances that exert pow­erful and, sometimes, unpredictable psycho­active effects on the user.

Self-mutilation and suicidal ideation also have been documented among those who ingested bath salts. These reports appear to be escalating across Europe and the United States. On a national level, U.S. poison cen­ters have reported an almost 20-fold increase in calls regarding bath salts between 2010 and 2011.⁵ It is of utmost importance for clini­cians and emergency personnel to familiar­ize themselves with the sympathomimetic toxidrome and management for bath salt consumption.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Attention-deficit/hyperactivity disorder (ADHD) is one of the most common pediatric psychiatric dis­orders, occurring in approximately 5% of children.¹ The disorder persists into adulthood in about one-half of those who are affected in childhood.² In adults and children, diagnosis continues to be based on the examiner’s subjec­tive assessment. (Box 1^3-9 describes how ADHD presents a compli­cated, moving target for the diagnostician.)

Patients who have ADHD are rarely studied with imag­ing; there are no established imaging findings associated with an ADHD diagnosis. Over the past 20 years, however, significant research has shown that molecular alterations along the dopaminergic−frontostriatal pathways occur in association with the behavioral constellation of ADHD symptoms—suggesting a pathophysiologic mechanism for this disorder.

In this article, we describe molecular findings from nuclear medicine imaging in ADHD. We also summarize imaging evidence for dysfunction of the dopaminergic-frontostriatal neural circuits as central in the pathophysiol­ogy of ADHD, with special focus on the dopamine reuptake transporter (DaT). Box 2^10,11 reviews our key observations and looks at the future of imaging in the management of ADHD.

Dopaminergic theory of ADHD
The executive functions that are disordered in ADHD (impulse control, judgment, main­taining attention) are thought to be centered in the infraorbital, dorsolateral, and medial frontal lobes. Neurotransmitters that have been implicated in the pathophysiology of ADHD include norepinephrine¹² and dopa­mine¹³; medications that selectively block reuptake of these neurotransmitters are used to treat ADHD.^14,15 Only the dopamine system has been extensively evaluated with molecular imaging techniques.

Because methylphenidate, a potent selec­tive dopamine reuptake inhibitor, has been shown to reduce disordered executive func­tional behaviors in ADHD, considerable imaging research has focused on the dopa­minergic neural circuits in the frontostriatal regions of the brain. The dopaminergic the­ory of ADHD is based on the hypothesis that alterations in the density or function of these circuits are responsible for behaviors that constitute ADHD.

Despite decades of efforts to delineate the underlying pathophysiology and neu­rochemistry of ADHD, no single unifying theory accounts for all imaging findings in all patients. This might be in part because of imprecision inherent in psychiatric diag­noses that are based on subjective observa­tions. The behavioral criteria for ADHD can manifest in several disorders. For example, anxiety-related symptoms seen in post­traumatic stress disorder, social anxiety disorder, and panic disorder also present as behaviors similar to those in ADHD diag­nostic criteria.

Molecular imaging might provide a window into the underlying pathophysiol­ogy of ADHD and, by identifying objective findings, (1) allow for patient stratification based on underlying physiologic subtypes, (2) refine diagnostic criteria, and (3) predict treatment response.

Nuclear medicine findings
In general, nuclear medicine investiga­tions of ADHD can be divided into studies of changes in regional cerebral blood flow (rCBF) or glucose metabolism (rCGM) and those that have assessed the concentration of synaptic structures, using highly specific radiolabeled ligands. Both kinds of studies provide limited anatomic resolution, unless co-registered with MRI or CT scans and either single photon emission computed tomography (SPECT) or positron emission tomography (PET).

Synaptic imaging using radiolabeled ligands with high biologic specificity for synaptic structures has high molecular resolution—that is, radiolabeled ligands used for selective imaging of the dopamine transporter or receptor do not identify sero­tonin transporters or receptors, and vice versa. (Details of SPECT and PET tech­niques are beyond the scope of this article but can be found in standard nuclear medi­cine textbooks.)

SPECT and PET of rCBF
Early investigations of rCBF in ADHD were performed using inhaled radioactive xenon-133 gas.¹⁶ Later, rCBF was assessed using fat-soluble radiolabeled ligands that rapidly distribute in the brain in proportion to blood flow by crossing the blood−brain barrier. Labeled with radioactive 99m-technetium, these ligands cross rapidly into brain cells after IV injection. Once intracellular, cova­lent bonds within the ligands cleave into 2 charged particles that do not easily recross the cell membrane. There is little redistribu­tion of tracer after initial uptake.

The imaging data set that results can be reconstructed as (1) surface images, on which defects indicate areas of reduced rCBF, or (2) tomographic slices on which color scales indicate relative rCBF values (Figure 1). Because of the minimal redistribution of the tracer, SPECT images obtained 1 or 2 hours after injection provide a snapshot of rCBF at the time tracer is injected. Patients can be injected under various conditions, such as at rest with eyes and ears open in a dimly lit, quiet room, and then under cognitive stress (Figure 2), such as performing a computer-based attention and impulse con­trol task, or during stimulant treatment.

Numerous investigators have found reduced frontal or striatal rCBF, or both, in patients with ADHD, unilaterally on the right¹⁷ or left,^18,19 or bilaterally.²⁰ Additionally, with stimulant therapy, normalization of striatal and frontal rCBF has been demon­strated^14,19—changes that correlate with reso­lution of behavioral symptoms of ADHD with stimulant treatment.²¹

SPECT of 32 boys with previously untreated ADHD. Kim et al²¹ found that the presence of reduced right or left, or both, frontal rCBF, which normal­ized with 8 weeks of stimulant therapy, predicted symptom improvement in 85% of patients. Absence of improve­ment of reduced frontal rCBF had a 75% negative predictive value for treatment response. (Additionally, hyperperfusion of the somatosensory cortex has been demonstrated in children with ADHD,^16,22 suggesting increased responsiveness to extraneous environmental input.)

SPECT of 40 untreated pediatric patients compared with 17 age-matched controls. Using SPECT, Lee et al²³ reported rCBF reductions in the orbitofrontal cortex and the medial temporal gyrus of participants; reductions corresponded to areas of motor and impulsivity control. The researchers also demonstrated increased rCBF in the somato­sensory area.

After methylphenidate treatment, blood flow to these areas normalized, and rCBF to higher visual and superior prefrontal areas decreased. Substantial clinical improve­ment occurred in 64% of patients—suggest­ing methylphenidate treatment of ADHD works by (1) increasing function of areas of the brain that control impulses, motor activ­ity, and attention, and (2) reducing function to sensory areas that lead to distraction by extraneous environmental sensory input.

O-15-labeled water PET of 10 adults with ADHD. Schweitzer et al²⁴ found that participants who demonstrated improve­ment in behavioral symptoms with chronic stimulant therapy had reduced rCBF in the striata at baseline—again, suggesting that baseline hypometabolism in the striata is associated with ADHD.

PET of regional cerebral glucose metabolism
Cerebral metabolism requires a constant supply of glucose; regional differences in cerebral glucose metabolism can be assessed directly with positron-emitting F-18-fluoro-2-deoxyglucose. Although metabolically inert, this agent is transported intracellularly simi­lar to glucose; once phosphorylated within brain cells, however, it can no longer undergo further metabolism or redistribution.

Studies using PET to assess rCGM were some of the earliest molecular imaging appli­cations in ADHD. Zametkin et al²⁵ reported low global cerebral glucose utilization in adults, but not adolescents,²⁶ with ADHD. However, further study, with normalization of the PET data, confirmed reduced rCGM in the left prefrontal cortex in both adolescents²⁶ and adults,²⁷ indicating hypometabolism of cortical areas associated with impulse con­trol and attention in ADHD. In adolescents, symptom severity was inversely related to rCBF in the left anterior frontal cortex.

Synaptic imaging
Nuclear imaging has been used to study several components of the striatal dopami­nergic synapse, including:
   • dopamine substrates, using fluorine- 18-labeled dopa or carbon-11-labeled dopa
   • dopamine receptors, using carbon- 11-labeled raclopride or iodine-123 iodobenzamide
   • the tDaT, using iodine-123 ioflupane, 99m-technetium TRODAT, or carbon-11 cocaine (Figure 3).

All of these synaptic imaging agents were used mainly as research tools until 2011, when the FDA approved the SPECT imag­ing agent iodine-123 ioflupane (DaTscan) for clinical use in assessment of Parkinson’s disease.²⁸ This commercially available agent has high specificity for the DaT, with little background activity noted on SPECT imag­ing (Figure 4).

Dopamine transporter imaging
Because the site of action of methylpheni­date is the DaT, imaging this component of the striatal dopaminergic synapse has been an area of intense investigation in ADHD. Located almost exclusively in the striata, DaT reduces synaptic concentrations of dopamine by means of reuptake channels in the cell membrane.²⁹ By reversibly bind­ing to, and occupying sites on, the DaT, methylphenidate impedes dopamine reup­take, which results in increased availability of dopamine at the synapse.³⁰

By demonstrating an increase in stria­tal DaT density in patients with ADHD— first reported by Dougherty et al³¹ using iodine-123 altropane (a dopaminergic uptake inhibitor) in 6 adults with ADHD—inves­tigators have hypothesized that excessive expression of the DaT protein in the striata, which may result from genetic or environ­mental factors, is a central causative agent of ADHD.³² Subsequent studies, however, have yielded contradictory findings: Hesse et al,³³ using SPECT imaging, and Volkow et al,³⁴ using carbon-11 cocaine PET imaging, found reduced DaT density in, respectively, 9 and 26 patients with ADHD.

To clarify the role of DaT levels in the eti­ology of ADHD and to explain discrepant results, Fusar-Poli et al³⁵ performed a meta-analysis of 9 published papers that reported the results of DaT imaging in a total of 169 ADHD patients and 129 controls. They noted that these studies included 6 differ­ent imaging agents and protocols. Patients were stimulant therapy-naïve (n = 137) or drug-free (refrained from stimulant therapy for a time [n = 32]). The team found that the degree of elevation of the striatal DaT con­centration correlated with a history of stimu­lant exposure, and that the drug-naïve group had a reduced DaT level.

Fusar-Poli’s hypothesis? Elevated DaT lev­els result from up-regulation in the presence of chronic methylphenidate therapy, which accounts for early reports that demonstrated increased striatal DaT density. Clinically, up-regulation might explain the lack of sustained relief of behavioral symptoms with stimulant therapy in 20% of patients with ADHD who showed clinical improvement initially.³⁶

Only limited conclusions can be drawn about the role of DaT levels in ADHD, given the small number of patients studied in pub­lished reports. In addition, the Fusar-Poli meta-analysis has come under strong criti­cism because of methodological errors with improper patient inclusion and characteriza­tion of treatment status,³⁷ calling into question the investigators’ conclusions.

Does the DaT level hold promise for practice? Despite a lack of clarity about the significance of DaT level in the etiology of ADHD, knowledge of a patient’s level might prove useful in predicting which patients will respond to methylphenidate. Namely, several researchers have found that:
   • an elevated baseline level of DaT (before stimulant therapy) correlates with robust clinical response
   • absence of an elevated baseline DaT level suggests that symptomatic improvement with stimulant therapy in unlikely.^38-40

Dresel et al³⁸ evaluated 17 drug-naïve adults, newly diagnosed with ADHD, using 99m-technetium TRODAT SPECT before and after methylphenidate therapy. They found a 15% increase in specific DaT binding in patients with ADHD, compared with con­trols, at baseline. After treatment, the research­ers observed a 28% reduction in specific DaT binding—a significant change from baseline that correlated with behavioral response.

Study: SPECT in 18 adults with ADHD given methylphenidate. Krause³⁹ used the same SPECT agent to study 18 adults before they received methylphenidate and 10 weeks after treatment. Participants were categorized as responders or nonresponders based on clinical assessment of ADHD symptoms after those 10 weeks. All 12 responders had an elevated striatal DaT concentration at baseline. Of the 6 nonresponders, 5 had a normal level of striatal DaT compared with age-matched controls.

Study: 22 Adult ADHD patients evalu­ated with 99m-technetium TRODAT SPECT. The same group of investigators⁴⁰ presented imaging findings in 22 additional adult patients. Seventeen had an elevated striatal DaT level, 16 of whom responded to stimulant therapy. The remaining 5 patients had reduced striatal DaT at base­line; none had a good clinical response to methylphenidate.

The positive clinical response to methylphenidate in 67%³⁷ and 77%⁴⁰ of patients is in good agreement with results from larger studies, which reported that approximately 75% of patients with ADHD show prompt clinical improvement with stimulants.⁴¹ Improvement might be related to an increase in functioning of the frontostriatal dopami­nergic circuit that is seen with stimulant therapy. Increased availability of dopamine at the synapse, resulting from stimulant blockade of the dopamine reuptake trans­porter, produces increased dopamine neu­rotransmission and increased activation of frontostriatal circuits.

In another study, rCBF in frontostriatal circuits was determined to be inversely proportional to DaT density; rCBF normalized with stimulant therapy.⁴²

Will imaging pave the way for therapeu­tic stratification? Baseline determinations of striatal DaT concentration with SPECT imaging might make it possible to stratify patients with ADHD symptoms into those likely to show significant behavioral symp­tom response to methylphenidate and those who are not likely to respond. There might be an objective imaging finding—striatal DaT density—that allows clinicians to dis­tinguish stimulant-responsive ADHD from stimulant-unresponsive ADHD.

Dopamine substrate imaging
Radiolabeled dopa (carbon-11 or fluorine-18) is transported into presynaptic dopaminer­gic neurons in the striatum, where it is decar­boxylated, converted to radio-dopamine, and stored within vesicles until released in response to neuronal excitation. Semi-quantitative assessment is achieved with calculation of specific (striatal) to nonspecific (background) uptake ratios. Increased val­ues are thought to indicate increased density of dopaminergic neurons.⁴³

Ernst et al⁴⁴ reported a 50% decrease in specific fluorine-18 dopa uptake in the left prefrontal cortex in 17 drug-naïve adults with ADHD, compared with 23 controls. The same team reported increased midbrain fluorine-18 dopa levels in 10 adolescents with ADHD—48% higher, overall, than what was seen in 10 controls.⁴³ They hypoth­esized that these opposite results were the results of a reduction in the dopaminergic neuronal density in adults, which might be part of the natural history of ADHD, or a normal age-related reduction in neuronal density, or both. Increased dopa levels in the team’s adolescent group were hypothesized to reflect up-regulation in dopamine syn­thesis due to low synaptic dopamine con­centrations that might result from increased dopamine reuptake.

