Pharmacotherapy of Attention-Deficit/Hyperactivity 49 Disorder Across the Life Span

Pharmacotherapy of Attention-Deficit/Hyperactivity 49 Disorder across the Life Span

Jefferson B. Prince, MD, Timothy E. Wilens, MD, Thomas J. Spencer, MD, and Joseph Biederman, MD

KEY POINTS www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafety InformationforPatientsandProviders/DrugSafetyInformation • Attention-deficit/hyperactivity disorder (ADHD) is a forHeathcareProfessionals/ucm165858.htm for the most common disorder in children, adolescents, and recent recommendations by the Food and Drug Administra- adults. tionA] [FD about monitoring for children and http://www.fda .gov/drugs/drugsafety/ucm279858.htm for the most recent • While the phenotype of ADHD changes across the recommendations about monitoring for adults). Clinicians life span, ADHD persists in many children, and patients/families should select an initial treatment, either adolescents, and adults. a stimulant or a non-stimulant; decide on a target dose (either • Formulations of stimulant and non-stimulant absolute or weight-based) titration schedule; and decide how medications are Food and Drug Administration- to monitor tolerability and response to treatment (using rating approved as pharmacological treatments for ADHD in scales, anchor points, or both). Patients should be educated children, adolescents, and adults. about the importance of adherence, safely maintaining medi- • Co-morbid psychiatric and learning disorders are cations (e.g., as in college students), and additional types of common in patients with ADHD across the life span. treatment (e.g., coaching and organizational help) that may be helpful. • When treating ADHD and co-morbid disorders, clinicians must prioritize and treat the most severe condition first, and regularly re-assess the symptoms STIMULANTS of ADHD and the co-morbid disorder. For over 60 years stimulants have been used safely and effectively in the treatment of ADHD21 and they are among the most well-established treatments in psychiatry.22,23 The stimulants most commonly used include methylphenidate (MPH), a mixture of amphetamine salts (MAS) and dextroampheta- OVERVIEW mine (DEX). The recent development of various novel delivery systems has significantly advanced the pharmacotherapy of Attention-deficit/hyperactivity disorder (ADHD) is a common ADHD (see Table 49-1 for a list of these medications). psychiatric condition shown to occur in 3% to 10% of school- age children worldwide, up to 8% of adolescents and up to 4% of adults.1–5 The classic triad of impaired attention, impul- Pharmacodynamic Properties of Stimulants sivity, and excessive motor activity characterizes ADHD, Stimulants increase intra-synaptic concentrations of dopamine although many patients may manifest only inattentive symp- (DA) and norepinephrine (NE).24–27 MPH primarily binds to toms.6,7 ADHD usually persists, to a significant degree, from theA D transporter protein (DAT), blocking the re-uptake of childhood through adolescence and into adulthood.8,9 Most DA, increasing intra-synaptic DA.25,27 While amphetamines children, adolescents, and adults with ADHD suffer significant diminish pre-synaptic re-uptake of DA by binding to DAT, functional impairment(s) in multiple domains,10 as well as these compounds also travel into the DA neuron, promoting co-morbid psychiatric or learning disorders.5,11–18 release of DA from reserpine-sensitive vesicles in the pre- Studies demonstrate that ADHD is frequently co-morbid synaptic neuron.25,26 In addition, stimulants (amphetamine > with oppositional defiant disorder (ODD), conduct disorder MPH) increase levels of NE and serotonin (5-HT) in the inter- (CD), multiple anxiety disorders (panic disorder, obsessive- neuronal space.24Although group studies comparing MPH and compulsive disorder [OCD], tic disorders), mood disorders amphetamines generally demonstrate similar efficacy,19,20 their (e.g., depression, dysthymia, and bipolar disorder [BPD]), pharmacodynamic differences may explain why a particular learning disorders (e.g., auditory processing problems and patienty ma respond to, or tolerate, one stimulant preferen- dyslexia), and substance use disorders (SUDs) and often com- tially over another. It is necessary to appreciate that while the plicates the development of patients with autism spectrum efficacy of amphetamine and MPH is similar, their potency disorders (ASDs). Co-morbid psychiatric, learning, and devel- differs, such that 5 mg of amphetamine is approximately opmental disorders need to be assessed in all patients with equally potent to 10 mg of MPH. ADHD and the relationship of these symptoms with ADHD 1,19,20 delineated. Methylphenidate Before using medications, clinicians should complete a through clinical evaluation that includes a complete history As originally formulated, MPH was produced as an equal of symptoms, a differential diagnosis, a review of prior mixture of d,l-threo-MPH and d,l-erythro-MPH. The erythro assessments/treatments, a medical history, and a description isomers of MPH appear to produce side effects, and thus MPH of current physical symptoms (including questions about the isw no manufactured as an equal racemic mixture of d,l-threo- physical history, including either a personal or family history MPH.28 Behavioral effects of immediate-release MPH peak 1 of cardiovascular symptoms or problems). Before treatment to 2 hours after administration, and tend to dissipate within with medications, it is usually important to measure baseline 3 to 5 hours. After oral administration immediate-release levels of height, weight, blood pressure, and pulse and to MPH is readily absorbed, reaching peak plasma concentra monitor them over the course of treatment (see http:// tion in 1.5 to 2.5 hours, and has an elimination half-life of 538

TABLE 49-1 Available FDA-approved Treatments for Attention-Deficit/Hyperactivity Disorder 49 Usual Absolute and (Weight- FDA-approved Generic Name Duration of based) Dosing Maximum Dose (Brand Name) Formulation and Mechanism Activity How Supplied Range for ADHD MPH (Ritalin)* Tablet of 50 : 50 racemic mixture 3–4 hours 5, 10, and 20 mg (0.3–2 mg/kg/day) 60 mg/day d,l-threo-MPH tablets Dex-MPH Tablet of d-threo-MPH 3–5 hours 2.5, 5, and 10 mg (0.15–1 mg/kg/day) 20 mg/day (Focalin)* tablets (2.5 mg Focalin equivalent to 5 mg Ritalin) MPH (Methylin)* Tablet of 50 : 50 racemic mixture 3–4 hours 5, 10, and 20 mg (0.3–2 mg/kg/day) 60 mg/day d,l-threo-MPH tablets MPH-SR Wax-based matrix tablet of 50 : 50 3–8 hours 20 mg tablets (0.3–2 mg/kg/day) 60 mg/day (Ritalin-SR)* racemic mixture d,l-threo-MPH Variable (amount absorbed appears to vary) MPH (Metadate Wax-based matrix tablet of 50 : 50 3–8 hours 10 and 20 mg (0.3–2 mg/kg/day) 60 mg/day ER)* racemic mixture d,l-threo-MPH Variable tablets (amount absorbed appears to vary) MPH (Methylin Hydroxypropyl methylcellulose 8 hours 10 and 20 mg (0.3–2 mg/kg/day) 60 mg/day ER)* base tablet of 50 : 50 racemic tablets mixture d,l-threo-MPH; no 2.5, 5, and 10 mg preservatives chewable tablets 5 mg/5 ml and 10 mg/5 ml oral solution MPH (Ritalin LA)* Two types of beads give bimodal 8 hours 20, 30, and 40 mg (0.3–2 mg/kg/day) 60 mg/day delivery (50% immediate-release capsules; can be and 50% delayed-release) of sprinkled 50 : 50 racemic mixture d,l-threo-MPH D-MPH (Focalin Two types of beads give bimodal 12 hours 5, 10, 15, 20, 25, 0.15–1 mg/kg/day 30 mg/day in XR) delivery (50% immediate-release 30, 35, and 40 mg youth; 40 mg/ and 50% delayed-release) of capsules day in adults d-threo-MPH MPH (Metadate Two types of beads give bimodal 8 hours 20 mg capsule; can (0.3–2 mg/kg/day) 60 mg/day CD)* delivery (30% immediate-release be sprinkled and 70% delayed-release) of 50 : 50 racemic mixture d,l-threo-MPH MPH (Daytrana)* MPH transdermal system 12 hours (patch 10, 15, 20, and 0.3–2 mg/kg/day 30 mg/day worn for 9 hours) 30 mg patches MPH (Concerta)* Osmotic pressure system delivers 12 hours 18, 27, 36, and (0.3–2 mg/kg/day) 72 mg/day 50 : 50 racemic mixture 54 mg caplets d,l-threo-MPH MPH (Quillivant Extended-release liquid 12 hours 25 mg/5 ml (0.3–2 mg/kg/day) 60 mg/day XR) AMPH† (Dexedrine d-AMPH tablet 4–5 hours 5 mg tablets (0.15–1 mg/kg/day) 40 mg/day Tablets) AMPH† d-AMPH tablet 4–5 hours 5 and 10 mg tablets (0.15–1 mg/kg/day) 40 mg/day (Dextrostat) AMPH† (Dexedrine Two types of beads in a 50 : 50 8 hours 5, 10, and 15 mg (0.15–1 mg/kg/day) 40 mg/day Spansules) mixture short and delayed- capsules absorption of d-AMPH Mixed salts of Tablet of d,l-AMPH isomers (75% 4–6 hours 5, 7.5, 10, 12.5, 15, (0.15–1 mg/kg/day) 40 mg/day AMPH† d-AMPH and 25% l-AMPH) 20, and 30 mg (Adderall) tablets Mixed salts of Two types of beads give bimodal At least 8 hours 5, 10, 15, 20, 25, (0.15–1 mg/kg/day) 30 mg/day in AMPH*‡ delivery (50% immediate-release (but appears to and 30 mg children (Adderall-XR) and 50% delayed-release) of last much longer capsules; can be Recommended 75 : 25 racemic mixture in certain sprinkled dose is d,l-AMPH patients) 20 mg/day in adults Continued on following page

TABLE 49-1 Available FDA-approved Treatments for Attention-Deficit/Hyperactivity Disorder (Continued) Usual Absolute and (Weight- FDA-approved Generic Name Duration of based) Dosing Maximum Dose (Brand Name) Formulation and Mechanism Activity How Supplied Range for ADHD Lisdexamfetamine Tablets of dextroamphetamine 12 hours 30, 50, and 70 mg 70 mg/day (Vyvanase)* and L-lysine tablets Atomoxetine*‡ Capsule of atomoxetine 5 hour plasma 10, 18, 25, 40, 60, 1.2 mg/kg/day 1.4 mg/kg/day (Strattera) half-life but CNS and 80 mg or 100 mg effects appear to capsules last much longer Guanfacine ER** Extended-release tablet of Labeled for 1,2,3 & 4 mg tablets Up to 4 mg per day Up to 4 mg per (Intuniv) guanfacine once-daily dosing day Clonidine Extended-release tablet of Labeled for 0.1 mg tablet 0.1–0.2 mg twice Up to 0.4 mg ER**(Kapvay) clonidine twice-daily daily daily dosing *Approved to treat ADHD age 6 years and older. †Approved to treat ADHD age 3 years and older. ‡Specifically approved for treatment of ADHD in adults. **Approved to treat ADHD in youth 6–17 years old as monotherapy or as adjunctive treatment with stimulant.