Dopamine-receptor imaging
The 5 distinct dopamine receptors (D1, D2, D3, D4, and D5) can be grouped into 2 subtypes, based on their coupling with G proteins. D1 and D5 constitute a group; D2, D3, and D4, a second group.

The D1 receptor is the most common dopamine receptor in the brain and is widely distributed in the striatum and pre­frontal cerebral cortex. D1 receptor knock­out mice demonstrate hyperactivity and poorer performance on learning tasks and are used as an animal model for ADHD.⁴⁵ D1 has been imaged using C-11 SCH 23390 PET⁴⁶ in rats, but its role in ADHD has yet to be evaluated. D5 is the most recently cloned and most widely distributed of the known dopamine receptors; however, there are no imaging studies of the D5 receptor.¹³

D2 receptors are present in presynaptic and postsynaptic neurons⁴⁷ in the neocor­tex, substantia nigra, nucleus accumbens, and olfactory tubercle, as well as in other structures.⁴⁸ Presynaptic D2 receptors act as autoregulators, inhibiting dopaminergic synthesis, firing rate, and release.⁴⁹

Using C-11 raclopride PET imaging, Lou et al⁵⁰ reported high D2/3 receptor availabil­ity in adolescents who had a history of peri­natal cerebral ischemia. They found that this availability is associated with an increase in the severity of ADHD symptoms. They pro­posed that the increase in “empty” receptor density might have been caused by perinatal ischemia-induced presynaptic dopaminer­gic neuronal loss or an increase in presynap­tic dopamine reuptake (Figure 5⁵⁰). Either mechanism could result in up-regulation in postsynaptic D2/3 receptors.

Volkow et al⁵¹ reported that D2 receptor density correlated with methylphenidate-induced changes in rCBF in frontal and tem­poral lobes in humans. They postulated that the variable therapeutic effects of methyl­phenidate seen in ADHD patients might be related to variations in baseline D2 receptor availability.

Lou et al⁵⁰ reported elevated D2 recep­tor density, demonstrated using carbon-11 raclopride, in children with ADHD, com­pared with normal adults.

Further support for a relationship between D2-receptor density and symptom­atic improvement with methylphenidate in ADHD was presented by Ilgin et al⁵² using iodine-123 iodobenzamide SPECT. They found elevated D2 receptor levels in 9 drug-naïve children with ADHD, which is 20% to 60% above what is seen in unaffected chil­dren. They noted that these patients showed improvement in hyperactivity when treated with methylphenidate.

In a similar study of 20 drug-naïve adults, Volkow et al⁵³ found that durable symptom­atic improvement with methylphenidate therapy was associated with increased D2 receptor availability.

Summing up
Striatal DaT is the most likely synaptic tar­get for stratifying patients with ADHD, now that a dopamine transporter imaging agent is available commercially. Stratification might allow for refinement in the diagnostic categorization of ADHD, with introduction of stimulant-responsive and stimulant-unresponsive subtypes that are based on DaT imaging findings.

Bottom Line
Given recent advances showing molecular alterations in the dopaminergic-frontostriatal pathway as central to attention-deficit/hyperactivity disorder, molecular imaging might be useful as an objective study for diagnosis.

Related Resources
• Schweitzer JB, Lee DO, Hanford RB, et al. A positron emis­sion tomography study of methylphenidate in adults with ADHD: alterations in resting blood flow and predict­ing treatment response. Neuropsychopharmacology. 2003;28(5):967-973.
• Raz A. Brain imaging data of ADHD. Psychiatric Times. http://www.psychiatrictimes.com/adhd/brain-imaging-data-adhd.

Drug Brand Names
Iodine-123 ioflupane • Methylphenidate • Ritalin DaTscan

Acknowledgment
Kylee M. L. Unsdorfer, a medical student at Northeast Ohio Medical University, helped prepare the manuscript of this article.

Disclosures
Dr. Thacker reports no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.
Dr. Binkovitz received 4 doses of ioflupane I123I (DaTscan) from General Electric for investigator-initiated research, used for animal imaging in 2012.

Lisdexamfetamine, approved by the FDA in 2007 for attention-deficit/hyperactivity disorder (ADHD), has a new indication: binge eating disorder (BED) (Table 1). BED is characterized by recurrent episodes of consuming a large amount of food in a short time. A prodrug of amphet­amine, lisdexamfetamine is a Schedule-II controlled substance, with a high potential for abuse and the risk of severe psychologi­cal or physical dependence.

Lisdexamfetamine is not indicated for weight loss or obesity.

Dosage
For BED, the initial dosage of lisdexamfet­amine is 30 mg/d in the morning, titrated by 20 mg/d per week to the target dos­age of 50 to 70 mg/d. Maximum dosage is 70 mg/d. Morning dosing is recommended to avoid sleep disturbance.

Efficacy
The clinical efficacy of lisdexamfetamine was assessed in two 12-week parallel group, flexible-dose, placebo-controlled trials in adults with BED (age 18 to 55). Primary efficacy measure was the num­ber of binge days per week. Both studies had a 4-week dose-optimization period and an 8-week dose-maintenance period and followed the same dosage protocol. Patients began treatment at 30 mg/d and after 1 week were titrated to 50 mg/d; increases to 70 mg/d were made if clini­cally necessary and well tolerated. Patients were maintained on the optimized dos­age during the 8-week dose-maintenance period. A dosage of 30 mg/d did not produce a statistically significant effect, but 50 mg/d and 70 mg/d dosages were statistically superior to placebo. Patients taking lisdexamfetamine also had greater improvement on the Clinical Global Impression—Improvement scores, 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating score.

The prescribing information does not state if lisdexamfetamine should be con­tinued long-term for treating BED.

Adverse reactions
In controlled trials, 5.1% of patients receiv­ing lisdexamfetamine for BED discontin­ued the drug because of an adverse event, compared with 2.4% of patients receiv­ing placebo. The most common adverse reactions in BED studies were dry mouth (36%), insomnia (20%), decreased appetite (8%), increased heart rate (8%), constipation (6%), and feeling jittery (6%). In trials of children, adolescents, and adults with ADHD, decreased appetite was more com­mon (39%, 34%, and 27%, respectively) than in BED trials (Table 2). Anaphylactic reac­tions, Stevens-Johnson syndrome, angio­edema, and urticaria have been described in postmarketing reports.

The safety of lisdexamfetamine for BED has not been studied in patients age <18, but has been studied in patients with ADHD.

Contraindications
Do not give lisdexamfetamine to patients who have a known hypersensitivity to amphetamine products or other ingredi­ents in lisdexamfetamine capsules.

Lisdexamfetamine is contraindicated in patients who are taking a monoamine oxi­dase inhibitor, because of a risk of hyper­tensive crisis.
 

Related Resources
• Wilens TE. Lisdexamfetamine for ADHD. Current Psychiatry. 2007;6(6):96-98,105.
• Peat CM, Brownley KA, Berkman ND, et al. Binge eating dis­order: evidence-based treatments. Current Psychiatry. 2012; 11(5):32-39.

Lisdexamfetamine, approved by the FDA in 2007 for attention-deficit/hyperactivity disorder (ADHD), has a new indication: binge eating disorder (BED) (Table 1). BED is characterized by recurrent episodes of consuming a large amount of food in a short time. A prodrug of amphet­amine, lisdexamfetamine is a Schedule-II controlled substance, with a high potential for abuse and the risk of severe psychologi­cal or physical dependence.

Lisdexamfetamine is not indicated for weight loss or obesity.

Dosage
For BED, the initial dosage of lisdexamfet­amine is 30 mg/d in the morning, titrated by 20 mg/d per week to the target dos­age of 50 to 70 mg/d. Maximum dosage is 70 mg/d. Morning dosing is recommended to avoid sleep disturbance.

Efficacy
The clinical efficacy of lisdexamfetamine was assessed in two 12-week parallel group, flexible-dose, placebo-controlled trials in adults with BED (age 18 to 55). Primary efficacy measure was the num­ber of binge days per week. Both studies had a 4-week dose-optimization period and an 8-week dose-maintenance period and followed the same dosage protocol. Patients began treatment at 30 mg/d and after 1 week were titrated to 50 mg/d; increases to 70 mg/d were made if clini­cally necessary and well tolerated. Patients were maintained on the optimized dos­age during the 8-week dose-maintenance period. A dosage of 30 mg/d did not produce a statistically significant effect, but 50 mg/d and 70 mg/d dosages were statistically superior to placebo. Patients taking lisdexamfetamine also had greater improvement on the Clinical Global Impression—Improvement scores, 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating score.

The prescribing information does not state if lisdexamfetamine should be con­tinued long-term for treating BED.

Adverse reactions
In controlled trials, 5.1% of patients receiv­ing lisdexamfetamine for BED discontin­ued the drug because of an adverse event, compared with 2.4% of patients receiv­ing placebo. The most common adverse reactions in BED studies were dry mouth (36%), insomnia (20%), decreased appetite (8%), increased heart rate (8%), constipation (6%), and feeling jittery (6%). In trials of children, adolescents, and adults with ADHD, decreased appetite was more com­mon (39%, 34%, and 27%, respectively) than in BED trials (Table 2). Anaphylactic reac­tions, Stevens-Johnson syndrome, angio­edema, and urticaria have been described in postmarketing reports.

The safety of lisdexamfetamine for BED has not been studied in patients age <18, but has been studied in patients with ADHD.

Contraindications
Do not give lisdexamfetamine to patients who have a known hypersensitivity to amphetamine products or other ingredi­ents in lisdexamfetamine capsules.

Lisdexamfetamine is contraindicated in patients who are taking a monoamine oxi­dase inhibitor, because of a risk of hyper­tensive crisis.
 

Related Resources
• Wilens TE. Lisdexamfetamine for ADHD. Current Psychiatry. 2007;6(6):96-98,105.
• Peat CM, Brownley KA, Berkman ND, et al. Binge eating dis­order: evidence-based treatments. Current Psychiatry. 2012; 11(5):32-39.

Lisdexamfetamine, approved by the FDA in 2007 for attention-deficit/hyperactivity disorder (ADHD), has a new indication: binge eating disorder (BED) (Table 1). BED is characterized by recurrent episodes of consuming a large amount of food in a short time. A prodrug of amphet­amine, lisdexamfetamine is a Schedule-II controlled substance, with a high potential for abuse and the risk of severe psychologi­cal or physical dependence.

Lisdexamfetamine is not indicated for weight loss or obesity.

Dosage
For BED, the initial dosage of lisdexamfet­amine is 30 mg/d in the morning, titrated by 20 mg/d per week to the target dos­age of 50 to 70 mg/d. Maximum dosage is 70 mg/d. Morning dosing is recommended to avoid sleep disturbance.

Efficacy
The clinical efficacy of lisdexamfetamine was assessed in two 12-week parallel group, flexible-dose, placebo-controlled trials in adults with BED (age 18 to 55). Primary efficacy measure was the num­ber of binge days per week. Both studies had a 4-week dose-optimization period and an 8-week dose-maintenance period and followed the same dosage protocol. Patients began treatment at 30 mg/d and after 1 week were titrated to 50 mg/d; increases to 70 mg/d were made if clini­cally necessary and well tolerated. Patients were maintained on the optimized dos­age during the 8-week dose-maintenance period. A dosage of 30 mg/d did not produce a statistically significant effect, but 50 mg/d and 70 mg/d dosages were statistically superior to placebo. Patients taking lisdexamfetamine also had greater improvement on the Clinical Global Impression—Improvement scores, 4-week binge cessation, and greater reduction in the Yale-Brown Obsessive Compulsive Scale Modified for Binge Eating score.

The prescribing information does not state if lisdexamfetamine should be con­tinued long-term for treating BED.

Adverse reactions
In controlled trials, 5.1% of patients receiv­ing lisdexamfetamine for BED discontin­ued the drug because of an adverse event, compared with 2.4% of patients receiv­ing placebo. The most common adverse reactions in BED studies were dry mouth (36%), insomnia (20%), decreased appetite (8%), increased heart rate (8%), constipation (6%), and feeling jittery (6%). In trials of children, adolescents, and adults with ADHD, decreased appetite was more com­mon (39%, 34%, and 27%, respectively) than in BED trials (Table 2). Anaphylactic reac­tions, Stevens-Johnson syndrome, angio­edema, and urticaria have been described in postmarketing reports.

The safety of lisdexamfetamine for BED has not been studied in patients age <18, but has been studied in patients with ADHD.

Contraindications
Do not give lisdexamfetamine to patients who have a known hypersensitivity to amphetamine products or other ingredi­ents in lisdexamfetamine capsules.

Lisdexamfetamine is contraindicated in patients who are taking a monoamine oxi­dase inhibitor, because of a risk of hyper­tensive crisis.
 

Related Resources
• Wilens TE. Lisdexamfetamine for ADHD. Current Psychiatry. 2007;6(6):96-98,105.
• Peat CM, Brownley KA, Berkman ND, et al. Binge eating dis­order: evidence-based treatments. Current Psychiatry. 2012; 11(5):32-39.

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Attention-deficit/hyperactivity disorder (ADHD) often persists beyond childhood into adulthood. One of the therapeutic challenges of treat­ing ADHD is identifying comorbidities, including underlying mood and anxiety disorders, and ongoing substance abuse. Effective treatment modalities tend to pri­oritize management of substance abuse, but the patient’s age may dictate the overall assessment plan.

So-called 'reward' center
Treating childhood ADHD with stimu­lants might reduce the risk for future drug abuse.¹ It is estimated that approximately 10 million people with ADHD are undiag­nosed in the United States²; characteristic ADHD symptoms—inattention, hyperac­tivity, impulsivity—can persist in adult­hood, and affected persons might not meet societal expectations. Previously uniden­tified attention difficulties may emerge during early adulthood because of increas­ingly complex tasks at school and work.

Persons with undiagnosed ADHD might turn to potentially self-destructive means of placating inner tension. Cocaine has phar­macological properties in common with stimulants such as methylphenidate, which often is prescribed for ADHD. Cocaine and methylphenidate both work on altering brain chemistry with a similar mechanism of action, allowing for increased dopamine in the nucleus accumbens, also known as the “reward center” of the brain.

Adults with ADHD have a 300% higher risk of developing a substance use disorder than adults without ADHD.³ An estimated 15% to 25% of adults with substance abuse have comorbid ADHD. Although these patients abuse of a variety of substances including Cannabis and alcohol, cocaine is one of the most commonly abused substances among this population. These observations could point to a self-medication hypothesis.
 

Why self-medicate?
The self-medication hypothesis, formu­lated by Khantzian in 1985, was based on several clinical observations. Khantzian stated that an abuser’s drug of choice is not selected at random but, rather, by an inherent desire to suppress the attri­butes of the condition that seems to oth­erwise wreak havoc on his (her) life. Almost a century earlier, Freud men­tioned that cocaine is an antidepressant. Among persons with ADHD who have not been given that diagnosis, or treated for the disorder, cocaine is a popular drug. Because of the antidepressant features of cocaine and its ability to produce a rapid increase of dopamine levels that exert a pro-euphoric effect, coupled with a seem­ingly paradoxical calming influence that leads to increased productivity, it is not surprising to find that cocaine is abused. Reportedly, persons who have not been treated because their ADHD is undiag­nosed turn to cocaine because it improves attention, raises self-esteem, and allows users to harness a level of focus that they could not otherwise achieve.⁴

Mechanism of action
Methylphenidate reduces ADHD symp­toms by increasing extracellular dopamine in the brain, acting by means of a mechanism that is similar to that of cocaine.⁵ By block­ing reuptake of dopamine and allowing an extracellular surplus, users continue to experience the pleasurable effect the neuro-transmitter produces. Methylphenidate has been shown to be an even more potent inhibitor of the same autoreceptors. Injecting methylphenidate has been shown to produce a rapid release of dopamine sim­ilar to that of cocaine.⁵

However, methylphenidate causes a much slower increase in dopamine; its effect on the brain has been shown to be similar to that of cocaine without the increased abuse potential. Cocaine use remodels the brain by reconfiguring con­nections that are essential for craving and self-control.⁵ Therefore, substituting meth­ylphenidate for cocaine could help ADHD patients by:
   • improving overall executive functioning
   • decreasing feelings of low self-worth
   • increasing daily functioning
   • minimizing craving and the risk of sub­sequent cocaine abuse.
 

Treatment recommendations
Carefully consider pharmacodynamics and pharmacokinetics when prescribing ADHD medication. In general, children and adolescents with ADHD respond more favorably to stimulants than adults do. In children, the mainstay of treatment is slow-dose stimulants such as methylphenidate; second-line treatments are immediate-release stimulants and atomoxetine, a selec­tive norepinephrine reuptake inhibitor.⁶ Adults with ADHD might benefit from a nonstimulant, in part because of the pres­ence of complex comorbidities.⁶ Modafinil often is prescribed for adults with ADHD.

Atomoxetine readily increases norepi­nephrine and dopamine in the prefrontal cortex as it bypasses the nucleus accum­bens. Although atomoxetine is not a stimu­lant, the efficacy of the drug is based on its ability to increase norepinephrine through selective inhibition of the norepineph­rine transporter. Norepinephrine modu­lates higher cortical functions—attention, executive function, arousal—that lead to a reduction in hyperactivity, inattention, and impulsivity.

Because dopamine is released in the prefrontal cortex—not in the nucleus accumbens—the addiction potential of atomoxetine is low.⁷ The drug might be an effective intervention for patients who are using cocaine to self-medicate. Stimulants such as methylphenidate have proven effective in safely mimicking the mecha­nism of action of cocaine. Nonstimulants, such as atomoxetine and modafinil, lack abuse potential and are excellent options for treating adults with ADHD.

Clinicians generally are advised to treat a patient’s underlying ADHD symptoms before addressing ongoing substance abuse. If a patient abruptly discontinues cocaine use before ADHD symptoms are properly controlled, her (his) condition might deterio­rate further and the treatment plan might fail to progress. Some patients have experienced a reduction in craving for cocaine after they began stimulant therapy; these people no longer felt a need to self-medicate because their symptoms were being addressed.⁴

Adult attention-deficit/hyperactivity disorder (ADHD) can be challenging to assess accurately. Adult ADHD differs significantly from childhood ADHD, in that hyperactivity often is absent or greatly diminished, comorbid disorders (depression or substance use) are common, and previously compensated attention deficits in school can manifest in the patient’s personal and professional life.¹

The mnemonic DISTRACTED can help when recalling key components in assessing adult ADHD.² Because ADHD is a developmental disorder—there are signs of onset in childhood—it is important to maintain a longitudinal view when asking about patterns of behavior or thinking.

Distractibility. Is there a pattern of getting “off track” in conversations or in school or work situations because of straying thoughts or daydreams? Is there a tendency to over-respond to extraneous stimuli (eg, cell phones, computers, television) that impedes the patient’s ability to converse, receive information, or follow directions?

Impulsivity. Does the patient have a history of saying things “off the cuff,” interrupting others, or “walking on” someone else’s words in a conversation? Is impulsivity evident in the person’s substance use or spending patterns?

School history. This domain is important in diagnosing ADHD in adults because there needs to be evidence that the disorder was present from an early age. How did the patient perform in school (ie, grades, organization, completion of homework assignments)? Was there a behavioral pattern that reflected hyperactivity (could not stay seated) or emotional dysregulation (frequent outbursts)?

Task completion. Does the patient have trouble finishing assignments at work, staying focused on a project that is considered boring, or completing a home project (eg, fixing a leaky faucet) in a timely fashion?

Rating scales. Rating scales should be used to help support the diagnosis, based on the patient’s history and life story. There are >12 scales that can be utilized in a
clinical setting³; the ADHD/Hyperactivity Disorder Self-Report Scale is a brief and easy measure of core ADHD symptoms.

Accidents. Adults with ADHD often are accident-prone because of inattention, hyperactivity, or impulsivity. Does the patient have a history of unintentionally hurting himself because he “wasn’t paying attention” (falls, burns), or was too impatient (traffic accidents or citations)?

Commitments. Does the patient fail to fulfill verbal obligations (by arriving late, forgetting to run errands)? Has this difficulty to commit created problems in relationships over time?

Time management. How difficult is it for the patient to stay organized while balancing work expectations, social obligations, and family needs? Is there a pattern of chaotic scheduling with regard to meals, work, or sleeping?

Employment. Has the patient changed jobs because the work becomes “too boring” or “uninteresting”? Is there a pattern of being terminated because of poor work quality based on time management or job performance?

Decisions. Adults with ADHD often make hasty, ill-informed choices or procrastinate so that they do not have to make a decision. Does the patient’s decision-making reveal a pattern of being too distracted to hear the information needed, or too impatient to consider all the details?

Remember: No single component of this mnemonic alone suffices to make a diagnosis of adult ADHD. However, these considerations will help clarify what lies behind your DISTRACTED patient’s search for self-understanding and appropriate medical care.

Disclosure

Dr. Christensen reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Adult attention-deficit/hyperactivity disorder (ADHD) can be challenging to assess accurately. Adult ADHD differs significantly from childhood ADHD, in that hyperactivity often is absent or greatly diminished, comorbid disorders (depression or substance use) are common, and previously compensated attention deficits in school can manifest in the patient’s personal and professional life.¹

The mnemonic DISTRACTED can help when recalling key components in assessing adult ADHD.² Because ADHD is a developmental disorder—there are signs of onset in childhood—it is important to maintain a longitudinal view when asking about patterns of behavior or thinking.

Distractibility. Is there a pattern of getting “off track” in conversations or in school or work situations because of straying thoughts or daydreams? Is there a tendency to over-respond to extraneous stimuli (eg, cell phones, computers, television) that impedes the patient’s ability to converse, receive information, or follow directions?

Impulsivity. Does the patient have a history of saying things “off the cuff,” interrupting others, or “walking on” someone else’s words in a conversation? Is impulsivity evident in the person’s substance use or spending patterns?

School history. This domain is important in diagnosing ADHD in adults because there needs to be evidence that the disorder was present from an early age. How did the patient perform in school (ie, grades, organization, completion of homework assignments)? Was there a behavioral pattern that reflected hyperactivity (could not stay seated) or emotional dysregulation (frequent outbursts)?

Task completion. Does the patient have trouble finishing assignments at work, staying focused on a project that is considered boring, or completing a home project (eg, fixing a leaky faucet) in a timely fashion?

Rating scales. Rating scales should be used to help support the diagnosis, based on the patient’s history and life story. There are >12 scales that can be utilized in a
clinical setting³; the ADHD/Hyperactivity Disorder Self-Report Scale is a brief and easy measure of core ADHD symptoms.

Accidents. Adults with ADHD often are accident-prone because of inattention, hyperactivity, or impulsivity. Does the patient have a history of unintentionally hurting himself because he “wasn’t paying attention” (falls, burns), or was too impatient (traffic accidents or citations)?

Commitments. Does the patient fail to fulfill verbal obligations (by arriving late, forgetting to run errands)? Has this difficulty to commit created problems in relationships over time?

Time management. How difficult is it for the patient to stay organized while balancing work expectations, social obligations, and family needs? Is there a pattern of chaotic scheduling with regard to meals, work, or sleeping?

Employment. Has the patient changed jobs because the work becomes “too boring” or “uninteresting”? Is there a pattern of being terminated because of poor work quality based on time management or job performance?

Decisions. Adults with ADHD often make hasty, ill-informed choices or procrastinate so that they do not have to make a decision. Does the patient’s decision-making reveal a pattern of being too distracted to hear the information needed, or too impatient to consider all the details?

Remember: No single component of this mnemonic alone suffices to make a diagnosis of adult ADHD. However, these considerations will help clarify what lies behind your DISTRACTED patient’s search for self-understanding and appropriate medical care.

Disclosure

Dr. Christensen reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Adult attention-deficit/hyperactivity disorder (ADHD) can be challenging to assess accurately. Adult ADHD differs significantly from childhood ADHD, in that hyperactivity often is absent or greatly diminished, comorbid disorders (depression or substance use) are common, and previously compensated attention deficits in school can manifest in the patient’s personal and professional life.¹

The mnemonic DISTRACTED can help when recalling key components in assessing adult ADHD.² Because ADHD is a developmental disorder—there are signs of onset in childhood—it is important to maintain a longitudinal view when asking about patterns of behavior or thinking.

Distractibility. Is there a pattern of getting “off track” in conversations or in school or work situations because of straying thoughts or daydreams? Is there a tendency to over-respond to extraneous stimuli (eg, cell phones, computers, television) that impedes the patient’s ability to converse, receive information, or follow directions?

Impulsivity. Does the patient have a history of saying things “off the cuff,” interrupting others, or “walking on” someone else’s words in a conversation? Is impulsivity evident in the person’s substance use or spending patterns?

School history. This domain is important in diagnosing ADHD in adults because there needs to be evidence that the disorder was present from an early age. How did the patient perform in school (ie, grades, organization, completion of homework assignments)? Was there a behavioral pattern that reflected hyperactivity (could not stay seated) or emotional dysregulation (frequent outbursts)?

Task completion. Does the patient have trouble finishing assignments at work, staying focused on a project that is considered boring, or completing a home project (eg, fixing a leaky faucet) in a timely fashion?

Rating scales. Rating scales should be used to help support the diagnosis, based on the patient’s history and life story. There are >12 scales that can be utilized in a
clinical setting³; the ADHD/Hyperactivity Disorder Self-Report Scale is a brief and easy measure of core ADHD symptoms.

Accidents. Adults with ADHD often are accident-prone because of inattention, hyperactivity, or impulsivity. Does the patient have a history of unintentionally hurting himself because he “wasn’t paying attention” (falls, burns), or was too impatient (traffic accidents or citations)?

Commitments. Does the patient fail to fulfill verbal obligations (by arriving late, forgetting to run errands)? Has this difficulty to commit created problems in relationships over time?

Time management. How difficult is it for the patient to stay organized while balancing work expectations, social obligations, and family needs? Is there a pattern of chaotic scheduling with regard to meals, work, or sleeping?

Employment. Has the patient changed jobs because the work becomes “too boring” or “uninteresting”? Is there a pattern of being terminated because of poor work quality based on time management or job performance?

Decisions. Adults with ADHD often make hasty, ill-informed choices or procrastinate so that they do not have to make a decision. Does the patient’s decision-making reveal a pattern of being too distracted to hear the information needed, or too impatient to consider all the details?

Remember: No single component of this mnemonic alone suffices to make a diagnosis of adult ADHD. However, these considerations will help clarify what lies behind your DISTRACTED patient’s search for self-understanding and appropriate medical care.

Disclosure

Dr. Christensen reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Molly, age 9, is diagnosed with attention-deficit/hyperactivity disorder (ADHD) by her psychiatrist, who prescribes a long-acting methylphenidate formulation at 1 mg/kg. She tolerates the medication without side effects and shows significant improvement in her academic performance and on-task behavior in school. Molly takes methylphenidate before school at 7:00 am; this dose usually wears off at approximately 3:30 pm.

Molly and her parents are pleased with her response to methylphenidate, but report that she has difficulty getting ready for school because of distractibility. In the evenings Molly has trouble staying seated to do homework and often interrupts and argues with family members, but cannot tolerate afternoon dosing of immediate-release methylphenidate because of insomnia.

ADHD, the most common childhood neurobehavioral disorder, is characterized by difficulties with attention, impulse control, and modulating activity level. The pathophysiology of ADHD is thought to involve dysregulation of brain dopamine and norepinephrine systems.¹ Managing ADHD includes pharmacotherapeutic and nonpharmacotherapeutic—ie, behavioral and psychoeducational—interventions.^2,3

In this article, we provide an overview of the efficacy, side effects, and dosing for the 3 classes of ADHD medication—psychostimulants, atomoxetine, and α₂ adrenergic agonists—including guidance on medication choice and combination treatment. We also discuss the effects of psychostimulants on tics, cardiovascular concerns, and substance abuse potential.

Psychostimulants

Methylphenidates and amphetamines are first-line agents for ADHD. Their primary mechanism of action involves blocking dopamine transporters, with additional effects including blockade of norepinephrine transporters, dampening action of monoamine oxidase (which slows dopamine and norepinephrine degradation), and enhanced release of dopamine into the synaptic space.¹

Efficacy and response rates are similar for methylphenidate and amphetamine medications, although as many as 25% of patients may respond to only 1 agent.¹ More than 90% of patients will have a positive response to one of the psychostimulants.¹ The beneficial effects of psychostimulants on inattention, hyperactivity, and impulsivity are well documented.²Improvements in noncompliance, aggression, social interactions, and academic productivity also have been observed.^4,5

Because of increased recognition of pervasive ADHD-related impairments, which can affect functioning in social, family, and extracurricular settings, practitioners have shifted to long-acting psychostimulants to reduce the need for in-school dosing, improve compliance, and obtain more after-school treatment effects. Long-acting formulations produce a slower rise and fall of psychostimulant levels in the brain, which may decrease side effects and potential for later drug abuse.⁶ See Table 1^2,7-9 and Table 2^2,7,9  for titration, dosing, and duration of action of psychostimulants.