2.5–3.5 hours. After oral administration, but prior to reaching Ritalin-LA (MPH-ERC), another beaded-stimulant prepara- the plasma, the enzyme carboxylesterase (CES-1), which is tion, which may be sprinkled,28 is available in capsules of 10, located in the walls of the stomach and liver, extensively 20, 30, and 40 mg, essentially equivalent to 5, 10, 15 and metabolizes MPH via hydrolysis and de-esterification, with 20 mg of IR-MPH delivered BID. MPH-ERC uses the beaded little oxidation.29,30 Individual differences in CES-1’s hydrolyz- Spheroidal Oral Drug Absorption System (SODAS) technol- ing activity may result in variable metabolism and serum MPH ogy to achieve a bi-modal release profile that delivers 50% of levels.31 While generic MPH has a similar pharmacokinetic its d,l-threo-MPH initially and another bolus approximately 3 profile to Ritalin, it is more rapidly absorbed and peaks to 4 hours later, providing around 8 hours of coverage. The sooner.32 Due to its wax-matrix preparation, the absorption of efficacy of MPH-ERC has been demonstrated in youth with the sustained-release MPH preparation (Ritalin-SR) is varia- ADHD.44 ble,33 with peak MPH plasma levels in 1 to 4 hours, a half-life The primarily active form of MPH appears to be the d-threo of 2 to 6 hours, and behavioral effects that may last up to 8 isomer,45–47 which is available in both immediate-release hours.34 The availability of the various new extended-delivery tablets (Focalin 2.5, 5, and 10 mg) and, employing the SODAS stimulant formulations has greatly curtailed use of MPH-SR. technology, extended-delivery capsules (Focalin XR 5, 10, 15, Concerta (OROS-MPH) uses the Osmotic Releasing Oral and0 2 mg). The efficacy of D-MPH is well established in System (OROS) technology to deliver a 50 : 50 racemic mixture children, adolescents, and adults under open- and double- of d,l-threo-MPH.35 OROS-MPH, indicated for the treatment blind conditions.48–51 D-MPH is approved to treat ADHD in of ADHD in children and adolescents, is available in 18, 27, children, adolescents, and adults in doses of up to 20 mg per 36, and 54 mg doses and is indicated in doses up to 72 mg day and has been labeled to provide a 12-hour duration of daily. The 18 mg caplet of OROS-MPH provides an initial coverage.28 Although not definitive, 10 mg of MPH appears to bolus of 4 mg of MPH, delivering the remaining MPH in an be approximately equivalent to 5 mg of d-MPH, and clinicians ascending pattern, such that peak concentrations are generally can reasonably use this estimate in clinical practice.52 reached around 8 hours after dosing; it is labeled for 12 hours The MPH transdermal system (MTS; Daytrana) delivers of coverage.28,36 A single morning dose of 18, 27, 36, 54,or MPH through the skin via the DOT Matrix transdermal system. 72 mg of OROS-MPH is approximately bioequivalent to 5, The patches are applied once daily and intended to be worn 7.5, 10,15,or 20 mg of immediate-release MPH administered for, 9 hours although in clinical practice they can be worn for three times daily, respectively. The effectiveness and tolerabil- shorter and longer periods of time. The MTS usually takes ity of OROS-MPH have been demonstrated in children,37–39 effect within 2 hours and provides coverage for 3 hours after adolescents,40 and adults41 with ADHD. Data support OROS- removal. MTS is available in 10, 15, 20, and 30 mg patches.53– MPH’s continued efficacy in many of those with ADHD over 55 Since the MPH is absorbed through the skin, it does not the course of 24 months of treatment.42 undergo first-pass metabolism by CES-1 in the liver, resulting Metadate CD (MPH MR), the first available extended- in higher plasma MPH levels.56 ,Therefore patients may require delivery stimulant preparation to employ beaded technology, lower doses with MTS compared to oral preparations (10 mg is available in capsules of 10, 20, 30, 40, 50, and 60 mg, which of MTS = 15 mg of extended-release oral MPH). MTS may be may be sprinkled. Using Eurand’s Diffucaps technology, MPH a particularly useful treatment option for patients who have MR contains two types of coated beads, IR-MPH and extended- difficulty swallowing or tolerating oral stimulant formulations release-MPH (ER-MPH). Metadate delivers 30% of d,l-threo- or for patients who need flexibility in the duration of medica- MPH initially, and 70% of d,l-threo-MPH several hours later. tion effect. MPH MR is designed to simulate twice-daily (BID) dosing of Recently an extended-delivery MPH oral suspension for- IR MPH providing approximately 8 hours of coverage. The mulation became available (MEROS or Quillivant XR efficacy of MPH MR capsules has been demonstrated,43 and it 25 mg/5 ml). Although head-to-head trials haven’t been pub- is approved for treatment in youth with ADHD in doses of up lished and clinical experience to date is limited, this formula- to 60 mg/day.28 An extended-delivery tablet form of Metadate tion appears to provide similar efficacy and duration of effect (Metadate ER) is also available in doses of 10 and 20 mg. as other extended-delivery MPH preparations.57,58 This

Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder across the Life Span 541 preparation may be particularly helpful for youth who prefer difficulty falling asleep, obsessiveness, headaches, dry mouth, a liquid preparation or who experience skin reactions to the rebound phenomena, anxiety, nightmares, dizziness, irritabil- 49 transdermal patch. Prior to dosing, the manufacturer recom- ity, dysphoria, and weight loss).1,20,74–77 Rates and types of mends shaking the contents in the bottle to ensure an even stimulant side effects appear to be similar in ADHD patients, distribution of medication. regardless of age. In patients with a current co-morbid mood/ anxiety disorder, clinicians should consider whether an adverse Amphetamines effect reflects the co-morbid disorder, a side effect of the treatment, or an exacerbation of the co-morbidity. Moreover, while Amphetamine is available in three forms, dextroamphetamine stimulants can cause these side effects, many ADHD patients (DEX; Dexedrine), mixed amphetamine salts (MAS; Adderall), experience these problems before treatment; therefore, it is and lisdexamfetaminedimesylate (LDX, Vyvanase). DEX important for clinicians to document these symptoms at tablets achieve peak plasma levels 2 to 3 hours after oral baseline.76 Recommendations about management of some administration, and have a half-life of 4 to 6 hours. Behavioral common side effects are listed in Table 49-2. effects of DEX tablets peak 1 to 2 hours after administration, and last 4 to 5 hours. For DEX spansules, these values are some- what longer. MAS consist of equal portions of d-amphetamine Growth saccharate, d,l-amphetamine asparate, d-amphetamine sulfate, The impact of stimulant treatment on growth remains a and d,l-amphetamine sulfate, and a single dose results in a concern, and the data are conflicting. For instance, in the MTA 28 ratio of approximately 3 : 1 d- to l-amphetamine. oThe tw study, ADHD youth, treated with a stimulant medication con- isomers have different pharmacodynamic properties, and tinuously over a 24-month period, experienced a deceleration some patients with ADHD preferentially respond to one of about 1 cm per year. Despite this slowing, except for those isomer over another. The efficacy of MAS tablets is well estab- subjects in the lowest percentile for height, these children 59 60 lished in ADHD youth and adults. An extended-delivery remained within the normal curves.78 Recently, Biederman preparation of MAS is available as a capsule containing two and colleagues reported on growth trajectories in two case- types of Micotrol beads (MAS XR; Adderall XR). The beads are control samples of boys and girls with ADHD compared to present in a 50 : 50 ratio, with immediate-release beads controls.79 Over 10–11 years of follow-up these authors found designed to release MAS in a fashion similar to MAS tablets, no significant impact of ADHD or its treatment on growth and delayed-release beads designed to release MAS 4 hours parameters except in subjects with ADHD and depression, after dosing. The efficacy of MAS XR is well established in chil- where girls were larger and boys smaller. Despite reassuring 61,62 63 64,65 dren, adolescents, and adults. Furthermore, open data clinicians, parents and patients healthy physical develop- treatment with MAS XR appears to be effective in the treatment ment and these difficulties do not usually pose significant 66 of many ADHD youths over a 24-month period. clinical problems for most patients. To effectively address LDX is FDA-approved for treatment of ADHD in children, these concerns the AACAP practice parameters for ADHD rec- 28 adolescents, and adults. LDX is an amphetamine pro-drug in ommend routine monitoring of height and weight, including which L-lysine, a naturally occurring amino acid, is covalently serial plotting of growth parameters.1,20 Crossing two percen- linked to d-amphetamine. After oral administration, the pro- tile lines of height and/or weight may indicate a clinically drug is metabolically hydrolyzed in the body to release significant change in growth that should be addressed clini- d-amphetamine. LDX appears to reduce abuse liability (e.g., cally. A variety of options may be considered, including a misuse, abuse, and overdose) as intravenously and intra- medication holiday, dose adjustment, a change in medication, nasally administered LDX results in similar effects as oral and/or consultation. Ultimately impact on growth should be 67,68 administration. It is available in capsules of 20, 30, 40, 50, balanced with the overall benefits of treatment. 60,0 and 7 mg that appear to be comparable to MAS XR doses of 10, 15, 20, 25, 30, and 35 mg, respectively. Sleep Parents often report sleep disturbances in their children with Clinical Use of Stimulants ADHD before80–83 and during treatment.84–87 Various strategies (including improving sleep hygiene, making behavioral modi- Guidelines and recent excellent clinical reviews regarding the fications, adjusting timing or type of stimulant, and switching use of stimulant medications in children, adolescents, and 1,7,19,20,69–72 to an alternative ADHD treatment) have been suggested to adults in clinical practice have been published. Treat- help make it easier for patients with ADHD to fall asleep.88,89 ment with immediate-release preparations generally starts at Complementary pharmacological treatments to consider 5 mg of MPH or amphetamine once daily and is titrated include the following: melatonin (1 to 3 mg), clonidine (0.1 upward every 3 to 5 days until an effect is noted or adverse to 0.3 mg),90 diphenhydramine (25 to 50 mg), trazodone (25 effects emerge. Typically, the half-life of the short-acting stimu- to0 5 mg), and mirtazapine (3.75 to 15 mg). Recently, interest lants necessitates at least twice-daily dosing, with the addition in the use of melatonin, a hormone secreted by the pineal of similar or reduced afternoon doses dependent on break- gland that helps regulate circadian rhythms,91 to address sleep through symptoms. In a typical adult, dosing of immediate- problems in children has been growing.92 Melatonin used release MPH is generally up to 30 mg three to four times daily alone93 and in conjunction with sleep hygiene techniques94 or amphetamine 15 to 20 mg three to four times a day. Cur- appears to improve sleep in youths with ADHD. In these two rently, most adults with ADHD will be treated with a stimulant well-designed but small studies, the most concerning adverse that has an extended delivery. Since there is no way to deter- events included migraine (n = 1), nightmares (n = 1), and mine which stimulant will be best tolerated and most effective, aggression (n = 1). Although not yet studied, another consid- it is wise to consider including trials with extended-delivery eration is ramelteon, a synthetic melatonin receptor agonist.95 preparations of both MPH and amphetamine.73 Appetite Suppression Side Effects of Stimulants Patients treated with stimulants often experience a dose-related Although generally well tolerated, stimulants can cause clini- reduction in appetite, and in some cases weight loss.74 Although cally significant side effects (including anorexia, nausea, appetite suppression often decreases over time,42 clinicians