The most common side effects of psychostimulants are appetite loss, abdominal pain, headaches, and sleep disturbances.² Emotional symptoms—irritability and nervousness—may be observed with psychostimulant use, but these behaviors may improve, rather than become worse, with treatment.⁵ Methylphenidates and amphetamines share many of the same side effects,² with many studies indicating no differences between their side-effect profiles.¹ Other studies indicate that sleep and emotional side effects may be more prominent with amphetamines than methylphenidates,¹⁰ although response varies by individual.

There is little evidence that methylphenidate, low-dose amphetamine, or low-dose dextroamphetamine makes tics worse in most children who have them, although significant tic exacerbation has been observed with higher-dose dextroamphetamine.^11,12 In patients with comorbid ADHD and tic disorders, a trial of psychostimulants with monitoring for worsening tics is appropriate.

Changes in heart rate and blood pressure generally are not clinically significant in patients taking psychostimulants (average increases: 1 or 2 beats per minute and 1 to 4 mm Hg for systolic and diastolic blood pressures).¹² However, psychostimulants may be associated with more substantial increases in heart rate and blood pressure in a subset of individuals (5% to 15%).¹² Large studies of children and adults in the general population have not found an association between psychostimulant use and severe cardiovascular events (sudden cardiac death, myocardial infarction, stroke).^12-14 Because of reports of sudden cardiac death in children with underlying heart disease who take a psychostimulant,¹⁵ clinicians are advised to screen patients and consider an electrocardiogram or evaluation by a cardiologist before starting a psychostimulant in a patient who has a personal or family history of specific cardiovascular risk factors (see Perrin et al¹⁶ and Cortese et al¹² for screening questions and conditions).

Modest reductions in height (1 or 2 cm after 3 years of psychostimulant treatment) appear to be dose-dependent, and are similar across the methylphenidate and amphetamine classes. Some studies have shown reversal of growth deficits after treatment is stopped treatment and no adverse effects on final adult height.^12,17 More study is needed to clarify the effects of continuous psychostimulant treatment from childhood to adulthood on growth.

Studies have failed to show an increased risk of substance abuse in persons with ADHD who were treated with psychostimulants during childhood. Some studies document a lower rate of later substance abuse in youths who received ADHD medications, although other reports show no effect of psychostimulant treatment on subsequent substance use disorder risk.¹² Be aware that psychostimulants can be misused (eg, to get “high,” for performance enhancement, to suppress appetite, etc.). Misuse of psychostimulants is most common with short-acting preparations, and generally more difficult with long-acting preparations because extracting the active ingredients for snorting is difficult.^2,12 Monitor refill requests and patient behavior for signs of misuse, and be alert for signs of illegal drug use in the patient’s family.

Psychotic symptoms—including hallucinations, delusions, mania, and extreme agitation—with psychostimulant treatment are rare, occurring at a rate of 1.5%.¹²

Atomoxetine

Approved by the FDA in 2002 for ADHD, atomoxetine is effective and generally well tolerated, although it is not as effective as psychostimulants.² Atomoxetine is a potent norepinephrine reuptake inhibitor¹⁸ that does not produce euphoria, does not have potential for abuse, and has not been linked to increased tic onset or severity.¹⁹ Atomoxetine treatment is associated with a lower rate of sleep initiation difficulty compared with psychostimulants.¹⁸ Some studies suggest that atomoxetine may have mild beneficial effects on anxiety disorders,¹⁸ making it a reasonable choice for patients with significant anxiety or insomnia during psychostimulant treatment. Table 1^2,7-9 and Table 3^2,7,9 include information on dosing and duration of action for atomoxetine.

Common side effects of atomoxetine include sedation and fatigue, upset stomach, nausea and vomiting, reduced appetite, headache, and irritability.¹⁸ Inform patients that atomoxetine carries an FDA black-box warning for suicide risk; a review of 14 studies showed suicidal ideation was more common with atomoxetine than placebo, although no suicides occurred in any trials.²⁰

Hepatotoxicity is rare with atomoxetine.²¹ Although routine liver enzyme testing is not required, discontinue atomoxetine if jaundice develops or elevated levels of liver enzymes are noted. Other rare but potentially serious side effects include changes in heart rate (≥20 beats per min) or blood pressure that occur in 5% to 10% of patients taking atomoxetine.²² The risk of serious cardiovascular events and sudden cardiac death with atomoxetine is extremely low, but patients should be screened for a personal and family history of cardiovascular risk factors and, if any of these are present, evaluated further before starting atomoxetine. Routine heart rate and blood pressure monitoring is recommended for all patients.^12-14,16

Last, atomoxetine has been linked to growth delays in the first 1 or 2 years of treatment, with a return to expected measurements after an average 2 or 3 years of treatment; persistent decreases in growth rate were observed in patients who were taller or heavier than average before treatment.²³

α₂ Adrenergic agonists

Guanfacine ER and clonidine ER, the extended release (ER) formulations of α₂ adrenergic agonists, were FDA-approved for treating ADHD in 2009 and 2010, respectively. Short-acting guanfacine and clonidine also are used for treating ADHD.²⁴ Their mechanism of action involves stimulation of the pre-synaptic and post-synapic α₂ adrenergic receptors, which control the release of norepinephrine and the rate of cell firing.²⁵ The α₂ agonists are considered a second-line treatment for ADHD because their efficacy and response rate for core ADHD symptoms lags behind those of psychostimulants.²⁵ In addition to treating core ADHD symptoms, guanfacine and clonidine are used to treat tics and oppositional/aggressive behavior comorbid with ADHD.^24,26 Clonidine, which is more sedating than guanfacine, can be used to treat comorbid ADHD and sleep disorders.²⁴ The α₂ agonists do not produce euphoria and do not have drug abuse potential.²Table 1^2,7-9 and Table 3^2,7,9 provide guidelines for prescribing guanfacine ER and clonidine ER.

The most common adverse effect is drowsiness; other common side effects include dizziness, irritability, headache, and abdominal pain.²⁴ Short-term studies of α₂ agonist treatment of ADHD have shown small, non-clinically significant reductions in heart rate and blood pressure; α₂ agonist-associated bradycardia, increased QT interval, and cardiac arrhythmias have been reported,^7,24,27 as well as rebound hypertension with abrupt discontinuation.²⁴ Screen patients for a personal and family history of cardiovascular risk factors and, if present, evaluate further before initiating α₂ agonists.

Combining ADHD medication classes

Combination therapy with >1 ADHD medications is employed when 1 class does not provide adequate symptom coverage or produces problematic side effects.^8,24 Psychostimulants can be combined with low-dose atomoxetine (0.5 to 1.0 mg/kg/d) when atomoxetine does not adequately cover ADHD symptoms in school, or when psychostimulants do not adequately cover evening symptoms or patients experience problems with evening psychostimulant rebound.⁸ To date, prospective data on the safety and efficacy of combining atomoxetine and psychostimulants are limited, but what evidence is available suggests improved symptom control for some, but not all, patients, and a lack of serious adverse events.²⁸

Psychostimulants have been combined with α₂agonists when children have an inadequate response to psychostimulants alone, or in cases of ADHD comorbid with aggression or tics.²⁴ Although early case reports raised concern about the safety of combining psychostimulants and α₂ agonists, subsequent studies suggest that clonidine and guanfacine generally are well-tolerated when co-administered with psychostimulants.^24,27,29

Case continued

Molly has derived substantial benefit from long-acting methylphenidate during the school day, but continues to have significant ADHD-related impairment in the mornings and evenings. Her physician tried afternoon dosing of immediate-release methylphenidate to address evening difficulties, but Molly experienced insomnia. It would be reasonable to consider adjunctive therapy with a non-stimulant medication. A medication that can provide round-the-clock ADHD symptom coverage—such as atomoxetine, guanfacine ER, or clonidine ER—could be added to her current day-time psychostimulant treatment, potentially improving her functioning at home before school and in the evenings.

Additional considerations

Combining medication and behavior therapy offers greater improvements on academic, conduct, and family satisfaction measures than either treatment alone.² Clinicians can choose to employ behavior therapy alone, particularly if parents feel uncomfortable with—or children have not tolerated—medication.^2,3 Evidence-based behavioral parent training and classroom management strategies (implemented by teachers) have shown the strongest and most consistent effects among nonpharmacotherapeutic interventions for ADHD.² Most studies comparing behavior therapy to psychostimulants have found a stronger effect on core ADHD symptoms from psychostimulants than from behavior therapy.

When a patient does not respond adequately to FDA-approved ADHD medications alone or in combination, consider bupropion, an antidepressant with indirect dopamine and noradrenergic effects. Off-label bupropion has been shown to be effective for ADHD in controlled trials of both children and adults.³⁰

Clinicians often encounter children who meet criteria for ADHD and an anxiety or mood disorder. Table 4^8,31 summarizes treatment recommendations for these patients.

Clinical considerations

• Begin treatment with a psychostimulant at a low dosage, and titrate gradually until symptoms are controlled or side effects develop.
• Keep in mind that an effective dosage of a psychostimulant is not closely correlated with age, weight, or severity of symptoms.
• Monitor refill requests and patient behavior for signs of psychostimulant misuse. Be alert for signs of illegal drug use in patient family members.
• Lisdexamfetamine, dermal methylphenidate, and osmotic release oral system methylphenidate are the formulations least likely to be misused because their delivery systems make it difficult to extract the active ingredient for snorting or intravenous injection.
• Psychostimulants have not been shown to exacerbate tics in most children who have comorbid ADHD and a tic disorder. When a stimulant is associated with an exacerbation of tics, switching treatment to atomoxetine or α₂ agonists is reasonable.
• For patients whose use of a stimulant is limited by an adverse effect on sleep, consider atomoxetine and α₂ adrenergic agonists as alternative or adjunctive treatments.
• All 3 classes of FDA-approved ADHD medications (psychostimulants, atomoxetine, and adrenergic agonists) have been associated with adverse cardiac events in children who have underlying cardiovascular conditions. Before initiating treatment, screen patients for a personal or family history of cardiovascular risk factors, and undertake further evaluation as indicated.

Bottom Line

In general, the evidence supports psychostimulants as initial pharmacotherapy for ADHD, with additional options including atomoxetine and α₂ agonists. When one medication class does not provide adequate coverage for ADHD symptoms, combining medication classes can be beneficial.

Related Resources

• National Institute of Mental Health. What is attention deficit hyperactivity disorder (ADHD, ADD)?” www.nimh.nih.gov/health/topics/attention-deficit-hyperactivity-disorder-adhd/index.shtml.
• National Resource Center on AD/HD. Managing medication for children and adolescents with ADHD. www.help4adhd.org/en/treatment/medication/WWK3.

Drug Brand Names

Atomoxetine • Strattera

Lisdexamfetamine • Vyvanse

Bupropion • Wellbutrin, Zyban

Clonidine extended release • Kapvay

Guanfacine extended release • Intuniv

Dexmethylphenidate • Focalin, Focalin XR

Mixed amphetamine salts • Adderall, Adderall XR

Dextroamphetamine • Dexedrine, Dexedrine SR, DextroStat, ProCentra

Methylphenidate • Ritalin, Methylin, Metadate CD, Metadate ER, Methylin ER, Ritalin LA, Ritalin SR, Concerta, Quillivant XR, Daytrana

Disclosures

Dr. Froehlich receives support from the National Institute of Mental Health Grant K23 MH083881. Dr. Delgado has received research support from Pfizer, Inc. Dr. Anixt reports no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Angry and depressed

Y is a 16-year-old male who presents with his mother to our clinic for medication evaluation because of anger issues and problems learning in school. He says he has been feeling depressed for several months and noticed significant irritability. Y sleeps excessively, sometimes for more than 12 hours a day, and eats more than he usually does. He reports feeling hopeless, helpless, and guilty for letting his family down. Y, who is in the 10th grade, acknowledges trouble focusing and concentrating but attributed this to a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD). He stopped taking his stimulant medication several months ago because he did not like taking it. He denies thoughts of self-harm or thinking about death.

Y’s mother reports that her son had been athletic but had to stop playing football because he has had 5 concussions. Y’s inability to play sports appears to be a precipitating factor in his decline in mood (Box). He had his first concussion at age 13; the last one was several months before his presenting to the clinic. Y experienced loss of consciousness and unsteady gait after his concussions and was hospitalized for some of them. Y says his life goals are “playing sports and being a marine,” which may be compromised because of his head injuries.

His mother reports Y is having more anger outbursts and says his personality is changing. Y viewed this change as just being more assertive and fails to see that others may be scared by his behavior. He is getting into more fights at school and is more impulsive and unpredictable, according to his mother. Y is struggling in school with cognitive deficits and memory problems; his grade point average (GPA) drops from 3.5 to 0.3 over several months. He had been homeschooled initially because of uncontrolled impulsivity and aggression, but was reintegrated to public school. Y has a history of a mathematics disorder but had done well without school accommodations before the head injuries. Lack of access to his peers and poor self-esteem because of his declining grades are making his mood worse. He denies a history of substance use and his urine drug screen is negative.

Recently, Y’s grandfather, with whom he had been close, died and 2 friends were killed in car accidents in the last few years. Y has no history of psychiatric hospitalization. He had seen a psychotherapist for depression. He had been on lisdexamfetamine, 30 mg/d, citalopram, 10 mg/d, and an unknown dose of dextroamphetamine. He had no major medical comorbidities. He lives with his mother. His parents are separated but he has frequent contact with his father. His developmental history is unremarkable. There was a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. There was no family history of suicide.

On his initial mental status examination, Y appears to be his stated age and is dressed appropriately. He is well dressed, suggesting that he puts a lot of care into his personal appearance. He is alert and oriented. He is cooperative and has fair eye contact. His gait is normal and no motor abnormalities are evident. His speech is normal in rate, rhythm, and volume. He can remember events with great accuracy. He reports that his mood is depressed and “down.” His affect appears irritable and he has low frustration tolerance, especially towards his mother. He is easy to anger but is re-directable. He does not endorse thoughts of suicidality or harm to others. He denies auditory or visual hallucinations, and paranoia. He does not appear to be responding to internal stimuli. His judgment and insight are fair.