TABLE 49-2 Pharmacological Strategies in Challenging Cases of Attention-Deficit/Hyperactivity Disorder Symptoms Interventions Worsening or unchanged ADHD Change medication dose (increase or decrease) symptoms (inattention, Change timing of dose impulsivity, hyperactivity) Change preparation, substitute stimulant Evaluate for possible tolerance Consider adjunctive treatment (antidepressant, alpha-adrenergic agent, cognitive enhancer) Consider adjusting non-pharmacological treatment (cognitive-behavioral therapies or coaching or re-evaluating neuropsychological profile for executive function capacities) Intolerable side effects Evaluate if side effect is drug-induced Assess medication response versus tolerability of side effect Aggressive management of side effect (change timing of dose; change preparation of stimulant; adjunctive or alternative treatment) Symptoms of rebound Change timing of dose Supplement with small dose of short-acting stimulant or alpha-adrenergic agent 1 hour before symptom onset Change preparation Increase frequency of dosage Development of tics or Tourette’s Assess persistence of tics or TS syndrome (TS) or use with If tics abate, re-challenge co-morbid tics or TS If tics are clearly worsened with stimulant treatment, discontinue Consider stimulant use with adjunctive anti-tic treatment (haloperidol, pimozide) or use of alternative treatment (antidepressants, alpha-adrenergic agents) Emergence of dysphoria, Assess for toxicity or rebound irritability, acceleration, agitation Evaluate development or exacerbation of co-morbidity (mood, anxiety, and substance use [including nicotine and caffeine]) Reduce dose Change stimulant preparation Assess sleep and mood Consider alternative treatment Emergence of major depression, Assess for toxicity or rebound mood lability, or marked anxiety Evaluate development or exacerbation of co-morbidity symptoms Reduce or discontinue stimulant Consider use of antidepressant or anti-manic agent Assess substance use Consider non-pharmacological interventions Emergence of psychosis or mania Discontinue stimulant Assess co-morbidity Assess substance use Treat psychosis or mania

shoulde giv guidance on improving the patient’s nutritional should be monitored closely.100 In fact, co-administration of options with higher caloric intake to balance the consequences stimulants with MAOIs is the only true contraindication. of decreased food intake.19 While appetite suppression is a Despite the increasing use of stimulants for patients with common side effect of stimulants, little research has been done ADHD, many of them may not respond, experience untoward studying remedies. Cyproheptadine, in doses of 4 to 8 mg, has side, effects or manifest co-morbidity, which stimulants may recently been reported to improve appetite in ADHD patients exacerbate or be ineffective in treating.17,101 Over the last 10 with stimulant-associated appetite suppression.96 years ATMX has been systematically evaluated and is FDA- approved for the treatment of ADHD in children, adolescents, 28 Medication Interactions with Stimulants and. adults The interactions of stimulants with other prescription and ATOMOXETINE non-prescription medications are generally mild and not a major source of concern.97,98 Concomitant use of sympatho- Unlike the stimulants, atomoxetine (ATMX; Strattera) is mimetic agents (e.g., pseudoephedrine) may potentiate the unscheduled; therefore, clinicians can prescribe refills. ATMX effects of both medications. Likewise, excessive intake of caf- actsy b blocking the NE re-uptake pump on the pre-synaptic feiney ma potentially compromise the effectiveness of the membrane, thus increasing the availability of intra-synaptic stimulants and exacerbate sleep difficulties. Although data on NE, with little affinity for other monoamine transporters or the co-administration of stimulants with tricyclic antidepres- neurotransmitter receptors.102 In addition to prominent effects sants (TCAs) suggest little interaction between these com- of ATMX on NE re-uptake inhibition, pre-clinical data also pounds,99 careful monitoring is warranted when prescribing show that the noradrenergic pre-synaptic re-uptake protein stimulants with either TCAs or anticonvulsants. Although regulatesA D in the frontal lobes and that by blocking this administering stimulants with ATMX is common in clinical protein ATMX increases DA in the frontal lobes.103 ATMX is practice, and appears to be safe, well tolerated, and effective rapidly absorbed following oral administration; food does not based on clinical experience, to date only small samples have appear to affect absorption, and Cmax occurs 1 to 2 hours after been studied; therefore, patients taking this combination dosing.104 While the plasma half-life appears to be around 5

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Pharmacotherapy of Attention-Deficit/Hyperactivity Disorder across the Life Span 543 hours, the central nervous system (CNS) effects appear to last Although ATMX treatment is associated with mean increases over 24 hours.105 ATMX is metabolized primarily in the in heart rate of 6 beats per minute, and increases in systolic and 49 liver to 4-hydroxyatomoxetine by the cytochrome (CYP) diastolic blood pressure of 1.5 mm Hg, the impact of ATMX on P450 2D6 enzyme.106,107 Although patients identified as “poor the cardiovascular system appears to be minimal.124–126 Exten- metabolizers” (i.e., with low 2D6 activity) appear to generally sive electrocardiogram (ECG) monitoring indicates that ATMX tolerate ATMX, these patients seem to have more side effects, has no apparent effect on QTc intervals, and ECG monitoring and a reduction in dose may be necessary.108,109 ,Therefore in outside of routine medical care does not appear to be neces- patients who are taking medications that are strong 2D6 inhibi- sary. Adults should have their vital signs checked prior to initi- tors (e.g., fluoxetine, paroxetine, quinidine), it may be neces- ating treatment with ATMX and periodically thereafter. sary to reduce the dose of ATMX. Clinically, ATMX is often Concerns have been raised that treatment with ATMX may prescribed in conjunction with stimulants. Although the safety, increase the risk of hepatitis. During post-marketing surveil- tolerability, and efficacy of this combination have not been lance,o tw patients (out of 3 million exposures) developed fully studied, reports suggest that this combination is well toler- hepatitis during treatment with ATMX.127 Patients and families ated and effective.100,110,111 ,Therefore although the full safety of should contact their doctors if they develop pruritus, jaundice, administering stimulants and ATMX together has not been fully dark, urine right upper quadrant tenderness, or unexplained established, there are good data from which to extrapolate, and “flu-like” symptoms.28 clinicians must balance the risks and benefits in each patient. TheA FD issued a public health advisory, and the manufacturer later added a black box warning regarding the develop- 28 Clinical Use of Atomoxetine ment of suicidal ideation in patients treated with ATMX. Similar to the selective serotonin re-uptake inhibitors (SSRIs), ATMX should be initiated at 0.5 mg/kg/day and after a few there was a slight increase in suicidal thinking in controlled days increased to a target dose of 1.2 mg/kg/day. Although trials. Parents and caregivers should be made aware of any ATMX has been studied in doses of up to 2 mg/kg/day, current such occurrences and should monitor unexpected changes in dosing guidelines recommend a maximum dosage of 1.4 mg/ mood or behavior. kg/day. Although some patients have an early response, it may take up to 10 weeks to see the full benefits of ATMX Alpha-adrenergic Agonists treatment.112–114 In the initial trials, ATMX was dosed BID (typically after breakfast and after dinner); however, recent studies Clonidine, an imidazoline derivative with alpha-adrenergic have demonstrated its efficacy and tolerability in many patients agonist properties, has been primarily used in the treatment dosed once a day.115–117 Although the effects of ATMX dosed of hypertension.128 twA lo doses, it appears to stimulate inhibi- once daily in the morning or at bedtime appear to be similar tory, pre-synaptic autoreceptors in the CNS.129 In 2010 the FDA (with a mean dose of 1.25 mg/kg/morning or 1.26 mg/kg/ approved an extended delivery oral formulation of clonidine, night), once-daily ATMX appears to be best tolerated when clonidine ER (Kapvay) as a treatment for ADHD in youth aged dosed in the evening. To date, plasma levels of ATMX have not 6–17 years.28 This formulation is approved both as mono- been used to guide dosing. However, Dunn and colleagues118 therapy and as adjunctive treatment with stimulants. Although found that patients with a plasma level of ATMX greater than clonidine reduces symptoms of ADHD,130 its overall effect is 800 ng/ml had more robust responses, although patients less than the stimulants,131 and likely smaller than ATMX, treated with higher doses also experienced more side effects. TCAs, and bupropion. Clonidine appears to be particularly ATMXy ma be particularly useful when anxiety, mood helpful in patients with ADHD and co-morbid CD or ODD,132– symptoms, or tics co-occur with ADHD. For example, a large, 134 tic disorders,135,136 ADHD-associated sleep disturbances,90,137 14-week multi-site study of ATMX in adults with ADHD and andy ma reduce anxiety and hypervigilance in traumatized social anxiety disorder reported clinically significant effects on children.138 both ADHD and on anxiety.119 Although untested, because of Clonidine is a relatively short-acting compound with a its lack of abuse liability,120 yATMX ma be particularly of use plasma half-life ranging from approximately 5.5 hours (in in adults with current substance use issues. For instance, children) to 8.5 hours (in adults). Clonidine ER is usually Wilens and associates121 demonstrated in a 12-week controlled initiated a dose of 0.1 mg HS for several days and titrated up trial that treatment with ATMX in recently abstinent alcoholics to a maximum recommended dose of 0.2 mg BID. Immediate was associated with improved ADHD and reduced drinking, release clonidine usually initiated at the lowest manufactured although absolute abstinent rates were unaffected. Moreover, dose of a half or quarter tablet of 0.1 mg. Usual daily doses ATMX has not been reported to have significant or serious drug ranges from 3 to 10 μg/kg given generally in divided doses, interactions with alcohol or marijuana.122 BID, three times daily (TID), or four times daily (QID), and there is a transdermal preparation. The most common short- Side Effects of Atomoxetine term adverse effect of clonidine is sedation, which tends to subside with continued treatment. It can also produce, in Although generally well tolerated, the most common side some, cases hypotension, dry mouth, vivid dreams, depres- effects in children and adolescents taking ATMX include sion, and confusion. A recent summary of the safety of reduced appetite, dyspepsia, and dizziness,28 although height Kapvay is available at http://www.fda.gov/downloads/Advisory and weight in long-term use appear to be on target.113 ,In adults Committees/CommitteesMeetingMaterials/PediatricAdvisory ATMX treatment may be associated with dry mouth, insomnia, Committee/UCM319363.pdf. Overdoses of clonidine in chil- nausea, decreased appetite, constipation, decreased libido, diz- dren under 5 years of age may have life-threatening conse- ziness, and sweating.123 Furthermore, some men taking ATMX quences.139 Since abrupt withdrawal of clonidine has been may have difficulty attaining or maintaining erections. Several associated with rebound hypertension, slow tapering is easy strategies can be used to manage ATMX’s side effects. advised.140,141 In addition, extreme caution should be exercised When patients experience nausea, the dose of ATMX should with the co-administration of clonidine with beta-blockers or be divided and administered with food. Sedation is often calcium channel blockers.142 Although concerns about the transient, but may be helped by either administering the dose safety of co-administration of clonidine with stimulants have at night or by dividing the dose. If mood swings occur, patients been debated,143 recent data supports the tolerability, safety, should be evaluated and their diagnosis reassessed. and efficacy of this combination.144 Current guidelines are to

Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 544 PART X Treatment Approaches monitor blood pressure when initiating and tapering cloni- the severity of ADHD and co-morbid disorders should be the dine, but ECG monitoring is not usually necessary.145 first guide to select treatments, with stimulants being the Guanfacine, the most selective alpha2A-adrenergic agonist medication of choice. Long-lasting, extended-release formula- currently available, appears to act by mimicking NE binding tions are preferred for reasons of adherence to treatment, for in the pre-frontal cortex.146 In 2009, an extended delivery for- protection against abuse, to avoid rebound symptoms, and to mulation guanfacine ER (Intuniv) was FDA-approved for the provide symptomatic relief throughout the day without the treatment of ADHD as monotherapy or as adjunctive treat- need for multiple doses. Every few days the dose may be ment with stimulants.28 Guanfacine ER is usually started at increased to optimize response. Frequently, patients benefit 1 mg daily at bedtime and titrated to a maximum dose of from adding immediate-release amphetamine or MPH in 4 mg. Possible advantages of guanfacine over clonidine combination with longer-acting preparations in order to include less sedation, a longer duration of action, and since it sculpt the dose to the patient’s individual needs,152 although has little affinity for the brainstem imidazoline I1 receptors, the efficacy of this practice is not well studied. Additionally, may have a milder cardiovascular profile.146 Recent informa- psychotherapy is recommended in combination with stimu- tion from the FDA about post-marketing experience with lant treatment in order to relieve additional impairments.70 Intuniv is available at http://www.fda.gov/downloads/ Consideration of another stimulant or ATMX is recom- AdvisoryCommittees/CommitteesMeetingMaterials/ mended when symptoms aren’t unresponsive or the patient PediatricAdvisoryCommittee/UCM255105.pdf. Anecdotal experiences clinically significant side effects to the initial med- information suggests that guanfacine may be more useful in ication. Given their pharmacodynamic differences,26 if a MPH improving the cognitive deficits of ADHD. School-aged chil- product was initially selected, then moving to an amphetamine- dren with ADHD and co-morbid tic disorder, treated with based medication is appropriate. Although some patients are immediate release guanfacine in doses ranging from 0.5 mg able to take ATMX once daily, many benefit from BID dosing.123 BID to 1 mg TID, showed reduction in both tics and Patients must also be made aware that the full benefits of ADHD.147,148 Guanfacine treatment is associated with minor, ATMXy ma not occur for several weeks and they may not “feel” clinically insignificant decreases in blood pressure and pulse anything like they may have with the stimulants. Monitoring rate. The adverse effects of guanfacine include sedation, irrita- routine side effects, vital signs, and the misuse of the medica- bility, and depression. Several cases of apparent guanfacine- tion is warranted. induced mania have been described, but the impact of guanfacine on mood disorders remains unclear.149 Alpha- adrenergic medications may be particularly useful in youth SAFETY OF MEDICATIONS USED TO TREAT with primarily a hyperactive/impulsive and/or aggressive com- ATTENTION-DEFICIT/HYPERACTIVITY DISORDER ponent.150 However, there is a dearth of data on using the alpha agonists in adults with ADHD. The FDA’s Pediatric Drugs Advisory Committee (PDAC) reviewed data concerning the cardiovascular (CV) effects of SUGGESTED MANAGEMENT STRATEGIES medications used to treat ADHD, as well as concerns regarding psychosis, mania, and suicidal thinking. ACROSS THE LIFE SPAN Having made the diagnosis of ADHD, the adult needs to be Cardiovascular Safety of Attention-Deficit/ familiarized with the risks and benefits of pharmacotherapy, Hyperactivity Disorder Treatments the availability of alternative treatments, and the likely adverse effects. Patient expectations need to be explored and realistic Treatment with stimulants is associated with small increases goals of treatment need to be clearly delineated.151 ,Likewise in heart rate and blood pressure that are weakly correlated the clinician should review with the patient the various phar- with. dose There has been concern about CV safety/risk in macological options available and that each will require sys- patients receiving stimulants.153 However, recent work has tematic trials of the anti-ADHD medications for reasonable shed light on the CV risk of stimulants in adults. Habel and durations of time and at clinically meaningful doses. Patients colleagues retrospectively investigated serious CV events in a with ADHD who have psychiatric co-morbidity, residual large group of medication users and non-users (n = 443,198 symptomatology despite treatment, or report psychological adults aged 25–64). The authors reported on 806,182 person- distress related to their ADHD (e.g., self-esteem issues, self- years of follow-up (median, 1.3 years per person), and found sabotaging patterns, interpersonal disturbances) should be no relationship between past or current ADHD medication directed to appropriate psychotherapeutic intervention with use and serious CV or stroke outcomes. As highlighted by clinicians knowledgeable in ADHD treatment. these authors125 among young and middle-aged adults, current Recognizing the morbidity associated with ADHD, its effect or new use of ADHD medications, compared with non-use or on psychological, social, and emotional development, as well remote use, was not associated with an increased risk of as co-morbid/residual psychiatric and ADHD symptoms, it is serious cardiovascular events. These results mirror the findings necessary to tailor a comprehensive treatment plan. The foun- of a similarly-designed study in youth with ADHD126 and a dations of such planning involve education, pharmacother- recent review of the cardiovascular literature related to stimu- apy, and psychosocial treatments. Support with educational lant exposure in ADHD154 and seems to suggest that the vital planning, social interactions, and the work environment is sign changes seen acutely and chronically are usually not clini- often helpful and complimentary to pharmacotherapy. cally significant. Please see Table 49-3 for one way to screen The stimulant medications, ATMX, guanfacine ER, and clo- forV C symptoms prior to the initiation of pharmacotherapy nidine ER are FDA-approved and are considered the first-line and while monitoring treatment. therapy for ADHD across the life span. Although there are no The PDAC cited the baseline rate of sudden unexplained evidence-based guidelines in selecting a first choice of medica- death in the pediatric population to range from 0.6 to 6 occur- tion for patients with ADHD, it is important to consider issues rences per 100,000 patient-years.155 From the FDA’s research, of co-morbidity, tolerability, efficacy, and duration of the PDAC presented data indicating that the rates of sudden action.1,19,20,70,72 The European Network Adult ADHD pub- unexplained death in the pediatric population between 1992 lished a consensus outlining guidelines regarding ADHD and February 2005, treated with MPH, amphetamine, or treatment with stimulants. The guidelines recommended that ATMX, were 0.2, 0.3, and 0.5 cases per 100,000 patient-years,

TABLE 49-3 A Strategy to Screen for Cardiovascular Symptoms 49 Cardiovascular History Yes No Comment

PERSONAL HISTORY Congenital or acquired cardiac disease? Coronary artery disease? Chest pain? Palpitations? Shortness of breath? Dizziness? Syncope? Change in exercise tolerance or tolerance to usual physical activities? FAMILY HISTORY (<30 YEARS OF AGE) Early myocardial infarction? Cardiac death? Significant arrhythmia(s)? Long QT syndrome? OBJECTIVE Baseline (off medication) blood pressure and heart rate within normal limits This tool may be useful for screening at initial assessment and prior to initiation of medication(s) used to treat ADHD. As a part of follow-up visits this tool may be used as one way to monitor ongoing treatment as well as prior to changing medication dose(s). During ongoing treatment we encourage clinicians to inquire about current cardiovascular symptoms, measure pulse and blood pressure as well as changes to family history aCopyright Timothy E. Wilens, MD Published with permission. bIf positive on an item, recommend referral to primary care physician or cardiology for further assessment prior to initiating medications (Adapted from Massachusetts General Hospital Cardiovascular Screena,b)

respectively. Based on these data, the PDAC rejected adding risks outweigh the benefits that the child obtains from the a black box warning, but recommended that current labeling treatment. language for amphetamine drugs on CV risks in patients with structural cardiac abnormalities should be extended Psychotic or Manic Symptoms during to all medications approved for the treatment of ADHD. Treatment with Attention-Deficit/Hyperactivity Details regarding these issues are provided in two recent reviews.156,157 Disorder Medications The American Heart Association has previously com- TheA FD has received hundreds of reports of psychotic or mented on CV monitoring of youths taking psychotropic manic symptoms, particularly hallucinations, associated with 145 medications. Despite the generally benign CV effects of ADHD medication use in children and adolescents. FDA drug- these medications, caution is warranted in the presence of a safety analysts recommended adding warnings to ADHD compromised CV system (e.g., untreated hypertension, medication-labeling advising that ADHD medications should arrhythmias, and known structural heart defects). It remains be stopped if a patient experiences signs and symptoms of prudent to monitor symptoms referable to the CV system (e.g., psychosis or mania. A recent review of stimulant trials revealed syncope, palpitations, and chest pain) and vital signs at base- that psychotic-like or manic-like symptoms might occur in line and with treatment in all patients with ADHD. For most approximately 0.25% of children (or 1 in 400) treated with pediatric patients it is not necessary to check an ECG at base- stimulant medications.160 line or with treatment. In patients at risk for CV symptoms, it In conclusion, the PDAC recommended that a medication is important to collaborate with the patient’s primary care guide be issued for all ADHD medications describing the physician and to ensure that hypertension is not an issue. potential psychiatric, aggression, and CV risks and that these Recent data from an open-label study of ADHD treatment in risks be clearly elucidated in the product labeling of all ADHD adults suggest that if hypertension is well controlled, stimu- medications. However, the PDAC concluded that potential 158 lantsy ma be safely used in the short term. Safety remains episodes of psychosis, aggression, suicidality, and cardiac the paramount concern; thus, in each case the physician and events during treatment with ADHD medications in children patient must weigh the risks and benefits of treatment. do not warrant a black box warning. Currently the only black box warning for stimulants warns Aggression during Treatment with about the potential for substance abuse. Attention-Deficit/Hyperactivity Disorder Medications ALTERNATIVE (NOT FDA-APPROVED) From the FDA’s research, the PDAC presented data reporting TREATMENTS FOR ATTENTION-DEFICIT/ episodes of aggression with all ADHD medications during HYPERACTIVITY DISORDER clinical trials and in post-marketing surveillance. However, Bupropion aggression in patients with ADHD usually responds to stimulant treatment.159 During clinical trials, rates of aggression Bupropion hydrochloride (Wellbutrin), a unicyclic aminoke- were observed to be similar with active and placebo treatment. tone, approved for treatment of depression and as an aid for The PDAC recommended that the decision about whether to smoking cessation in adults,28 has been reported to be moder- continue therapy following an aggression event is complex ately helpful in reducing ADHD symptoms in children, adoles- and that the physician and parent should evaluate whether the cents,161–163 .and adults 164–167 Although helpful, the magnitude

Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 546 PART X Treatment Approaches of effect of bupropion is less than that seen with either stimu- of treatment with a TCA to help determine the risk–benefit lants or ATMX. Bupropion is often used in patients with ADHD ratio of such an intervention. A serious adverse event associ- and co-morbidities and has been studied in small groups of ated with use of TCAs is overdose. Hence, close supervision of adolescents with ADHD and nicotine dependence,168 sub- the administration and storage of TCAs is necessary. stance use and mood disorders,169 substance abuse and conduct disorder,170 and depression.171 In light of the high rates of marijuana use in patients with ADHD,172 it is important for Modafinil clinicians to note that adolescents treated with bupropion Modafinil, a novel stimulant that is distinct from ampheta- may experience increased irritability during marijuana with- mine, is approved for the treatment of narcolepsy.28 Unlike the drawal.173 In addition, bupropion has been helpful in ADHD 174 175,176 broad activation observed with amphetamine, modafinil adults with BPD, substance use or with co-existing 187,188 177 appears to activate specific hypothalamic regions. cardiac abnormalities. Although one controlled trial in ADHD adults was positive,189 Bupropion modulates both NE and DA. It appears to be a recent large (n = 330) multi-center (18 locations) ran more stimulating than other antidepressants, may cause irri- 178 domized, double-blind treatment study in adults with ADHD tability, has been reported to exacerbate tics, and is associ- did not find significant reductions in subjects treated with ated with higher rates of drug-induced seizures than other 190 28 modafinil compared to those treated with placebo. However, antidepressants. These seizures appear to be dose-related these investigators noted that certain subjects experienced sig- (>450 mg/day) and more likely to occur in patients with nificant benefit and suggest that this agent may warrant further bulimia or a seizure disorder, and thus should be avoided in investigation. Although controlled trials of modafinil in chil- patients with these problems. In ADHD adults, bupropion IR dren with ADHD demonstrated efficacy, 191–193 Athe FD PDAC and SR should be given in divided doses, with no single dose voted that modafinil is “not approvable” for pediatric ADHD of the IR exceeding 150 mg, or SR 200 mg. Dosing for ADHD due to possible Stevens-Johnson syndrome (SJS) and toxic appears to be similar to that for depression. The once-daily epidermal necrolysis (TEN). Clinically, it may be reasonable preparation of bupropion is usually initiated at 150 mg XL to consider combining modafinil with stimulants,194,195 and once in AM and titrated every 7–14 days to maximum dose of clinicians should be aware of the potential to exacerbate 450 mg XL daily. Common side effects include insomnia, mania.196 edginess, tremor, and a risk for seizures, primarily with immediate-release preparations. NOVEL TREATMENTS FOR ATTENTION-DEFICIT/ Tricyclic Antidepressants HYPERACTIVITY DISORDER Although controlled trials in ADHD youths179 and adults180 Nicotinic Agents demonstrate TCAs’ efficacy, the effects are less robust than with Given the cognitive enhancing properties of nicotine,197 nico- stimulants. Compared to the stimulants, TCAs have negligible tinic agents have been studied in the treatment of ADHD. abuse liability, have once-daily dosing, and may be useful in 181 182 Whereas smaller cross-over studies of nicotinic analogs with patients with co-morbid anxiety, ODD, ,tics and, theoreti- either full or partial agonistic properties demonstrated efficacy cally, depression (adults). However, given concerns about in adults with ADHD,198–200 follow-up larger multi-site parallel potential cardiotoxicity and the available of ATMX, guanfacine design studies failed to show a significant effect of this com- ER and clonidine ER, use of the TCAs has been significantly pound on reducing ADHD symptomatology201 and the role of curtailed. nicotinic agents remains investigational. Before treatment with a TCA, a baseline ECG should be obtained (as well as inquiry into any family history of early- onset or sudden cardiac arrhythmias).183 Dosing for ADHD Medications Used in the Treatment of appears to be similar to that for depression. ECGs should be Alzheimer’s Disease obtained as the dose is increased. Monitoring serum levels of TCAs is more helpful in avoiding toxicity than it is in deter- Although compelling based on efficacy in Alzheimer’s disease mining optimal levels for response. and some positive initial experience in ADHD patients202 trials Common short-term adverse consequences of the TCAs in ADHD adults with donepezil203 and galantamine204 were include dry mouth, blurred vision, orthostasis, and constipa- negative.t A this time there are no data to support the use of tion. Since the anticholinergic effects of TCAs limit salivary these cholinergic agents in the treatment of ADHD. Recently, flow, they may cause dental problems. Following the sudden Surman and colleagues205 openly treated 34 ADHD adults death of a number of children receiving desipramine (DMI), with the N-methyl-D-aspartate (NMDA) receptor antagonist concerns were raised regarding the possible cardiac toxicity of memantine. In this pilot study, memantine, titrated to a TCAs in children.184 However, epidemiological evaluation of maximum dose of 10 mg BID, was generally well tolerated and the association between DMI and sudden death in children resulted in improvements in measures of ADHD symptoms has not supported a causal relationship.185 TCAs predictably and neuropsychological measures. These encouraging but pre- increase heart rate and are associated with conduction delays, liminary results warrant controlled study. usually affecting the right bundle, thus requiring ECG moni- 186 toring. However, these effects, when small, rarely seem to Metadoxine be pathophysiologically significant in non-cardiac patients with normal baseline ECGs. In patients with documented con- Recently, MG01CI, an extended-release formulation of meta- genital or acquired cardiac disease, pathological rhythm doxine has been studied in adults with ADHD. Metadoxine is disturbances (e.g., atrioventricular block, supraventricular an ion-pair salt of pyridoxine (vitamin B6) and 2-pyrrolidone- tachycardia, ventricular tachycardia, and Wolff-Parkinson- 5-carboxylate used in Europe for over 30 years in the treatment White syndrome), family history of sudden cardiac death or of acute alcohol intoxication and withdrawal. In a short-term cardiomyopathy, diastolic hypertension (>90 mm Hg), or controlled trial with MG01CI, subjects experienced improve- when in doubt about the CV state of the patient, a complete ments in ADHD symptoms as well as neuropsychological (non-invasive) cardiac evaluation is indicated before initiation measures and overall functioning.206