The authors' observations

Traumatic brain injury (TBI) affects 1.7 to 3.8 million people in the United States. More than 473,000 children present to the emergency room annually with TBI, approximately 75% of whom are given a label of mild TBI in the United States.^1-3 TBI patients present with varying degrees of problems ranging from headaches to cognitive deficits and death. Symptoms may be transient or permanent.⁴ Prepubescent children are at higher risk and are more likely to sustain permanent damage post-TBI, with problems in attention, executive functioning, memory, and cognition.^5-7

Prognosis depends on severity of injury and environmental factors, including socioeconomic status, family dysfunction, and access to resources.⁸ Patients may present during the acute concussion phase with physical symptoms, such as headaches, nausea, vomiting, sensitivity to light and sounds, and memory deficits, and psychiatric complaints such as anger, irritability, and mood swings. Symptoms may persist post-concussion, leading to problems in personal relationships and social and occupational functioning, and neuropsychiatric manifestations, including changes in personality, depression, suicidal thoughts, and substance dependence. As seen in this case, Y had neuropsychiatric manifestations after his TBI but other factors, such as his ADHD diagnosis and the death of his grandfather and friends, may have contributed to his presentation.

Up to one-half of children with brain injuries may be at increased risk for unfavorable behavioral outcomes, which include internalizing and externalizing presentations.⁹ These behavioral problems may emerge several years after the injury and often persist or get worse with time. Behavioral functioning before injury usually dictates long-term outcomes post injury. The American Academy of Neurology recently released guidelines for the assessment and treatment of athletes with concussions (see Related Resources).

TREATMENT Restart medication

We restart Y on citalopram, 10 mg/d, which he tolerated in the past, and increase it to 20 mg/d after 4 days to address his depression and irritability. He also is restarted on lisdexamfetamine, 30 mg/d, for his ADHD. We give his mother the Child Behavior Checklist and Teacher’s Report Forms to gather additional collateral information. We ask Y to follow up in 1 month and we encourage him to continue seeing his psychotherapist.

EVALUATION Testing

Although Y denies feeling depressed to the neuropsychologist, the examiner notes her concerns about his depression based on his mental status examination during testing.

Neuropsychological testing reveals a discrepancy noted between normal verbal skills and perceptual intellectual skills that were in the borderline range (Table). Testing revealed results supporting executive dysfunction and distractibility, which are consistent with his history of ADHD. Y’s broad reading scores are in the 20th percentile and math scores in the 30th percentile. Although he has a history of a mathematics disorder, his reading deficits are considered a decline compared with his previous performance.

The authors' observations

Y is a 16-year-old male who presented with anger, depression, and academic problems. He had genetic loading with a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. Other than his concussions, Y was healthy, however, he had pre-morbid, untreated ADHD. He was doing well academically until his concussions, after which he started to see a steep decline in his grades. He was struggling with low self-esteem, which affected his mood. Multiple contributors perpetuated his difficulties, including, his inability to play sports; being home-schooled; removal from his friends; deaths of close friends and family; and a concern that his medical limitation to refrain from physical activities was affecting his career ambitions, contributing to his sense of hopelessness.

Y responded well to the stimulant and antidepressant, but it is important to note the increased risk of non-compliance in teenagers, even when they report seemingly minor side effects, despite doing well clinically. Y required frequent psychiatric follow up and repeat neuropsychological evaluation to monitor his progress.

OUTCOME Back on the playing field

At Y’s 1 month follow up, he reports feeling less depressed but citalopram, 20 mg/d, makes him feel “plain.” His GPA increases to 2.5 and he completes 10th grade. Lisdexamfetamine is titrated to 60 mg/d, he is focusing at school, and his anger is better controlled. Y’s mother is hesitant to change any medications because of her son’s overall improvement.

A few weeks before his next follow up appointment, Y’s mother calls stating that his depression is worse as he has not been taking citalopram because he doesn’t like how it makes him feel. He is started on fluoxetine, 10 mg/d. At his next appointment, Y says that he tolerates fluoxetine. His mood improves substantially and he is doing much better. Y’s mother says she feel that her son is more social, smiling more, and sleeping and eating better.

Several months after Y’s school performance, mood, and behaviors improve, his physicians give him permission to play non-contact sports. He is excited to play baseball. Because of his symptoms, we recommend continuing treating his ADHD and depressive symptoms and monitoring the need for medication. We discussed with Y nonpharmacotherapeutic options, including access to an individualized education plan at school, individual therapy, and formalized cognitive training.

Bottom Line

Traumatic brain injury (TBI) affects children and adults with long-term sequelae, which affects outcomes. Outcome is dependent on several risk factors. Many patients with TBI also suffer from neuropsychiatric symptoms that affect their functioning at home and in social and occupational settings. Those with premorbid psychiatric conditions need to be closely monitored because they may be at greater risk for problems with mood and executive function. Treatment should be targeted to individual complaints.

Related Resources

• Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(24): 2250-2257.
• Reardon CL, Factor RM. Sport psychiatry: a systematic review of diagnosis and medical treatment of mental illness in athletes. Sports Med. 2010;40(11):961-980.

Drug Brand Names

Citalopram • Celexa            Dextroamphetamine • Adderall

Fluoxetine • Prozac             Lisdexamfetamine dimesylate • Vyvanse

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Angry and depressed

Y is a 16-year-old male who presents with his mother to our clinic for medication evaluation because of anger issues and problems learning in school. He says he has been feeling depressed for several months and noticed significant irritability. Y sleeps excessively, sometimes for more than 12 hours a day, and eats more than he usually does. He reports feeling hopeless, helpless, and guilty for letting his family down. Y, who is in the 10th grade, acknowledges trouble focusing and concentrating but attributed this to a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD). He stopped taking his stimulant medication several months ago because he did not like taking it. He denies thoughts of self-harm or thinking about death.

Y’s mother reports that her son had been athletic but had to stop playing football because he has had 5 concussions. Y’s inability to play sports appears to be a precipitating factor in his decline in mood (Box). He had his first concussion at age 13; the last one was several months before his presenting to the clinic. Y experienced loss of consciousness and unsteady gait after his concussions and was hospitalized for some of them. Y says his life goals are “playing sports and being a marine,” which may be compromised because of his head injuries.

His mother reports Y is having more anger outbursts and says his personality is changing. Y viewed this change as just being more assertive and fails to see that others may be scared by his behavior. He is getting into more fights at school and is more impulsive and unpredictable, according to his mother. Y is struggling in school with cognitive deficits and memory problems; his grade point average (GPA) drops from 3.5 to 0.3 over several months. He had been homeschooled initially because of uncontrolled impulsivity and aggression, but was reintegrated to public school. Y has a history of a mathematics disorder but had done well without school accommodations before the head injuries. Lack of access to his peers and poor self-esteem because of his declining grades are making his mood worse. He denies a history of substance use and his urine drug screen is negative.

Recently, Y’s grandfather, with whom he had been close, died and 2 friends were killed in car accidents in the last few years. Y has no history of psychiatric hospitalization. He had seen a psychotherapist for depression. He had been on lisdexamfetamine, 30 mg/d, citalopram, 10 mg/d, and an unknown dose of dextroamphetamine. He had no major medical comorbidities. He lives with his mother. His parents are separated but he has frequent contact with his father. His developmental history is unremarkable. There was a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. There was no family history of suicide.

On his initial mental status examination, Y appears to be his stated age and is dressed appropriately. He is well dressed, suggesting that he puts a lot of care into his personal appearance. He is alert and oriented. He is cooperative and has fair eye contact. His gait is normal and no motor abnormalities are evident. His speech is normal in rate, rhythm, and volume. He can remember events with great accuracy. He reports that his mood is depressed and “down.” His affect appears irritable and he has low frustration tolerance, especially towards his mother. He is easy to anger but is re-directable. He does not endorse thoughts of suicidality or harm to others. He denies auditory or visual hallucinations, and paranoia. He does not appear to be responding to internal stimuli. His judgment and insight are fair.

The authors' observations

Traumatic brain injury (TBI) affects 1.7 to 3.8 million people in the United States. More than 473,000 children present to the emergency room annually with TBI, approximately 75% of whom are given a label of mild TBI in the United States.^1-3 TBI patients present with varying degrees of problems ranging from headaches to cognitive deficits and death. Symptoms may be transient or permanent.⁴ Prepubescent children are at higher risk and are more likely to sustain permanent damage post-TBI, with problems in attention, executive functioning, memory, and cognition.^5-7

Prognosis depends on severity of injury and environmental factors, including socioeconomic status, family dysfunction, and access to resources.⁸ Patients may present during the acute concussion phase with physical symptoms, such as headaches, nausea, vomiting, sensitivity to light and sounds, and memory deficits, and psychiatric complaints such as anger, irritability, and mood swings. Symptoms may persist post-concussion, leading to problems in personal relationships and social and occupational functioning, and neuropsychiatric manifestations, including changes in personality, depression, suicidal thoughts, and substance dependence. As seen in this case, Y had neuropsychiatric manifestations after his TBI but other factors, such as his ADHD diagnosis and the death of his grandfather and friends, may have contributed to his presentation.

Up to one-half of children with brain injuries may be at increased risk for unfavorable behavioral outcomes, which include internalizing and externalizing presentations.⁹ These behavioral problems may emerge several years after the injury and often persist or get worse with time. Behavioral functioning before injury usually dictates long-term outcomes post injury. The American Academy of Neurology recently released guidelines for the assessment and treatment of athletes with concussions (see Related Resources).

TREATMENT Restart medication

We restart Y on citalopram, 10 mg/d, which he tolerated in the past, and increase it to 20 mg/d after 4 days to address his depression and irritability. He also is restarted on lisdexamfetamine, 30 mg/d, for his ADHD. We give his mother the Child Behavior Checklist and Teacher’s Report Forms to gather additional collateral information. We ask Y to follow up in 1 month and we encourage him to continue seeing his psychotherapist.

EVALUATION Testing

Although Y denies feeling depressed to the neuropsychologist, the examiner notes her concerns about his depression based on his mental status examination during testing.

Neuropsychological testing reveals a discrepancy noted between normal verbal skills and perceptual intellectual skills that were in the borderline range (Table). Testing revealed results supporting executive dysfunction and distractibility, which are consistent with his history of ADHD. Y’s broad reading scores are in the 20th percentile and math scores in the 30th percentile. Although he has a history of a mathematics disorder, his reading deficits are considered a decline compared with his previous performance.

The authors' observations

Y is a 16-year-old male who presented with anger, depression, and academic problems. He had genetic loading with a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. Other than his concussions, Y was healthy, however, he had pre-morbid, untreated ADHD. He was doing well academically until his concussions, after which he started to see a steep decline in his grades. He was struggling with low self-esteem, which affected his mood. Multiple contributors perpetuated his difficulties, including, his inability to play sports; being home-schooled; removal from his friends; deaths of close friends and family; and a concern that his medical limitation to refrain from physical activities was affecting his career ambitions, contributing to his sense of hopelessness.

Y responded well to the stimulant and antidepressant, but it is important to note the increased risk of non-compliance in teenagers, even when they report seemingly minor side effects, despite doing well clinically. Y required frequent psychiatric follow up and repeat neuropsychological evaluation to monitor his progress.

OUTCOME Back on the playing field

At Y’s 1 month follow up, he reports feeling less depressed but citalopram, 20 mg/d, makes him feel “plain.” His GPA increases to 2.5 and he completes 10th grade. Lisdexamfetamine is titrated to 60 mg/d, he is focusing at school, and his anger is better controlled. Y’s mother is hesitant to change any medications because of her son’s overall improvement.

A few weeks before his next follow up appointment, Y’s mother calls stating that his depression is worse as he has not been taking citalopram because he doesn’t like how it makes him feel. He is started on fluoxetine, 10 mg/d. At his next appointment, Y says that he tolerates fluoxetine. His mood improves substantially and he is doing much better. Y’s mother says she feel that her son is more social, smiling more, and sleeping and eating better.

Several months after Y’s school performance, mood, and behaviors improve, his physicians give him permission to play non-contact sports. He is excited to play baseball. Because of his symptoms, we recommend continuing treating his ADHD and depressive symptoms and monitoring the need for medication. We discussed with Y nonpharmacotherapeutic options, including access to an individualized education plan at school, individual therapy, and formalized cognitive training.

Bottom Line

Traumatic brain injury (TBI) affects children and adults with long-term sequelae, which affects outcomes. Outcome is dependent on several risk factors. Many patients with TBI also suffer from neuropsychiatric symptoms that affect their functioning at home and in social and occupational settings. Those with premorbid psychiatric conditions need to be closely monitored because they may be at greater risk for problems with mood and executive function. Treatment should be targeted to individual complaints.

Related Resources

• Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(24): 2250-2257.
• Reardon CL, Factor RM. Sport psychiatry: a systematic review of diagnosis and medical treatment of mental illness in athletes. Sports Med. 2010;40(11):961-980.

Drug Brand Names

Citalopram • Celexa            Dextroamphetamine • Adderall

Fluoxetine • Prozac             Lisdexamfetamine dimesylate • Vyvanse

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE Angry and depressed

Y is a 16-year-old male who presents with his mother to our clinic for medication evaluation because of anger issues and problems learning in school. He says he has been feeling depressed for several months and noticed significant irritability. Y sleeps excessively, sometimes for more than 12 hours a day, and eats more than he usually does. He reports feeling hopeless, helpless, and guilty for letting his family down. Y, who is in the 10th grade, acknowledges trouble focusing and concentrating but attributed this to a previous diagnosis of attention-deficit/hyperactivity disorder (ADHD). He stopped taking his stimulant medication several months ago because he did not like taking it. He denies thoughts of self-harm or thinking about death.

Y’s mother reports that her son had been athletic but had to stop playing football because he has had 5 concussions. Y’s inability to play sports appears to be a precipitating factor in his decline in mood (Box). He had his first concussion at age 13; the last one was several months before his presenting to the clinic. Y experienced loss of consciousness and unsteady gait after his concussions and was hospitalized for some of them. Y says his life goals are “playing sports and being a marine,” which may be compromised because of his head injuries.

His mother reports Y is having more anger outbursts and says his personality is changing. Y viewed this change as just being more assertive and fails to see that others may be scared by his behavior. He is getting into more fights at school and is more impulsive and unpredictable, according to his mother. Y is struggling in school with cognitive deficits and memory problems; his grade point average (GPA) drops from 3.5 to 0.3 over several months. He had been homeschooled initially because of uncontrolled impulsivity and aggression, but was reintegrated to public school. Y has a history of a mathematics disorder but had done well without school accommodations before the head injuries. Lack of access to his peers and poor self-esteem because of his declining grades are making his mood worse. He denies a history of substance use and his urine drug screen is negative.

Recently, Y’s grandfather, with whom he had been close, died and 2 friends were killed in car accidents in the last few years. Y has no history of psychiatric hospitalization. He had seen a psychotherapist for depression. He had been on lisdexamfetamine, 30 mg/d, citalopram, 10 mg/d, and an unknown dose of dextroamphetamine. He had no major medical comorbidities. He lives with his mother. His parents are separated but he has frequent contact with his father. His developmental history is unremarkable. There was a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. There was no family history of suicide.

On his initial mental status examination, Y appears to be his stated age and is dressed appropriately. He is well dressed, suggesting that he puts a lot of care into his personal appearance. He is alert and oriented. He is cooperative and has fair eye contact. His gait is normal and no motor abnormalities are evident. His speech is normal in rate, rhythm, and volume. He can remember events with great accuracy. He reports that his mood is depressed and “down.” His affect appears irritable and he has low frustration tolerance, especially towards his mother. He is easy to anger but is re-directable. He does not endorse thoughts of suicidality or harm to others. He denies auditory or visual hallucinations, and paranoia. He does not appear to be responding to internal stimuli. His judgment and insight are fair.

The authors' observations

Traumatic brain injury (TBI) affects 1.7 to 3.8 million people in the United States. More than 473,000 children present to the emergency room annually with TBI, approximately 75% of whom are given a label of mild TBI in the United States.^1-3 TBI patients present with varying degrees of problems ranging from headaches to cognitive deficits and death. Symptoms may be transient or permanent.⁴ Prepubescent children are at higher risk and are more likely to sustain permanent damage post-TBI, with problems in attention, executive functioning, memory, and cognition.^5-7

Prognosis depends on severity of injury and environmental factors, including socioeconomic status, family dysfunction, and access to resources.⁸ Patients may present during the acute concussion phase with physical symptoms, such as headaches, nausea, vomiting, sensitivity to light and sounds, and memory deficits, and psychiatric complaints such as anger, irritability, and mood swings. Symptoms may persist post-concussion, leading to problems in personal relationships and social and occupational functioning, and neuropsychiatric manifestations, including changes in personality, depression, suicidal thoughts, and substance dependence. As seen in this case, Y had neuropsychiatric manifestations after his TBI but other factors, such as his ADHD diagnosis and the death of his grandfather and friends, may have contributed to his presentation.

Up to one-half of children with brain injuries may be at increased risk for unfavorable behavioral outcomes, which include internalizing and externalizing presentations.⁹ These behavioral problems may emerge several years after the injury and often persist or get worse with time. Behavioral functioning before injury usually dictates long-term outcomes post injury. The American Academy of Neurology recently released guidelines for the assessment and treatment of athletes with concussions (see Related Resources).

TREATMENT Restart medication

We restart Y on citalopram, 10 mg/d, which he tolerated in the past, and increase it to 20 mg/d after 4 days to address his depression and irritability. He also is restarted on lisdexamfetamine, 30 mg/d, for his ADHD. We give his mother the Child Behavior Checklist and Teacher’s Report Forms to gather additional collateral information. We ask Y to follow up in 1 month and we encourage him to continue seeing his psychotherapist.

EVALUATION Testing

Although Y denies feeling depressed to the neuropsychologist, the examiner notes her concerns about his depression based on his mental status examination during testing.

Neuropsychological testing reveals a discrepancy noted between normal verbal skills and perceptual intellectual skills that were in the borderline range (Table). Testing revealed results supporting executive dysfunction and distractibility, which are consistent with his history of ADHD. Y’s broad reading scores are in the 20th percentile and math scores in the 30th percentile. Although he has a history of a mathematics disorder, his reading deficits are considered a decline compared with his previous performance.

The authors' observations

Y is a 16-year-old male who presented with anger, depression, and academic problems. He had genetic loading with a questionable family history of schizophrenia, “nervous breakdowns,” depression, and bipolar disorder. Other than his concussions, Y was healthy, however, he had pre-morbid, untreated ADHD. He was doing well academically until his concussions, after which he started to see a steep decline in his grades. He was struggling with low self-esteem, which affected his mood. Multiple contributors perpetuated his difficulties, including, his inability to play sports; being home-schooled; removal from his friends; deaths of close friends and family; and a concern that his medical limitation to refrain from physical activities was affecting his career ambitions, contributing to his sense of hopelessness.

Y responded well to the stimulant and antidepressant, but it is important to note the increased risk of non-compliance in teenagers, even when they report seemingly minor side effects, despite doing well clinically. Y required frequent psychiatric follow up and repeat neuropsychological evaluation to monitor his progress.

OUTCOME Back on the playing field

At Y’s 1 month follow up, he reports feeling less depressed but citalopram, 20 mg/d, makes him feel “plain.” His GPA increases to 2.5 and he completes 10th grade. Lisdexamfetamine is titrated to 60 mg/d, he is focusing at school, and his anger is better controlled. Y’s mother is hesitant to change any medications because of her son’s overall improvement.

A few weeks before his next follow up appointment, Y’s mother calls stating that his depression is worse as he has not been taking citalopram because he doesn’t like how it makes him feel. He is started on fluoxetine, 10 mg/d. At his next appointment, Y says that he tolerates fluoxetine. His mood improves substantially and he is doing much better. Y’s mother says she feel that her son is more social, smiling more, and sleeping and eating better.

Several months after Y’s school performance, mood, and behaviors improve, his physicians give him permission to play non-contact sports. He is excited to play baseball. Because of his symptoms, we recommend continuing treating his ADHD and depressive symptoms and monitoring the need for medication. We discussed with Y nonpharmacotherapeutic options, including access to an individualized education plan at school, individual therapy, and formalized cognitive training.

Bottom Line

Traumatic brain injury (TBI) affects children and adults with long-term sequelae, which affects outcomes. Outcome is dependent on several risk factors. Many patients with TBI also suffer from neuropsychiatric symptoms that affect their functioning at home and in social and occupational settings. Those with premorbid psychiatric conditions need to be closely monitored because they may be at greater risk for problems with mood and executive function. Treatment should be targeted to individual complaints.

Related Resources

• Giza CC, Kutcher JS, Ashwal S, et al. Summary of evidence-based guideline update: evaluation and management of concussion in sports: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2013;80(24): 2250-2257.
• Reardon CL, Factor RM. Sport psychiatry: a systematic review of diagnosis and medical treatment of mental illness in athletes. Sports Med. 2010;40(11):961-980.

Drug Brand Names

Citalopram • Celexa            Dextroamphetamine • Adderall

Fluoxetine • Prozac             Lisdexamfetamine dimesylate • Vyvanse

Disclosure

The authors report no financial relationships with any company whose products are mentioned in this article or with manufacturers of competing products.

We psychiatrists should take a biopsychosocial approach to assessing our patients. However, we are enamored with biology and individual psychodynamics. Thus, we often overlook the influence of culture, or the lack thereof, on human behavior.

The assertion of Dr. Douglas K. Novins that using foundational cultural beliefs and practices strengthens interventions with people of color is particularly powerful. Furthermore, Dr. Novins’s findings inform us about the importance of culture in the protective factors and risky behaviors of our patients.

Culture Protects

While doing HIV prevention work in Durban, South Africa, I found it striking that 40% of the black African Zulu people were HIV positive, 6% of the white South Africans were HIV positive, but only 1% of the East Indian South Africans were HIV positive.

As it turns out, the East Indian South African culture (with its intact religious rituals, proscribed clothing customs, age-old mating practices, and so on) protected them. Meanwhile, the black African Zulu culture and its protective cultural influence had been stripped from them, making them vulnerable to activities such as risky sexual behavior, substance abuse, and violence.

In addition, it appears that the white South African culture is eroding, which is resulting in higher levels of HIV-positive individuals.

Culture Destroys

The latest Youth Risk Behavior Surveillance data offer a glimpse into just how paradoxical our world has become. The investigators looked at six categories of health-risk behaviors among young people and young adults.

Among their findings: The prevalence of having carried a weapon in general was higher among white males (27.2%) than among their black counterparts (21%). The prevalence of having carried a weapon onto school property was higher among white males (7.8%) than black males (6.7%). The prevalence of having ever used cocaine was higher among white males (7.6%) than black males (4.2%). Yet, people of color make up a higher proportion of children and young adults who are incarcerated. In fact, in 2010, the imprisonment rate for black non-Hispanic males (3,074/100,000 U.S. black male residents) was almost seven times higher than it was for white non-Hispanic males (459/100,000), according to the U.S. Bureau of Justice Statistics.

Some of these disparities can be deconstructed by looking at housing patterns. Structurally, we understand that most mid- and large-size cities have more absolute numbers of low-income whites than low-income blacks. But few low-income white neighborhoods exist because low-income whites have scattered-site housing, while low-income blacks are concentrated in inner cities. Police have a more difficult time finding and incarcerating illegal drug users when they live in scattered-site housing. Therefore, blacks who use illegal drugs are incarcerated more often than whites who use illegal drugs.

We also must acknowledge that some of these disparities are tied to the human construct of race. Buy-in to this construct explains why law enforcement officers traditionally "hunted" runaway slaves and returned them to their owners. It potentially explains the motivations of former Chicago police officer Jon Burge, who was convicted 2 years ago of lying about the torture of innocent black men in order to get confessions over many decades. Finally, this reality explains the thinking behind this saying in Chicago’s black community: "The police hunt black males!"

International psychiatrist Suman Fernando makes the point in his book "Mental Health, Race and Culture: Third Edition" (New York: Palgrave Macmillan, 2010) that much of Western culture is inherently racist. Derald Wing Sue, Ph.D., the preeminent multicultural scholar, reminds us of "ethnocentric monoculturalism," the notion that the only culture in the Western world that has any value is Western culture, and all other cultural values and practices are "primitive." Dr. Sue points out that ethnocentric monoculturalism and whiteness define a reality that puts those who are white European American males at an advantage (American Psychologist 2004;59:761-9).

In Canada, these destructive, entrenched views led to the removal of children from First Nations communities. This cultural dislocation, in turn, led to the loss of cultural protective factors, which ultimately contributed to the engagement in risky behaviors tied to suicide, intragroup homicide, and substance abuse. As I’ve discussed previously, many of the disruptive behaviors that result in incarceration can be traced back to alcohol consumption (Preventing fetal alcohol syndrome, April 12, 2012). It is well known that this syndrome is a leading cause of speech and language disorders, attention-deficit/hyperactivity disorder, and other developmental/cognitive disorders. These are often responsible for affect dysregulation, which leads to disruptive behaviors – which, in turn, can lead to incarceration.

It is heartening to see research like that produced by Dr. Novins and his colleagues. Their work reaffirms that culture protects. It also is a reminder that psychiatrists need to understand the sociological forces that exacerbate the emotional pain suffered by our patients – particularly those who are marginalized. We must redouble our efforts to incorporate respectful cultural components into our interventions. Doing so will produce better outcomes.

Dr. Bell is president and chief executive officer of Community Mental Health Council Inc. in Chicago. He also serves as director of the Institute for Juvenile Research at the University of Illinois at Chicago, and is director of public health and community psychiatry at the university.

We psychiatrists should take a biopsychosocial approach to assessing our patients. However, we are enamored with biology and individual psychodynamics. Thus, we often overlook the influence of culture, or the lack thereof, on human behavior.

The assertion of Dr. Douglas K. Novins that using foundational cultural beliefs and practices strengthens interventions with people of color is particularly powerful. Furthermore, Dr. Novins’s findings inform us about the importance of culture in the protective factors and risky behaviors of our patients.

Culture Protects

While doing HIV prevention work in Durban, South Africa, I found it striking that 40% of the black African Zulu people were HIV positive, 6% of the white South Africans were HIV positive, but only 1% of the East Indian South Africans were HIV positive.

As it turns out, the East Indian South African culture (with its intact religious rituals, proscribed clothing customs, age-old mating practices, and so on) protected them. Meanwhile, the black African Zulu culture and its protective cultural influence had been stripped from them, making them vulnerable to activities such as risky sexual behavior, substance abuse, and violence.

In addition, it appears that the white South African culture is eroding, which is resulting in higher levels of HIV-positive individuals.

Culture Destroys

The latest Youth Risk Behavior Surveillance data offer a glimpse into just how paradoxical our world has become. The investigators looked at six categories of health-risk behaviors among young people and young adults.

Among their findings: The prevalence of having carried a weapon in general was higher among white males (27.2%) than among their black counterparts (21%). The prevalence of having carried a weapon onto school property was higher among white males (7.8%) than black males (6.7%). The prevalence of having ever used cocaine was higher among white males (7.6%) than black males (4.2%). Yet, people of color make up a higher proportion of children and young adults who are incarcerated. In fact, in 2010, the imprisonment rate for black non-Hispanic males (3,074/100,000 U.S. black male residents) was almost seven times higher than it was for white non-Hispanic males (459/100,000), according to the U.S. Bureau of Justice Statistics.

Some of these disparities can be deconstructed by looking at housing patterns. Structurally, we understand that most mid- and large-size cities have more absolute numbers of low-income whites than low-income blacks. But few low-income white neighborhoods exist because low-income whites have scattered-site housing, while low-income blacks are concentrated in inner cities. Police have a more difficult time finding and incarcerating illegal drug users when they live in scattered-site housing. Therefore, blacks who use illegal drugs are incarcerated more often than whites who use illegal drugs.

We also must acknowledge that some of these disparities are tied to the human construct of race. Buy-in to this construct explains why law enforcement officers traditionally "hunted" runaway slaves and returned them to their owners. It potentially explains the motivations of former Chicago police officer Jon Burge, who was convicted 2 years ago of lying about the torture of innocent black men in order to get confessions over many decades. Finally, this reality explains the thinking behind this saying in Chicago’s black community: "The police hunt black males!"

International psychiatrist Suman Fernando makes the point in his book "Mental Health, Race and Culture: Third Edition" (New York: Palgrave Macmillan, 2010) that much of Western culture is inherently racist. Derald Wing Sue, Ph.D., the preeminent multicultural scholar, reminds us of "ethnocentric monoculturalism," the notion that the only culture in the Western world that has any value is Western culture, and all other cultural values and practices are "primitive." Dr. Sue points out that ethnocentric monoculturalism and whiteness define a reality that puts those who are white European American males at an advantage (American Psychologist 2004;59:761-9).

In Canada, these destructive, entrenched views led to the removal of children from First Nations communities. This cultural dislocation, in turn, led to the loss of cultural protective factors, which ultimately contributed to the engagement in risky behaviors tied to suicide, intragroup homicide, and substance abuse. As I’ve discussed previously, many of the disruptive behaviors that result in incarceration can be traced back to alcohol consumption (Preventing fetal alcohol syndrome, April 12, 2012). It is well known that this syndrome is a leading cause of speech and language disorders, attention-deficit/hyperactivity disorder, and other developmental/cognitive disorders. These are often responsible for affect dysregulation, which leads to disruptive behaviors – which, in turn, can lead to incarceration.