Selegiline monitoring as various side effects may be anticipated. These include sedation or extrapyramidal symptoms (EPS), which 49 Selegiline (l-deprenyl), an irreversible type B monoamine usually occur during initiation of therapy, while others, such oxidase inhibitor (MAOI) that is metabolized into ampheta- as akathisia or dyskinesia/dystonias, may develop after several mine and methamphetamine, has been compared to MPH in months of therapy. Clinicians are encouraged to monitor these 207,208 209 two trials of ADHD youths and alone in adults. Previ- side effects and to document abnormal movements using the ous work with selegiline in children with ADHD and Tourette’s Abnormal Involuntary Movement Scale (AIMS) on a periodic 210,211 syndrome suggests that it may reduce symptoms of ADHD. basis. Patients treated with atypical antipsychotics should also Although to date its role in the treatment of ADHD has been be monitored for sedation, hyperprolactinemia, CV symp- limitedy b both the availability of alternative treatments and toms, weight gain, and development of a metabolic syndrome. potential for the “cheese reaction,” its formulation as a Although not specifically written for children, the American 212 patch, ywhich ma diminish this reaction, may increase inter- Diabetes Association recommends that while treating patients est in its use. with atypical antipsychotics clinicians should inquire about a family history of diabetes, as well as regularly monitor patients’ body mass index, waist circumference, blood pressure, fasting PHARMACOTHERAPY OF ATTENTION-DEFICIT/ blood glucose, and fasting lipid profile.227,228 Safety remains HYPERACTIVITY DISORDER AND COMMON the paramount consideration, and after a period of remission of the aggressive symptoms, consideration should be given CO-MORBID PSYCHIATRIC DISORDERS to tapering off of the atypical antipsychotic. Tapering atypical Attention-Deficit/Hyperactivity antipsychotics should proceed slowly in order to prevent Disorder and Aggression withdrawal dyskinesias and to allow adequate time to adjust to the reduced dose. If there is evidence of severe mood The importance of aggression should not be underestimated, instability, other mood stabilizers should be considered (see as these patients often suffer severe psychopathology, adversely below). affect their families/communities, and have high rates of service utilization.213 Although medications are usually effective in reducing symptoms of ADHD and impulsive aggres- Attention-Deficit/Hyperactivity Disorder Plus sion,22,23 these patients usually benefit from multi-modal treatment.214–216 Medications should initially treat the most Anxiety Disorders severe underlying disorder, after which targeting specific symp- Anxiety disorders, including agoraphobia, panic, over-anxious toms (e.g., irritability, hostility, hypervigilance, impulsivity, disorder, simple phobia, separation anxiety disorder, and fear, or emotional dysregulation) is appropriate.217,218 These OCD, frequently occur in children, adolescents, and adults patients often display aggression before, and during, the with ADHD.5,11,23,229 The effect of stimulant treatment in course of treatment, making it imperative to document their youths with ADHD and anxiety has been variable. Earlier aggressive behaviors before the introduction of medications studies found increased placebo response, increased side and to make these behaviors an explicit target of treatment. effects, and a reduced response to stimulants in patients with The PDAC of the FDA suggests that if and when a patient both conditions,230–232 whereas others observed stimulant displays worsening of aggressive behaviors during medication treatment to be well tolerated and effective.23,220,233 yMan treatment for ADHD, the clinician should make a judgment youths with ADHD and anxiety experience robust improve- regarding the tolerability and efficacy of the treatment (see ments with stimulant treatment and may not experience exac- www.fda.gov for the most recent recommendations). erbations of anxiety.234,235 Of interest, ATMX is reported to In patients with co-morbid ADHD and ODD/CD, the clini- reduce anxiety in ADHD youths236 and adults.119 The Texas cian should first attempt to optimize the pharmacotherapy of Medication Algorithm Project (TMAP) Consensus Panel rec- ADHD219 followed by augmentation with behavioral treat- ommends beginning pharmacotherapy for patients with ments. Supporting this strategy, a meta-analysis of studies ADHD and a co-morbid anxiety disorder with either ATMX from 1975 to 2001 found that stimulants significantly reduced aimed at both the ADHD and anxiety or prescribing a stimu- both overt and covert aggression as rated by parents, teachers, lant first to address the ADHD, then adding an SSRI to address and clinicians.159 During the MTA trial, ADHD youths with the anxiety if necessary.219 and without ODD or CD responded robustly and equally well to stimulant medication.220 Furthermore, in the MTA study, behavioral therapy without concomitant medication was less Attention-Deficit/Hyperactivity Disorder Plus effective in subjects with ADHD and ODD/CD. Similarly, in ADHD youth treatment with ATMX, MAS XR, and OROS-MPH Obsessive-compulsive Disorder reduced ODD symptoms.42,221–223 While these interventions are Considerable overlap exists between pediatric ADHD and often sufficient, a significant number of these patients have OCD,237 including rates of ADHD in up to 51% of children severe symptoms that necessitate treatment with additional or and 36% of adolescents with OCD.238,239 In general, patients alternative medications. Neuroleptic use should be limited to with OCD and ADHD require treatment for both conditions. those ADHD patients with severe aggression or disruptive or The, SSRIs especially in combination with cognitive-behavioral mood disorders.224,225 therapy (CBT), are well-established treatments for pediatric In recent years the use of atypical antipsychotics in pediat- and adult OCD.240 Although stimulants may exacerbate tics, ric populations has increased considerably.226 The American obsessions, or compulsions, they are frequently used in Academy of Child and Adolescent Psychiatry has published patients with these conditions, often in combination with treatment recommendations for the use of antipsychotic med- SSRIs.19,241,242 ,Therefore clinicians should identify and priori- ications in aggressive youth.215,216 Clinicians are encouraged to tize treatment of the most severe condition first, then address optimize psychosocial/educational interventions, followed by secondary concerns, while monitoring for signs of worsening appropriate pharmacotherapy of the primary psychiatric dis- symptoms while recognizing that patients successfully treated order, followed by use of an atypical antipsychotic medication. have much residual morbidity and that CBT is an essential Treatment with atypical antipsychotics warrants careful component of long-term management.

Attention-Deficit/Hyperactivity Disorder Plus with ADHD and depression, TCAs remain a reasonable choice andy ma be helpful for both conditions. As discussed previ- Tic Disorders ously, the use of TCAs requires close monitoring. Tics and tic disorders commonly occur in patients with ADHD,241 as well as in students receiving special education Attention-Deficit/Hyperactivity Disorder Plus services.243 A community-based study of 3,006 children (6 to 12 years of age) found that 27% with ADHD also had tics, Bipolar Disorder and 56% with tics had ADHD.244 Tics occurred more com- Although BPD is recognized in ADHD patients, ADHD may monly in males (2 : 1 to 6 : 1) and in youths with combined- complicate the presentation, diagnosis, and treatment of type ADHD. Children, adolescents, and adults may suffer the BPD.255–257 Differentiating BPD from ADHD can be challeng- triad, of tics ADHD, and OCD.245 Pharmacotherapy of youths ing as these disorders share many features (including symp- with ADHD and tic disorders is challenging. First-line treat- toms of distractibility, hyperactivity, impulsivity, talkativeness, ment about tics is education. In most patients, tics are mild and sleep disturbance).258–263 Clinicians are faced with the to moderate in severity, have a fluctuating course, even when challenging and important task of differentiating BPD, ADHD, taking a tic-suppressing medication and generally decline by ADHD with emotional dysregulation and the new DSM-5 early adulthood. Although stimulants may exacerbate tics and diagnosis of Disruptive Mood Dysregulation Disorder.264 Data are listed as a contraindication to the use of MPH,28 stimulants to guide clinicians in this area are emerging, but often conflict- have been well tolerated and effective in these patients.241,242,246,247 ingy and ma be confusing.265–268 Previous data show that BPD Randomized treatment with MPH (26.1 mg/day), clonidine appears to occur at increased rates in ADHD children and (0.25 mg/day), or MPH plus clonidine (26.1 mg/day plus adolescents of both genders at baseline (11%) and during 0.28 mg/day) was studied in 136 children with ADHD and longitudinal 4-year follow-up (23%) compared to matched chronic tic disorders.241 While MPH treatment improved non-ADHD controls (P < 0.01).269 A large study of BPD in ADHD and clonidine reduced tics, the greatest effect was adults funded by the National Institute of Mental Health observed with the combination treatment. Tic severity reduced (NIMH), the Systematic Treatment Enhancement Program for with all active treatments and in the following order: clonidine Bipolar Disorder (STEP-BD), observed that 9.5% of adults plus MPH, clonidine alone, and MPH alone. No clinically who present for treatment of BPD had lifetime co-morbid significant CV adverse events were noted. The frequency of tic ADHD, with 6% meeting current criteria.270,271 yAn arra of worsening was similar, and not significantly different, in sub- information about and rating scales to evaluate BPD can jects treated with MPH (20%), clonidine (26%), and placebo be found at www.manicdepressive.org, www.bpkids.org, and (22%). Follow-up of children with ADHD and tics treated www.schoolpsychiatry.org. with MPH over a 2-year period observed improvements in Given the severe morbidity of pediatric BPD, families and ADHD symptoms without worsening of tics.242 Given the data patients usually benefit from an integrated and coordinated on clonidine, interest in guanfacine treatment has grown, and treatment plan that includes medications (often more than it appears to be effective in reducing symptoms of both ADHD one is necessary and appropriate), psychotherapies (individ- and. tics 147,148 ual, group, and family), educational/occupational interven- Palumbo and colleagues248 observed similar rates of tics tions (accommodations or modifications in school or work), during short-term blinded treatment with placebo (3.7%), and psychoeducation and parent/family support (available IR-MPH (2.3%), or OROS-MPH (4.0%). During 24-month through national organizations such as the National Alliance open-label treatment with OROS-MPH, the rate of tics for the Mentally Ill and the Child and Adolescent Bipolar remained steady. However, clinicians must still discuss these Foundation). issues and obtain informed consent from patients and fami- Medications are usually a fundamental part of the treatment lies before using stimulants in patients with tic disorders. plan of all patients with BPD. The reader is referred to practice Investigations have demonstrated utility of noradrenergic guidelines for both pediatric patients272 .and adults 273 The adult agents, including DMI182 and ATMX.249 Although treatment guidelines do not specifically address pharmacotherapy of BPD with ATMX was not associated with significant reductions in in the context of co-morbid ADHD; clinicians should first tics compared to placebo (with reductions of Yale Global Tic ensure mood stability before the initiation of treatment for Severity Scale −5.5 ± 6.9 versus −3.3 ± 8.9; P = 0.063), tic ADHD. Patients with BPD type I without symptoms of psycho- severity did not worsen and symptoms of ADHD were signifi- sis should receive monotherapy with either a mood stabilizer cantly improved. In patients who do not tolerate or respond (e.g., lithium, valproic acid, or carbamazepine) or an atypical to treatment with stimulants, noradrenergic agents, or alpha- antipsychotic (e.g., risperidone, olanzapine, or quetiap- adrenergic agents, or their combination, consideration should ine).272,274 In patients with only a partial response, the initial be given to treatment with a neuroleptic.219 medication should be augmented with either an additional mood stabilizer or an atypical antipsychotic. The combination Attention-Deficit/Hyperactivity of lithium and valproic acid has been shown to substantially Disorder Plus Depression reduce symptoms of mania and depression in children, and in patients with BPD type I with psychosis, both a mood stabilizer Depression and dysthymia are commonly co-morbid with and an atypical antipsychotic should be started concurrently ADHD.5,11,17,250,251 In ADHD patients, depression is not an (following the same augmentation strategy). artifact,252 and it must be distinguished from demoraliza- In patients with ADHD plus BPD, for example, the risk of tion.253 Although there are no formal evidence-based guide- mania or hypomania needs to be addressed and monitored lines, clinicians should, in general, assess the severity of ADHD during treatment of ADHD. Once the mood is euthymic, con- and depression and direct their initial treatment toward the servative introduction of anti-ADHD medications along with most impairing condition. In treating pediatric depression, mood-stabilizing agents should be considered.275 Scheffer and clinicians must keep in mind recent black box warnings about colleagues276 recently demonstrated the tolerability and effi- antidepressants and the risk of suicide. Excellent information cacy of MAS XR in reducing ADHD symptoms over the short- for professionals, parents, and patients can be found at term in pediatric bipolar patients after successful mood www.parentsmedguide.org. Clinicians are also directed to a stabilization with VPA. Similarly, in a small short-term trial in review of the treatment of pediatric depression.254 In adults bipolar adults, bupropion successfully reduced symptoms of

ADHD without exacerbating mania.174 McIntyre and col- misuse of stimulant medications remain, making careful mon- leagues treated 40 mood-stabilized bipolar I/II adults with itoring necessary.302–304 In these populations use of extended- 49 LDX for their co-morbid ADHD.277 Short-term (9-week) treat- delivery stimulant preparations, which are more difficult to ment with a mean dose of 60 ± 01 mg daily subjects reported misuse, or non-stimulants should be considered.301 When significant improvements in self-ratings of ADHD and clini- administered orally in their intended dosages, stimulants do cians observed significant improvements in ADHD symptoms not appear to cause euphoria, nor do they appear to be and functioning without exacerbations on mania. Case reports addictive.305,306 also describe successful treatment of ADHD symptoms in 278 bipolar patients with ATMX alone and in combination with Attention-Deficit/Hyperactivity Disorder Plus OROS-MPH.279 However, clinicians should advise patients (and perhaps their families) to monitor any induction or Autism Spectrum Disorders exacerbation/worsening of mania or cycling during treatment 280–286 Children, adolescents and adults with ASD may display a with ADHD medications. In such situations it is neces- persistent and impairing pattern of hyperactivity, impulsivity, sary to prioritize the mood stabilization, which may also and inattention307–311; and when these symptoms can be dis- necessitate the discontinuation of the ADHD treatment until 272,287 tinguished from core features of ASD, DSM-5 allows clinicians euthymia has been achieved. to diagnose ADHD.264 In treating this group of patients, clinicians, in collaboration with parents, balance the risks and Attention-Deficit/Hyperactivity Disorder Plus benefits of treatments. In general, the philosophy is to identify Substance Use Disorders target symptoms and to prioritize impairments. Interest in the pharmacotherapy of ADHD and ASDs is Many adolescents and young adults with ADHD have either a growing. Although earlier work in small samples supported past or current alcohol or drug use disorder, and co-morbidity 17,172,288,289 the use of MPH in doses of 0.3 to 0.6 mg/kg/day, these patients within ADHD increases the risk. Patients with ADHD often experienced side effects (such as irritability) that limited frequently misuse a variety of substances (including alcohol, stimulant use.312,313 One of the Research Units in Pediatric marijuana, cocaine, stimulants, opiates, and nicotine). In fact, Psychopharmacology (RUPP) compared placebo to low, children with ADHD start smoking nicotine an average of 2 290 medium, and high doses of MPH in 72 children with pervasive years earlier than their non-ADHD peers and have increased developmental disorder and ADHD.314 In these subjects, rates of smoking as adults, more difficulty quitting although MPH treatment significantly improved attention and smoking,291,292 and nicotine dependence (achieved more 293,294 reduced distractibility, hyperactivity, and impulsivity, the rapidly and lasting longer compared to controls). Since effect, sizes according to parent and teacher ratings, were the rates of substance abuse in patients with ADHD are smaller than those usually observed in ADHD children. Fur- increased,295 concerns persist that stimulant treatment contrib- 296 thermore, adverse effects, primarily irritability, led to MPH utes to subsequent substance abuse. Wilens and colleagues discontinuation in 18%, and occurred most often during treat- performed a pooled analysis of six studies that examined the ment with either the medium or high MPH doses. A recent relationship between stimulant treatment and substance trial in 24 youth with ASD and ADHD found that MPH was abuse. Their meta-analysis revealed that stimulant treatment generally well tolerated and efficacious in reducing symptoms resulted in a 1.9-fold reduction in risk for later substance of hyperactivity and impulsivity.315 ,Similarly data suggest that abuse among youths treated with a stimulant for ADHD, as ATMXy ma be useful in ASD patients with ADHD symp- compared to those youths receiving no pharmacotherapy for 316,317 296 toms. For a full review of pharmacological treatments in their ADHD. The protective effect was greater through ado- ASDs, the interested reader is referred to excellent recent lescence and less into adulthood. Longitudinal follow-ups reviews.318–320 also suggest that stimulant pharmacotherapy of ADHD does not increase risk of developing SUD.297–299 A careful history of substance use/misuse/abuse should be Attention-Deficit/Hyperactivity Disorder completed as part of the ADHD evaluation in adolescents and Plus Epilepsy adults.300 When substance misuse/abuse/dependence is a clinical concern, the clinician should assess the relative severity of Children with epilepsy often display difficulties with behavior the ADHD and the SUD. Furthermore, addictions often affect and cognition, and anticonvulsants may have cognitive side cognition, behavior, sleep, and mood/anxiety, which make it effects. On the other hand, treatment with anticonvulsants challenging to assess ADHD symptoms. Stabilizing the addic- may lead to improved seizure control and result in improved tion and addressing co-morbid disorder(s) are generally the cognition and behavior. Although there is ongoing concern that treatment with stimulants may lower the seizure thresh- priority when treating ADHD patients with SUD. Treatment 28 for patients with ADHD and SUD usually includes a combina- old, recent reviews and data challenge the traditional warning tion of addiction treatment/psychotherapy and pharmaco- and provide evidence for the safe and effective use of stimu- 301 lants in patients with epilepsy when appropriate antiepileptic therapy. Patients with ongoing substance abuse or 321–324 dependence should generally not be treated for their ADHD treatment is used. Current recommendations for evalua- until appropriate addiction treatments have been undertaken tion, diagnosis, and treatment of ADHD acknowledge incon- and the patient has maintained a drug- and alcohol-free sistent findings in the literature on the overlap of ADHD and epilepsy, but do not recommend the use of routine electroen- period. The clinician should begin pharmacotherapy with 1,20,70 medications that have little likelihood of diversion or low cephalograms (EEGs) in the assessment of ADHD. liability, such as bupropion175 and ATMX,121 and, if necessary, progress to the stimulants. When using stimulants in this MANAGING SUB-OPTIMAL RESPONSES patient population, it is wise to prescribe an extended-delivery formulation with minimal risk of misuse (e.g., MTS or LDX), Despite the availability of various agents for adults with ADHD, as well as to agree on a method for monitoring the SUD and there appear to be a number of individuals who either do not adherence to the treatment plan. Moreover, since stimulants respond to, or are intolerant of adverse effects of, medications are Schedule II medications, concerns remain regarding their used to treat their ADHD. In managing difficult cases, several addictive potential. Concerns about possible diversion and therapeutic strategies are available (see Table 49-2). If