It is heartening to see research like that produced by Dr. Novins and his colleagues. Their work reaffirms that culture protects. It also is a reminder that psychiatrists need to understand the sociological forces that exacerbate the emotional pain suffered by our patients – particularly those who are marginalized. We must redouble our efforts to incorporate respectful cultural components into our interventions. Doing so will produce better outcomes.

Dr. Bell is president and chief executive officer of Community Mental Health Council Inc. in Chicago. He also serves as director of the Institute for Juvenile Research at the University of Illinois at Chicago, and is director of public health and community psychiatry at the university.

We psychiatrists should take a biopsychosocial approach to assessing our patients. However, we are enamored with biology and individual psychodynamics. Thus, we often overlook the influence of culture, or the lack thereof, on human behavior.

The assertion of Dr. Douglas K. Novins that using foundational cultural beliefs and practices strengthens interventions with people of color is particularly powerful. Furthermore, Dr. Novins’s findings inform us about the importance of culture in the protective factors and risky behaviors of our patients.

Culture Protects

While doing HIV prevention work in Durban, South Africa, I found it striking that 40% of the black African Zulu people were HIV positive, 6% of the white South Africans were HIV positive, but only 1% of the East Indian South Africans were HIV positive.

As it turns out, the East Indian South African culture (with its intact religious rituals, proscribed clothing customs, age-old mating practices, and so on) protected them. Meanwhile, the black African Zulu culture and its protective cultural influence had been stripped from them, making them vulnerable to activities such as risky sexual behavior, substance abuse, and violence.

In addition, it appears that the white South African culture is eroding, which is resulting in higher levels of HIV-positive individuals.

Culture Destroys

The latest Youth Risk Behavior Surveillance data offer a glimpse into just how paradoxical our world has become. The investigators looked at six categories of health-risk behaviors among young people and young adults.

Among their findings: The prevalence of having carried a weapon in general was higher among white males (27.2%) than among their black counterparts (21%). The prevalence of having carried a weapon onto school property was higher among white males (7.8%) than black males (6.7%). The prevalence of having ever used cocaine was higher among white males (7.6%) than black males (4.2%). Yet, people of color make up a higher proportion of children and young adults who are incarcerated. In fact, in 2010, the imprisonment rate for black non-Hispanic males (3,074/100,000 U.S. black male residents) was almost seven times higher than it was for white non-Hispanic males (459/100,000), according to the U.S. Bureau of Justice Statistics.

Some of these disparities can be deconstructed by looking at housing patterns. Structurally, we understand that most mid- and large-size cities have more absolute numbers of low-income whites than low-income blacks. But few low-income white neighborhoods exist because low-income whites have scattered-site housing, while low-income blacks are concentrated in inner cities. Police have a more difficult time finding and incarcerating illegal drug users when they live in scattered-site housing. Therefore, blacks who use illegal drugs are incarcerated more often than whites who use illegal drugs.

We also must acknowledge that some of these disparities are tied to the human construct of race. Buy-in to this construct explains why law enforcement officers traditionally "hunted" runaway slaves and returned them to their owners. It potentially explains the motivations of former Chicago police officer Jon Burge, who was convicted 2 years ago of lying about the torture of innocent black men in order to get confessions over many decades. Finally, this reality explains the thinking behind this saying in Chicago’s black community: "The police hunt black males!"

International psychiatrist Suman Fernando makes the point in his book "Mental Health, Race and Culture: Third Edition" (New York: Palgrave Macmillan, 2010) that much of Western culture is inherently racist. Derald Wing Sue, Ph.D., the preeminent multicultural scholar, reminds us of "ethnocentric monoculturalism," the notion that the only culture in the Western world that has any value is Western culture, and all other cultural values and practices are "primitive." Dr. Sue points out that ethnocentric monoculturalism and whiteness define a reality that puts those who are white European American males at an advantage (American Psychologist 2004;59:761-9).

In Canada, these destructive, entrenched views led to the removal of children from First Nations communities. This cultural dislocation, in turn, led to the loss of cultural protective factors, which ultimately contributed to the engagement in risky behaviors tied to suicide, intragroup homicide, and substance abuse. As I’ve discussed previously, many of the disruptive behaviors that result in incarceration can be traced back to alcohol consumption (Preventing fetal alcohol syndrome, April 12, 2012). It is well known that this syndrome is a leading cause of speech and language disorders, attention-deficit/hyperactivity disorder, and other developmental/cognitive disorders. These are often responsible for affect dysregulation, which leads to disruptive behaviors – which, in turn, can lead to incarceration.

It is heartening to see research like that produced by Dr. Novins and his colleagues. Their work reaffirms that culture protects. It also is a reminder that psychiatrists need to understand the sociological forces that exacerbate the emotional pain suffered by our patients – particularly those who are marginalized. We must redouble our efforts to incorporate respectful cultural components into our interventions. Doing so will produce better outcomes.

Dr. Bell is president and chief executive officer of Community Mental Health Council Inc. in Chicago. He also serves as director of the Institute for Juvenile Research at the University of Illinois at Chicago, and is director of public health and community psychiatry at the university.

CASE: Perfect breath

Mr. C, a 20-year-old college student, is diagnosed with obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and tic disorder (TD). His obsessions consist of a persistent sense that he is not breathing “correctly” or “perfectly.” He compulsively holds his breath to “rush blood to my head” until “the pressure feels just right.” Mr. C says that his OCD has had longstanding, significant negative impact on his academic performance and capacity to engage in other activities. Tics have been present for years and manifest as coughing and throat-clearing. After multiple syncopal epi-sodes from breath-holding with Valsalva maneuver—some of which caused falls and head injury—Mr. C is admitted to a residential psychiatric unit specializing in treating OCD. At the time of his admission, his Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores^1,2 are 23 total, 12 on the obsessions subscale, and 11 on the compulsions subscale, indicating moderate to severe illness. Cognitive-behavioral therapy (CBT) is offered, along with a combination of escitalopram, 60 mg/d, and quetiapine, 50 mg/d. Quetiapine is over-sedating at subtherapeutic doses and Mr. C’s compulsions worsen. He reports that “[it] took longer and longer to get the ‘just right’ feeling.’” Quetiapine is discontinued and risperidone, 0.5 mg/d, is started, which decreases the frequency of his tics. When he is discharged after a 36-day stay, Mr. C’s Y-BOCS scores are greatly improved at 13 total, 7 on the obsessions subscale, and 3 on the compulsions subscale.

Mr. C’s psychologist refers him to our outpatient clinic for continued psychiatric evaluation and treatment of his OCD, ADHD, and TD. At this time, he is prescribed escitalopram, 60 mg/d, and risperidone, 0.5 mg/d, along with CBT with his psychologist. We do not readminister the Y-BOCS at this time, but Mr. C reports that his OCD is “60% improved.” However, he describes prominent obsessive thoughts regarding his breathing similar to those he experienced before residential treatment. These obsessive thoughts arise in the context of specific environmental “triggers,” such as other people coughing or his own tics. The obsessions lead to compulsive urges to engage in breath-holding rituals. Mr. C experiences the thoughts and compulsions as deeply troubling and they consume 5 to 6 hours each day. Mr. C reports impaired concentration in class and during studying: “I can focus for 5 minutes, then not for 2 minutes, then for 3 minutes… I can never stay focused for more than a couple minutes,” before becoming distracted “by my OCD” or other environmental stimuli. We note on exam prominent breath-holding occurring several times per minute. Mr. C says his OCD has not impaired his ability to socialize.

Mr. C notes that he has been exposed to an array of CBT techniques, but he has difficulty using these techniques because his “mind wanders” or he lacks “motivation.” He admits he occasionally has taken a classmate’s ADHD medication (mixed amphetamine salts [MAS], dose unspecified) and found it improved his ability to focus on his academic work.

The authors’ observations

Researchers have established a relationship among OCD, ADHD, and TD across all combinations of comorbidity (OCD and ADHD,³ ADHD and TD,⁴ OCD and TD,^5,6 and all 3 entities⁷). Data suggests a poorer prognosis for OCD when comorbid with either or both of these conditions.⁸ Researchers have raised concerns that psychostimulants could exacerbate or potentiate tic behaviors in patients with ADHD,^9,10 although safe and effective use of these medications has been documented in controlled trials of patients with comorbid ADHD and tics.^11-13 Furthermore, tic suppression has been reported with psychostimulants,¹⁴ as well as a differential effect of stimulants on motor vs vocal tics.¹⁵ Despite these data (Table 1),^9-15 the FDA regards using psychostimulants in patients with TD as a contraindication,¹⁶ although clinicians often recognize that this practice may be unavoidable in some circumstances because of high comorbidity rates. Psychostimulants could exacerbate obsessions or compulsions in some patients because of their dopaminergic properties or through mitigation of the purported anti-obsessional properties of dopamine antagonists.¹⁷

Although there is evidence that the prevalence of prescribed psychostimulant abuse is low among ADHD patients,¹⁸ diversion of prescribed medication is a risk inherent in the use of these agents, particularly among college-age patients.^19,20

Table 1

Evidence of effect of psychostimulants on tics

TREATMENT: Weighing options

To manage impaired attention and executive function difficulties secondary to ADHD, we offer Mr. C several options, including bupropion, modafinil, and memantine augmentation. Mr. C asks for a psychostimulant because exam week is approaching and he wants a treatment with quick therapeutic effect. We discuss with Mr. C the potential for dopaminergic agents, such as psychostimulants, to exacerbate tics or OCD symptoms. Ultimately, we prescribe immediate-release MAS, 20 mg/d.

Two days later, Mr. C says he has taken 3 MAS doses and describes a marked reduction in obsessions, significant decrease in frequency of “triggers,” and greater capacity to use CBT saying, “when I am [triggered], I am able to move past the urges without doing any compulsions.” Daily time spent “stuck on” obsessions or compulsions decreases from 5 to 6 hours per day to “about 2 and a half minutes.”

Mr. C reports a modest increase in the prevalence of tics, experienced as “little throat clears and quick stuttering of breath.” He notes that, although in the past such tics would be followed by urges for “perfecting the tic and making it feel just right,” he presently “had no desire to do so.”

OUTCOME: Sharper focus

Increasing MAS immediate release from 20 mg/d to 30 mg/d suppresses Mr. C’s obsessions and compulsions for 8 hours. On the 19th day of treatment, MAS immediate release was replaced with an extended release formulation, 30 mg/d, which preserves therapeutic effect and tolerability for 16 weeks. Repeat Y-BOCS yields 9 total, 3 on obsessions subscale, and 6 on compulsions subscale scores.

One month later, Mr. C reports that his symptoms have been “improving ever since” the previous appointment. He continues to be able to access skills for managing his OCD and is doing well in his 2 accelerated summer courses, saying “I focus really well” in 3-hour class sessions. On exam, tic behaviors are nearly absent. Mr. C describes occasional bouts of anxiety associated with urges to engage in tic behaviors, in turn arising from fear of symptomatic recurrence as he worked toward stopping smoking as advised by his primary care physician and psychiatrist.

The authors’ observations

The results of the repeat Y-BOCS are consistent with improvement in obsessions but possible worsening of compulsions since Mr. C was discharged from residential treatment. Alternatively, compulsions may have worsened immediately after discharge and declined again with introduction of MAS.

A substantial body of literature describes the challenges associated with treating ADHD with comorbid tics, including the relative degree of risk of tic exacerbation associated with treating ADHD with psychostimulants. The range of FDA-approved pharmacologic options for treatment of this comorbidity is limited (Table 2),²¹ particularly given the risk for tardive dyskinesia associated with the typical antipsychotics haloperidol and chlorpromazine. Data support using the α-2 agonist clonidine to treat hyperactivity associated with ADHD²² and TD²³ and an extended-release preparation of this medication is FDA-approved for the former but not the latter indication (an α-2A receptor subtype agonist, guanfacine, also is FDA-approved for ADHD in pediatric patients). Mr. C’s experience of robust, sustained reduction in obsessions, if not compulsions, after treatment with MAS is consistent with the few studies of stimulant use in ADHD with comorbid OCD.^24,25

Effective treatment of ADHD may help Mr. C better access CBT strategies and thereby potentiate treatment of comorbid OCD.

Table 2

FDA-approved medications for ADHD, OCD, and TD

Related Resources

• Pliszka SR. Treating ADHD and comorbid disorders: psychosocial and psychopharmacological interventions. New York, NY: The Guilford Press; 2011.
• Pollak Y, Benarroch F, Kanengisser L, et al. Tourette syndrome-associated psychopathology: roles of comorbid attention-deficit hyperactivity disorder and obsessive-compulsive disorder. J Dev Behav Pediatr. 2009;30(5):413-419.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clonidine extended release • Kapvay
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Intuniv, Tenex
• Haloperidol • Haldol
• Lisdexamfetamine • Vyvanse
• Memantine • Namenda
• Methylphenidate • Methylin, Ritalin
• Modafinil • Provigil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Perfect breath

Mr. C, a 20-year-old college student, is diagnosed with obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and tic disorder (TD). His obsessions consist of a persistent sense that he is not breathing “correctly” or “perfectly.” He compulsively holds his breath to “rush blood to my head” until “the pressure feels just right.” Mr. C says that his OCD has had longstanding, significant negative impact on his academic performance and capacity to engage in other activities. Tics have been present for years and manifest as coughing and throat-clearing. After multiple syncopal epi-sodes from breath-holding with Valsalva maneuver—some of which caused falls and head injury—Mr. C is admitted to a residential psychiatric unit specializing in treating OCD. At the time of his admission, his Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores^1,2 are 23 total, 12 on the obsessions subscale, and 11 on the compulsions subscale, indicating moderate to severe illness. Cognitive-behavioral therapy (CBT) is offered, along with a combination of escitalopram, 60 mg/d, and quetiapine, 50 mg/d. Quetiapine is over-sedating at subtherapeutic doses and Mr. C’s compulsions worsen. He reports that “[it] took longer and longer to get the ‘just right’ feeling.’” Quetiapine is discontinued and risperidone, 0.5 mg/d, is started, which decreases the frequency of his tics. When he is discharged after a 36-day stay, Mr. C’s Y-BOCS scores are greatly improved at 13 total, 7 on the obsessions subscale, and 3 on the compulsions subscale.