Downloaded for Rohul Amin ([email protected]) at Uniformed Services Univ of the Health Sciences from ClinicalKey.com by Elsevier on September 29, 2018. For personal use only. No other uses without permission. Copyright ©2018. Elsevier Inc. All rights reserved. 550 PART X Treatment Approaches psychiatric adverse effects develop concurrent with a poor 20. Pliszka S. Practice parameter for the assessment and treatment medication response, alternative treatments should be pursued. of children and adolescents with attention-deficit/hyperactivity Severe psychiatric symptoms that emerge during the acute disorder. J Am Acad Child Adolesc Psychiatry 46(7):894–921, 2007. phase can be problematic, irrespective of the efficacy of the [Epub 2007/06/22]. medications for ADHD. These symptoms may require 21. Bradley C. The behavior of children receiving benzedrine. Am J Psychiatry 94:577–585, 1937. re-consideration of the diagnosis of ADHD and careful 23. Moderators and mediators of treatment response for children re-assessment of the presence of co-morbid disorders. For with attention-deficit/hyperactivity disorder: the Multimodal example, it is common to observe depressive symptoms in an Treatment Study of children with attention-deficit/hyperactivity adult with ADHD when symptoms are independent of the disorder. Arch Gen Psychiatry 56(12):1088–1096, 1999. ADHD or treatment. If reduction of dose or change in prepara- 36. Spencer TJ, Biederman J, Ciccone PE, et al. PET study examining tion., (i.e regular versus slow-release stimulants) does not pharmacokinetics, detection and likeability, and dopamine resolve the problem, consideration should be given to alterna- transporter receptor occupancy of short- and long-acting oral tive treatments. Neuroleptic medications should be considered methylphenidate. Am J Psychiatry 163(3):387–395, 2006. as part of the overall treatment plan in the face of co-morbid 70. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus statement on diagnosis and treatment of adult ADHD: The European BPD or extreme agitation. Concurrent non-pharmacological Network Adult ADHD. BMC Psychiatry 10:67, 2010. interventions (such as behavioral or cognitive therapy) may 71. Wilens TE, Morrison NR, Prince J. An update on the pharmaco- assist with symptom reduction and functional improvements. therapy of attention-deficit/hyperactivity disorder in adults. Expert Rev Neurother 11(10):1443–1465, 2011. 72. Weiss MD, Weiss JR. A guide to the treatment of adults with CONCLUSION ADHD. J Clin Psychiatry 65(Suppl. 3):27–37, 2004. 73. Ramtvedt BE, Roinas E, Aabech HS, et al. Clinical gains from In conclusion, the aggregate literature supports that pharma- including both dextroamphetamine and methylphenidate in cotherapy provides an effective treatment for children, adoles- stimulant trials. J Child Adolesc Psychopharmacol 23(9):597–604, cents, and adults with ADHD and co-morbid disorders. 2013. Effective pharmacological treatments for ADHD include stim- 75. Graham J, Banaschewski T, Buitelaar J, et al. European guidelines ulants and non-stimulants. Structured psychotherapy may be on managing adverse effects of medication for ADHD. Eur Child effective when used adjunctly with medications. Groups Adolesc Psychiatry 20(1):17–37, 2011. focused on coping skills, support, and interpersonal psycho- 79. Biederman J, Spencer TJ, Monuteaux MC, et al. A naturalistic therapyy ma also be very useful for these patients. For adults 10-year prospective study of height and weight in children with attention-deficit hyperactivity disorder grown up: sex and treat- who are considering advanced schooling, educational plan- ment effects. J Pediatr 157(4):635–640, 40 e1, 2010. ning and alterations in the school environment may be neces- 86. Barrett JR, Tracy DK, Giaroli G. To sleep or not to sleep: a sys- sary. Further controlled investigations assessing the efficacy of tematic review of the literature of pharmacological treatments of single and combination agents for patients with ADHD are insomnia in children and adolescents with attention-deficit/ necessary, with careful attention paid to diagnostics, symptom hyperactivity disorder. J Child Adolesc Psychopharmacol 23(10): and neuropsychological outcome, long-term tolerability, and 640–647, 2013. efficacy, as well as their use in specific ADHD sub-groups. 89. Cortese S, Brown TE, Corkum P, et al. Assessment and management of sleep problems in youths with attention-deficit/hyper- Access the complete reference list and multiple choice questions activity disorder. J Am Acad Child Adolesc Psychiatry 52(8):784–796, 2013. (MCQs) online at https://expertconsult.inkling.com 102. Arnsten AF, Pliszka SR. Catecholamine influences on prefrontal cortical function: relevance to treatment of attention deficit/ hyperactivity disorder and related disorders. Pharmacol Biochem KEY REFERENCES Behav 99(2):211–216, 2011. 1. Wolraich M, Brown L, Brown RT, et al. ADHD: Clinical practice 125. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and guideline for the diagnosis, evaluation, and treatment of risk of serious cardiovascular events in young and middle-aged attention-deficit/hyperactivity disorder in children and adoles- adults. JAMA 306(24):2673–2683, 2011. cents. Pediatrics 128(5):1007–1022, 2011. 126. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious 4. Merikangas KR, He JP, Burstein M, et al. Service utilization for cardiovascular events in children and young adults. N Engl J Med lifetime mental disorders in U.S. adolescents: results of the 365(20):1896–1904, 2011. National Comorbidity Survey-Adolescent Supplement (NCS-A). 145. Gutgesell H, Atkins D, Barst R, et al. Cardiovascular monitoring of J Am Acad Child Adolesc Psychiatry 50(1):32–45, 2011. children and adolescents receiving psychotropic drugs, Dallas 1999, 5. Kessler RC, Adler L, Barkley R, et al. The prevalence and corre- American Heart Association, pp 979–982. lates of adult ADHD in the United States: results from the 146. Arnsten AF. The use of alpha-2A adrenergic agonists for the treat- National Comorbidity Survey Replication. Am J Psychiatry ment of attention-deficit/hyperactivity disorder. Expert Rev Neu 163(4):716–723, 2006. rother 10(10):1595–1605, 2010. 7. Volkow ND, Swanson JM. Clinical practice: Adult attention 151. Haavik J, Halmoy A, Lundervold AJ, et al. Clinical assessment deficit-hyperactivity disorder. N Engl J Med 369(20):1935–1944, and diagnosis of adults with attention-deficit/hyperactivity dis- 2013. order. Expert Rev Neurother 10(10):1569–1580, 2010. 11. Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome 154. Hammerness PG, Perrin JM, Shelley-Abrahamson R, et al. Cardio- of attention deficit hyperactivity disorder: a controlled 10-year vascular risk of stimulant treatment in pediatric attention-deficit/ follow-up study. Psychol Med 36(2):167–179, 2006. hyperactivity disorder: update and clinical recommendations. 17. Biederman J, Faraone SV, Spencer T, et al. Patterns of psychiatric J Am Acad Child Adolesc Psychiatry 50(10):978–990, 2011. comorbidity, cognition, and psychosocial functioning in adults 157. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden with attention deficit hyperactivity disorder. Am J Psychiatry death: what is a physician to do? Pediatrics 118(3):1215–1219, 150:1792–1798, 1993. 2006. 18. Biederman J, Newcorn J, Sprich S. Comorbidity of attention 160. Ross RG. Psychotic and manic-like symptoms during stimulant deficit hyperactivity disorder with conduct, depressive, anxiety, treatment of attention deficit hyperactivity disorder. Am J Psy and other disorders. Am J Psychiatry 148:564–577, 1991. chiatry 163(7):1149–1152, 2006. 19. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for 183. Gutgesell H, Atkins D, Barst R, et al. AHA scientific statement: the use of stimulant medications in the treatment of children, Cardiovascular monitoring of children and adolescents receiving adolescents, and adults. J Am Acad Child Adolesc Psychiatry 41(2 psychotropic drugs. J Am Acad Child Adolesc Psychiatry 38(8):979– Suppl.):26S–49S, 2002. 982, 1999.

219. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s children in the Longitudinal Assessment of Manic Symptoms Medication Algorithm Project: revision of the algorithm for study. J Clin Psychiatry 73(10):1342–1350, 2012. 49 pharmacotherapy of attention-deficit/hyperactivity disorder. 268. Barkley RA. Differential diagnosis of adults with ADHD: the role J Am Acad Child Adolesc Psychiatry 45(6):642–657, 2006. of executive function and self-regulation. J Clin Psychiatry 220. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity 71(7):e17, 2010. findings from the MTA study: comparing comorbid subgroups. 274. Kowatch RA, Youngstrom EA, Horwitz S, et al. Prescription of J Am Acad Child Adolesc Psychiatry 40(2):147–158, 2001. psychiatric medications and polypharmacy in the LAMS cohort. 224. Loy JH, Merry SN, Hetrick SE, et al. Atypical antipsychotics for Psychiatr Serv 64(10):1026–1034, 2013. disruptive behaviour disorders in children and youths. Cochrane 289. Wilens TE, Martelon M, Joshi G, et al. Does ADHD predict Database Syst Rev (9):CD008559, 2012. substance-use disorders? A 10-year follow-up study of young 225. Linton D, Barr AM, Honer WG, et al. Antipsychotic and psycho- adults with ADHD. J Am Acad Child Adolesc Psychiatry 50(6):543– stimulant drug combination therapy in attention deficit/ 553, 2011. hyperactivity and disruptive behavior disorders: a systematic 296. Wilens T, Faraone S, Biederman J, et al. Does stimulant therapy review of efficacy and tolerability. Curr Psychiatry Rep 15(5):355, of attention-deficit/hyperactivity disorder beget later substance 2013. abuse? A meta-analytic review of the literature. Pediatrics 111(1): 235. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmaco- 179–185, 2003. therapy for children with comorbid attention-deficit/hyperactiv- 297. Biederman J, Monuteaux MC, Spencer T, et al. Stimulant therapy ity and anxiety disorders. J Am Acad Child Adolesc Psychiatry and risk for subsequent substance use disorders in male adults 44(5):418–427, 2005. with ADHD: a naturalistic controlled 10-year follow-up study. 241. Group TTsSS. Treatment of ADHD in children with tics: A ran- Am J Psychiatry 165(5):597–603, 2008. domized controlled trial. Neurology 58(4):527–536, 2002. 302. McCabe SE, Knight JR, Teter CJ, et al. Non-medical use of pre- 251. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/ scription stimulants among US college students: prevalence and hyperactivity disorder in adults with bipolar disorder or major correlates from a national survey. Addiction 100(1):96–106, depressive disorder: results from the international mood disor- 2005. ders collaborative project. Prim Care Companion J Clin Psychiatry 306. Swanson JM, Volkow ND. Serum and brain concentrations of 12(3):2010. methylphenidate: implications for use and abuse. Neurosci Biobe 252. Milberger S, Biederman J, Faraone S, et al. Attention deficit hav Rev 27(7):615–621, 2003. hyperactivity disorder and comorbid disorders: Issues of 310. Johnston K, Dittner A, Bramham J, et al. Attention deficit hyper- overlapping symptoms. Am J Psychiatry 152(12):1793–1799, activity disorder symptoms in adults with autism spectrum dis- 1995. orders. Autism 6(4):225–236, 2013. 258. Biederman J, Faraone SV, Wozniak J, et al. Clinical correlates of 315. Pearson DA, Santos CW, Aman MG, et al. Effects of extended bipolar disorder in a large, referred sample of children and ado- release methylphenidate treatment on ratings of attention- lescents. J Psychiatr Res 39(6):611–622, 2005. deficit/hyperactivity disorder (ADHD) and associated behavior 262. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal in children with autism spectrum disorders and ADHD symp- course of children and adolescents with bipolar spectrum disor- toms. J Child Adolesc Psychopharmacol 23(5):337–351, 2013. ders: the Course and Outcome of Bipolar Youth (COBY) study. 324. Santos K, Palmini A, Radziuk AL, et al. The impact of methyl- Am J Psychiatry 166(7):795–804, 2009. phenidate on seizure frequency and severity in children with 263. Mick E, Spencer T, Wozniak J, et al. Heterogeneity of irritability attention-deficit-hyperactivity disorder and difficult-to-treat epi- in attention-deficit/hyperactivity disorder subjects with and lepsies. Dev Med Child Neurol 655(7):654–660, 2013. without mood disorders. Biol Psychiatry 58(7):576–582, 2005. 266. Axelson D, Findling RL, Fristad MA, et al. Examining the proposed disruptive mood dysregulation disorder diagnosis in