Mr. C’s psychologist refers him to our outpatient clinic for continued psychiatric evaluation and treatment of his OCD, ADHD, and TD. At this time, he is prescribed escitalopram, 60 mg/d, and risperidone, 0.5 mg/d, along with CBT with his psychologist. We do not readminister the Y-BOCS at this time, but Mr. C reports that his OCD is “60% improved.” However, he describes prominent obsessive thoughts regarding his breathing similar to those he experienced before residential treatment. These obsessive thoughts arise in the context of specific environmental “triggers,” such as other people coughing or his own tics. The obsessions lead to compulsive urges to engage in breath-holding rituals. Mr. C experiences the thoughts and compulsions as deeply troubling and they consume 5 to 6 hours each day. Mr. C reports impaired concentration in class and during studying: “I can focus for 5 minutes, then not for 2 minutes, then for 3 minutes… I can never stay focused for more than a couple minutes,” before becoming distracted “by my OCD” or other environmental stimuli. We note on exam prominent breath-holding occurring several times per minute. Mr. C says his OCD has not impaired his ability to socialize.

Mr. C notes that he has been exposed to an array of CBT techniques, but he has difficulty using these techniques because his “mind wanders” or he lacks “motivation.” He admits he occasionally has taken a classmate’s ADHD medication (mixed amphetamine salts [MAS], dose unspecified) and found it improved his ability to focus on his academic work.

The authors’ observations

Researchers have established a relationship among OCD, ADHD, and TD across all combinations of comorbidity (OCD and ADHD,³ ADHD and TD,⁴ OCD and TD,^5,6 and all 3 entities⁷). Data suggests a poorer prognosis for OCD when comorbid with either or both of these conditions.⁸ Researchers have raised concerns that psychostimulants could exacerbate or potentiate tic behaviors in patients with ADHD,^9,10 although safe and effective use of these medications has been documented in controlled trials of patients with comorbid ADHD and tics.^11-13 Furthermore, tic suppression has been reported with psychostimulants,¹⁴ as well as a differential effect of stimulants on motor vs vocal tics.¹⁵ Despite these data (Table 1),^9-15 the FDA regards using psychostimulants in patients with TD as a contraindication,¹⁶ although clinicians often recognize that this practice may be unavoidable in some circumstances because of high comorbidity rates. Psychostimulants could exacerbate obsessions or compulsions in some patients because of their dopaminergic properties or through mitigation of the purported anti-obsessional properties of dopamine antagonists.¹⁷

Although there is evidence that the prevalence of prescribed psychostimulant abuse is low among ADHD patients,¹⁸ diversion of prescribed medication is a risk inherent in the use of these agents, particularly among college-age patients.^19,20

Table 1

Evidence of effect of psychostimulants on tics

TREATMENT: Weighing options

To manage impaired attention and executive function difficulties secondary to ADHD, we offer Mr. C several options, including bupropion, modafinil, and memantine augmentation. Mr. C asks for a psychostimulant because exam week is approaching and he wants a treatment with quick therapeutic effect. We discuss with Mr. C the potential for dopaminergic agents, such as psychostimulants, to exacerbate tics or OCD symptoms. Ultimately, we prescribe immediate-release MAS, 20 mg/d.

Two days later, Mr. C says he has taken 3 MAS doses and describes a marked reduction in obsessions, significant decrease in frequency of “triggers,” and greater capacity to use CBT saying, “when I am [triggered], I am able to move past the urges without doing any compulsions.” Daily time spent “stuck on” obsessions or compulsions decreases from 5 to 6 hours per day to “about 2 and a half minutes.”

Mr. C reports a modest increase in the prevalence of tics, experienced as “little throat clears and quick stuttering of breath.” He notes that, although in the past such tics would be followed by urges for “perfecting the tic and making it feel just right,” he presently “had no desire to do so.”

OUTCOME: Sharper focus

Increasing MAS immediate release from 20 mg/d to 30 mg/d suppresses Mr. C’s obsessions and compulsions for 8 hours. On the 19th day of treatment, MAS immediate release was replaced with an extended release formulation, 30 mg/d, which preserves therapeutic effect and tolerability for 16 weeks. Repeat Y-BOCS yields 9 total, 3 on obsessions subscale, and 6 on compulsions subscale scores.

One month later, Mr. C reports that his symptoms have been “improving ever since” the previous appointment. He continues to be able to access skills for managing his OCD and is doing well in his 2 accelerated summer courses, saying “I focus really well” in 3-hour class sessions. On exam, tic behaviors are nearly absent. Mr. C describes occasional bouts of anxiety associated with urges to engage in tic behaviors, in turn arising from fear of symptomatic recurrence as he worked toward stopping smoking as advised by his primary care physician and psychiatrist.

The authors’ observations

The results of the repeat Y-BOCS are consistent with improvement in obsessions but possible worsening of compulsions since Mr. C was discharged from residential treatment. Alternatively, compulsions may have worsened immediately after discharge and declined again with introduction of MAS.

A substantial body of literature describes the challenges associated with treating ADHD with comorbid tics, including the relative degree of risk of tic exacerbation associated with treating ADHD with psychostimulants. The range of FDA-approved pharmacologic options for treatment of this comorbidity is limited (Table 2),²¹ particularly given the risk for tardive dyskinesia associated with the typical antipsychotics haloperidol and chlorpromazine. Data support using the α-2 agonist clonidine to treat hyperactivity associated with ADHD²² and TD²³ and an extended-release preparation of this medication is FDA-approved for the former but not the latter indication (an α-2A receptor subtype agonist, guanfacine, also is FDA-approved for ADHD in pediatric patients). Mr. C’s experience of robust, sustained reduction in obsessions, if not compulsions, after treatment with MAS is consistent with the few studies of stimulant use in ADHD with comorbid OCD.^24,25

Effective treatment of ADHD may help Mr. C better access CBT strategies and thereby potentiate treatment of comorbid OCD.

Table 2

FDA-approved medications for ADHD, OCD, and TD

Related Resources

• Pliszka SR. Treating ADHD and comorbid disorders: psychosocial and psychopharmacological interventions. New York, NY: The Guilford Press; 2011.
• Pollak Y, Benarroch F, Kanengisser L, et al. Tourette syndrome-associated psychopathology: roles of comorbid attention-deficit hyperactivity disorder and obsessive-compulsive disorder. J Dev Behav Pediatr. 2009;30(5):413-419.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clonidine extended release • Kapvay
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Intuniv, Tenex
• Haloperidol • Haldol
• Lisdexamfetamine • Vyvanse
• Memantine • Namenda
• Methylphenidate • Methylin, Ritalin
• Modafinil • Provigil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

CASE: Perfect breath

Mr. C, a 20-year-old college student, is diagnosed with obsessive-compulsive disorder (OCD), attention-deficit/hyperactivity disorder (ADHD), and tic disorder (TD). His obsessions consist of a persistent sense that he is not breathing “correctly” or “perfectly.” He compulsively holds his breath to “rush blood to my head” until “the pressure feels just right.” Mr. C says that his OCD has had longstanding, significant negative impact on his academic performance and capacity to engage in other activities. Tics have been present for years and manifest as coughing and throat-clearing. After multiple syncopal epi-sodes from breath-holding with Valsalva maneuver—some of which caused falls and head injury—Mr. C is admitted to a residential psychiatric unit specializing in treating OCD. At the time of his admission, his Yale-Brown Obsessive Compulsive Scale (Y-BOCS) scores^1,2 are 23 total, 12 on the obsessions subscale, and 11 on the compulsions subscale, indicating moderate to severe illness. Cognitive-behavioral therapy (CBT) is offered, along with a combination of escitalopram, 60 mg/d, and quetiapine, 50 mg/d. Quetiapine is over-sedating at subtherapeutic doses and Mr. C’s compulsions worsen. He reports that “[it] took longer and longer to get the ‘just right’ feeling.’” Quetiapine is discontinued and risperidone, 0.5 mg/d, is started, which decreases the frequency of his tics. When he is discharged after a 36-day stay, Mr. C’s Y-BOCS scores are greatly improved at 13 total, 7 on the obsessions subscale, and 3 on the compulsions subscale.

Mr. C’s psychologist refers him to our outpatient clinic for continued psychiatric evaluation and treatment of his OCD, ADHD, and TD. At this time, he is prescribed escitalopram, 60 mg/d, and risperidone, 0.5 mg/d, along with CBT with his psychologist. We do not readminister the Y-BOCS at this time, but Mr. C reports that his OCD is “60% improved.” However, he describes prominent obsessive thoughts regarding his breathing similar to those he experienced before residential treatment. These obsessive thoughts arise in the context of specific environmental “triggers,” such as other people coughing or his own tics. The obsessions lead to compulsive urges to engage in breath-holding rituals. Mr. C experiences the thoughts and compulsions as deeply troubling and they consume 5 to 6 hours each day. Mr. C reports impaired concentration in class and during studying: “I can focus for 5 minutes, then not for 2 minutes, then for 3 minutes… I can never stay focused for more than a couple minutes,” before becoming distracted “by my OCD” or other environmental stimuli. We note on exam prominent breath-holding occurring several times per minute. Mr. C says his OCD has not impaired his ability to socialize.

Mr. C notes that he has been exposed to an array of CBT techniques, but he has difficulty using these techniques because his “mind wanders” or he lacks “motivation.” He admits he occasionally has taken a classmate’s ADHD medication (mixed amphetamine salts [MAS], dose unspecified) and found it improved his ability to focus on his academic work.

The authors’ observations

Researchers have established a relationship among OCD, ADHD, and TD across all combinations of comorbidity (OCD and ADHD,³ ADHD and TD,⁴ OCD and TD,^5,6 and all 3 entities⁷). Data suggests a poorer prognosis for OCD when comorbid with either or both of these conditions.⁸ Researchers have raised concerns that psychostimulants could exacerbate or potentiate tic behaviors in patients with ADHD,^9,10 although safe and effective use of these medications has been documented in controlled trials of patients with comorbid ADHD and tics.^11-13 Furthermore, tic suppression has been reported with psychostimulants,¹⁴ as well as a differential effect of stimulants on motor vs vocal tics.¹⁵ Despite these data (Table 1),^9-15 the FDA regards using psychostimulants in patients with TD as a contraindication,¹⁶ although clinicians often recognize that this practice may be unavoidable in some circumstances because of high comorbidity rates. Psychostimulants could exacerbate obsessions or compulsions in some patients because of their dopaminergic properties or through mitigation of the purported anti-obsessional properties of dopamine antagonists.¹⁷

Although there is evidence that the prevalence of prescribed psychostimulant abuse is low among ADHD patients,¹⁸ diversion of prescribed medication is a risk inherent in the use of these agents, particularly among college-age patients.^19,20

Table 1

Evidence of effect of psychostimulants on tics

TREATMENT: Weighing options

To manage impaired attention and executive function difficulties secondary to ADHD, we offer Mr. C several options, including bupropion, modafinil, and memantine augmentation. Mr. C asks for a psychostimulant because exam week is approaching and he wants a treatment with quick therapeutic effect. We discuss with Mr. C the potential for dopaminergic agents, such as psychostimulants, to exacerbate tics or OCD symptoms. Ultimately, we prescribe immediate-release MAS, 20 mg/d.

Two days later, Mr. C says he has taken 3 MAS doses and describes a marked reduction in obsessions, significant decrease in frequency of “triggers,” and greater capacity to use CBT saying, “when I am [triggered], I am able to move past the urges without doing any compulsions.” Daily time spent “stuck on” obsessions or compulsions decreases from 5 to 6 hours per day to “about 2 and a half minutes.”

Mr. C reports a modest increase in the prevalence of tics, experienced as “little throat clears and quick stuttering of breath.” He notes that, although in the past such tics would be followed by urges for “perfecting the tic and making it feel just right,” he presently “had no desire to do so.”

OUTCOME: Sharper focus

Increasing MAS immediate release from 20 mg/d to 30 mg/d suppresses Mr. C’s obsessions and compulsions for 8 hours. On the 19th day of treatment, MAS immediate release was replaced with an extended release formulation, 30 mg/d, which preserves therapeutic effect and tolerability for 16 weeks. Repeat Y-BOCS yields 9 total, 3 on obsessions subscale, and 6 on compulsions subscale scores.

One month later, Mr. C reports that his symptoms have been “improving ever since” the previous appointment. He continues to be able to access skills for managing his OCD and is doing well in his 2 accelerated summer courses, saying “I focus really well” in 3-hour class sessions. On exam, tic behaviors are nearly absent. Mr. C describes occasional bouts of anxiety associated with urges to engage in tic behaviors, in turn arising from fear of symptomatic recurrence as he worked toward stopping smoking as advised by his primary care physician and psychiatrist.

The authors’ observations

The results of the repeat Y-BOCS are consistent with improvement in obsessions but possible worsening of compulsions since Mr. C was discharged from residential treatment. Alternatively, compulsions may have worsened immediately after discharge and declined again with introduction of MAS.

A substantial body of literature describes the challenges associated with treating ADHD with comorbid tics, including the relative degree of risk of tic exacerbation associated with treating ADHD with psychostimulants. The range of FDA-approved pharmacologic options for treatment of this comorbidity is limited (Table 2),²¹ particularly given the risk for tardive dyskinesia associated with the typical antipsychotics haloperidol and chlorpromazine. Data support using the α-2 agonist clonidine to treat hyperactivity associated with ADHD²² and TD²³ and an extended-release preparation of this medication is FDA-approved for the former but not the latter indication (an α-2A receptor subtype agonist, guanfacine, also is FDA-approved for ADHD in pediatric patients). Mr. C’s experience of robust, sustained reduction in obsessions, if not compulsions, after treatment with MAS is consistent with the few studies of stimulant use in ADHD with comorbid OCD.^24,25

Effective treatment of ADHD may help Mr. C better access CBT strategies and thereby potentiate treatment of comorbid OCD.

Table 2

FDA-approved medications for ADHD, OCD, and TD

Related Resources

• Pliszka SR. Treating ADHD and comorbid disorders: psychosocial and psychopharmacological interventions. New York, NY: The Guilford Press; 2011.
• Pollak Y, Benarroch F, Kanengisser L, et al. Tourette syndrome-associated psychopathology: roles of comorbid attention-deficit hyperactivity disorder and obsessive-compulsive disorder. J Dev Behav Pediatr. 2009;30(5):413-419.

Drug Brand Names

• Atomoxetine • Strattera
• Bupropion • Wellbutrin, Zyban
• Chlorpromazine • Thorazine
• Clomipramine • Anafranil
• Clonidine extended release • Kapvay
• Dexmethylphenidate • Focalin
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Fluvoxamine • Luvox
• Guanfacine • Intuniv, Tenex
• Haloperidol • Haldol
• Lisdexamfetamine • Vyvanse
• Memantine • Namenda
• Methylphenidate • Methylin, Ritalin
• Modafinil • Provigil
• Pimozide • Orap
• Quetiapine • Seroquel
• Risperidone • Risperdal

Disclosure

The authors report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.