23. Moderators and mediators of treatment response for children REFERENCES with attention-deficit/hyperactivity disorder: the Multimodal 49 1. Wolraich M, Brown L, Brown RT, et al. ADHD: Clinical practice Treatment Study of children with attention-deficit/hyperactivity guideline for the diagnosis, evaluation, and treatment of disorder. Arch Gen Psychiatryiatry 56(12):1088–1096, 1999. attention-deficit/hyperactivity disorder in children and adoles- 24. Kuczenski R, Segal DS. Effects of methylphenidate on extracel- cents. Pediatrics 128(5):1007–1022, 2011. lular dopamine, serotonin, and norepinephrine: comparison 2. Barkley RA. International Consensus Statement on ADHD. J Am with amphetamine. J Neurochem 68(5):2032–2037, 1997. Acad Child Adolesc Psychiatry 41(12):1389, 2002. 25. Solanto MV. Neuropsychopharmacological mechanisms of stim- 3. Faraone SV, Sergeant J, Gillberg C, et al. The worldwide preva- ulant drug action in attention-deficit hyperactivity disorder: a lence of ADHD: Is it an American condition? World Psychiatry review and integration. Behav Brain Res 94(1):127–152, 1998. 2(2):104–113, 2003. 26. Wilens T, Spencer T. Pharmacology of amphetamines. In Tarter 4. Merikangas KR, He JP, Burstein M, et al. Service utilization for R, Ammerman R, Ott P, editors: Handbook of substance abuse: lifetime mental disorders in U.S. adolescents: results of the neurobehavioral pharmacology, New York, 1998, Plenum Press, pp National Comorbidity Survey-Adolescent Supplement (NCS-A). 501–513. J Am Acad Child Adolesc Psychiatry 50(1):32–45, 2011. 27. Volkow ND, Wang GJ, Fowler JS, et al. Therapeutic doses of oral 5. Kessler RC, Adler L, Barkley R, et al. The prevalence and corre- methylphenidate significantly increase extracellular dopamine lates of adult ADHD in the United States: results from the in human brain. J Neurosci 21:RC121:1–5, 2001. National Comorbidity Survey Replication. Am J Psychiatry 28. Physicians desk reference, Montvale, NJ, 2013, Medical Economics 163(4):716–723, 2006. Data Production Company. 6. Goldman L, Genel M, Bezman R, et al. Diagnosis and treatment 29. Patrick KS, Markowitz JS. Pharmacology of methylphenidate, of attention-deficit/hyperactivity disorder in children and ado- amphetamine enantiomers and pemoline in attention-deficit lescents. JAMA 279(14):1100–1107, 1998. hyperactivity disorder. Hum Psychopharmacol 12:527–546, 1997. 7. Volkow ND, Swanson JM. Clinical practice: Adult attention 30. Markowitz JS, Patrick KS. Differential pharmacokinetics and deficit-hyperactivity disorder. N Engl J Med 369(20):1935–1944, pharmacodynamics of methylphenidate enantiomers: does chi- 2013. rality matter? J Clin Psychopharmacol 28(3 Suppl. 2):S54–S61, 8. Biederman J, Faraone S, Mick E. Age dependent decline of 2008. ADHD symptoms revisited: Impact of remission definition and 31. Zhu HJ, Patrick KS, Yuan HJ, et al. Two CES1 gene mutations symptom subtype. Am J Psychiatry 157:816–817, 2000. lead to dysfunctional carboxylesterase 1 activity in man: clinical 9. Kessler RC, Adler LA, Barkley R, et al. Patterns and predictors of significance and molecular basis. Am J Hum Genet 82(6):1241– attention-deficit/hyperactivity disorder persistence into adult- 1248, 2008. hood: results from the national comorbidity survey replication. 32. Greenhill LL, Osman BB. Ritalin: theory and patient management, Biol Psychiatry 57(11):1442–1451, 2005. New York, 1999, Mary Ann Liebert, Inc. 10. Biederman J, Faraone SV, Spencer TJ, et al. Functional impair- 33. Patrick K, Straughn A, Jarvi E, et al. The absorption of sustained- ments in adults with self-reports of diagnosed ADHD: A control- release methylphenidate formulations compared to an immediate- led study of 1001 adults in the community. J Clin Psychiatry release formulation. Biopharm Drug Dispos 10:165–171, 1989. 67(4):524–540, 2006. 34. Birmaher B, Greenhill LL, Cooper TB, et al. Sustained release 11. Biederman J, Monuteaux MC, Mick E, et al. Young adult outcome methylphenidate: Pharmacokinetic studies in ADDH males. of attention deficit hyperactivity disorder: a controlled 10-year J Am Acad Child Adolesc Psychiatry 28(5):768–772, 1989. follow-up study. Psychol Med 36(2):167–179, 2006. 35. Swanson J, Gupta S, Lam A, et al. Development of a new once- 12. Wolraich ML, Wibbelsman CJ, Brown TE, et al. Attention-deficit/ a-day formulation of methylphenidate for the treatment of hyperactivity disorder among adolescents: a review of the diag- attention-deficit/hyperactivity disorder: proof-of-concept and nosis, treatment, and clinical implications. Pediatrics 115(6): proof-of-product studies. Arch Gen Psychiatryiatry 60(2):204–211, 1734–1746, 2005. 2003. 13. McGough JJ, Smalley SL, McCracken JT, et al. Psychiatric comor- 36. Spencer TJ, Biederman J, Ciccone PE, et al. PET study examining bidity in adult attention deficit hyperactivity disorder: findings pharmacokinetics, detection and likeability, and dopamine from multiplex families. Am J Psychiatry 162(9):1621–1627, transporter receptor occupancy of short- and long-acting oral 2005. methylphenidate. Am J Psychiatry 163(3):387–395, 2006. 14. Barkley RA, Fischer M, Smallish L, et al. Young adult follow-up 37. Pelham WE, Gnagy EM, Burrows-Maclean L, et al. Once-a-day of hyperactive children: antisocial activities and drug use. J Child Concerta methylphenidate versus three-times-daily methylphe- Psychol Psychiatry 45(2):195–211, 2004. nidate in laboratory and natural settings. Pediatrics 107(6):E105, 15. Wilens TE, Biederman J, Forkner P, et al. Patterns of comorbidity 2001. and dysfunction in clinically referred preschool and school-age 38. Wolraich ML, Greenhill LL, Pelham W, et al. Randomized, con- children with bipolar disorder. J Child Adolesc Psychopharmacol trolled trial of oros methylphenidate once a day in children with 13(4):495–505, 2003. attention-deficit/hyperactivity disorder. Pediatrics 108(4):883– 16. Angold A, Costello EJ, Erkanli A. Comorbidity. J Child Psychol 892, 2001. Psychiatry 40(1):57–87, 1999. 39. Swanson JM, Gupta SK, Williams L, et al. Development of a new 17. Biederman J, Faraone SV, Spencer T, et al. Patterns of psychiatric once-a -day formulation of methylphenidate for the treatment comorbidity, cognition, and psychosocial functioning in adults of ADHD: Effects on activity level in the classroom and on the with attention deficit hyperactivity disorder. Am J Psychiatry playground. J Am Acad Child Adolesc Psychiatry 41(11):1306– 150:1792–1798, 1993. 1314, 2002. 18. Biederman J, Newcorn J, Sprich S. Comorbidity of attention 40. Wilens TE, McBurnett K, Bukstein O, et al. Multisite controlled deficit hyperactivity disorder with conduct, depressive, anxiety, study of OROS methylphenidate in the treatment of adolescents and other disorders. Am J Psychiatry 148:564–577, 1991. with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc 19. Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for Med 160(1):82–90, 2006. the use of stimulant medications in the treatment of children, 41. Biederman J, Mick E, Surman C, et al. A randomized, placebo- adolescents, and adults. J Am Acad Child Adolesc Psychiatry 41(2 controlled trial of OROS methylphenidate in adults with Suppl.):26S–49S, 2002. attention-deficit/hyperactivity disorder. Biol Psychiatry 59(9): 20. Pliszka S. Practice parameter for the assessment and treatment 829–835, 2006. of children and adolescents with attention-deficit/hyperactivity 42. Wilens T, McBurnett K, Stein M, et al. ADHD treatment with disorder. J Am Acad Child Adolesc Psychiatry 46(7):894–921, 2007. once-daily OROS methylphenidate: final results from a long- [Epub 2007/06/22]. term open-label study. J Am Acad Child Adolesc Psychiatry 44(10): 21. Bradley C. The behavior of children receiving benzedrine. Am J 1015–1023, 2005. Psychiatry 94:577–585, 1937. 43. Greenhill LL, Findling RL, Swanson JM. A double-blind, placebo- 22. National Institute of Mental Health Multimodal Treatment controlled study of modified-release methylphenidate in chil- Study of ADHD follow-up: changes in effectiveness and growth dren with attention-deficit/hyperactivity disorder. Pediatrics after the end of treatment. Pediatrics 113(4):762–769, 2004. 109(3):E39, 2002.

44. Biederman J, Quinn D, Weiss M, et al. Efficacy and safety of (Adderal XR) in children with attention-deficit/hyperactivity Ritalin LA, a new, once daily, extended-release dosage form of disorder. Pediatrics 110(2 Pt 1):258–266, 2002. methylphenidate, in children with attention deficit hyperactivity 63. Spencer TJ, Wilens TE, Biederman J, et al. Efficacy and safety disorder. Paediatr Drugs 5(12):833–841, 2003. of mixed amphetamine salts extended release (Adderall XR) 45. Ding YS, Fowler JS, Volkow ND, et al. Chiral drugs: comparison in the management of attention-deficit/hyperactivity disorder of the pharmacokinetics of [11C]d-threo and L-threo-methylin adolescent patients: a 4-week, randomized, double-blind, phenidate in the human and baboon brain. Psychopharmacology placebo-controlled, parallel-group study. Clin Ther 28(2):266– (Berl) 131(1):71–78, 1997. 279, 2006. 46. Ding YS, Gatley SJ, Thanos PK, et al. Brain kinetics of methyl- 64. Weisler RH, Biederman J, Spencer TJ, et al. Mixed amphetamine phenidate (Ritalin) enantiomers after oral administration. salts extended-release in the treatment of adult ADHD: a ran Synapse 53(3):168–175, 2004. domized, controlled trial. CNS Spectr 11(8):625–639, 2006. 47. Patrick KS, Caldwell RW, Ferris RM, et al. Pharmacology of the 65. Biederman J, Spencer TJ, Wilens TE. Long-term safety and effec- enantiomers of threo-methylphenidate. J Pharmacol Exp Ther tiveness of mixed amphetamine salts extended release in adults 241(1):152–158, 1987. with ADHD. CNS Spectr 10(12 Suppl. 20):16–25, 2005. 48. Silva RR, Muniz R, Pestreich L, et al. Efficacy and duration of 66. McGough JJ, Biederman J, Wigal SB, et al. Long-term tolerability effect of extended-release dexmethylphenidate versus placebo in and effectiveness of once-daily mixed amphetamine salts schoolchildren with attention-deficit/hyperactivity disorder. (Adderall XR) in children with ADHD. J Am Acad Child Adolesc J Child Adolesc Psychopharmacol 16(3):239–251, 2006. Psychiatry 44(6):530–538, 2005. 49. Greenhill LL, Muniz R, Ball RR, et al. Efficacy and safety of 67. Jasinski DR, Krishnan S. Abuse liability and safety of oral lisdex- dexmethylphenidate extended-release capsules in children with amfetamine dimesylate in individuals with a history of stimu- attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc lant abuse. J Psychopharmacol 23(4):419–427, 2009. Psychiatry 45(7):817–823, 2006. 68. Jasinski DR, Krishnan S. Human pharmacology of intravenous 50. Silva R, Tilker HA, Cecil JT, et al. Open-label study of dexmethyl lisdexamfetamine dimesylate: abuse liability in adult stimulant phenidate hydrochloride in children and adolescents with abusers. J Psychopharmacol 23(4):410–418, 2009. attention deficit hyperactivity disorder. J Child Adolesc Psycho 69. Stevens JR, Wilens TE, Stern TA. Using stimulants for attention- pharmacology 14(4):555–563, 2004. deficit/hyperactivity disorder: clinical approaches and chal- 51. Wigal S, Swanson JM, Feifel D, et al. A double-blind, placebo- lenges. Primary Care Companion CNS Disord 15(2):2013. controlled trial of dexmethylphenidate hydrochloride and 70. Kooij SJ, Bejerot S, Blackwell A, et al. European consensus state- d,l-threo-methylphenidate hydrochloride in children with ment on diagnosis and treatment of adult ADHD: The European attention-deficit/hyperactivity disorder. J Am Acad Child Adolesc Network Adult ADHD. BMC Psychiatry 10:67, 2010. Psychiatry 43(11):1406–1414, 2004. 71. Wilens TE, Morrison NR, Prince J. An update on the pharmaco- 52. Quinn D, Wigal S, Swanson J, et al. Comparative pharmacody- therapy of attention-deficit/hyperactivity disorder in adults. namics and plasma concentrations of d-threo-methylphenidate Expert Rev Neurother 11(10):1443–1465, 2011. hydrochloride after single doses of d-threo-methylphenidate 72. Weiss MD, Weiss JR. A guide to the treatment of adults with hydrochloride and d,l-threo-methylphenidate hydrochloride in ADHD. J Clin Psychiatry 65(Suppl. 3):27–37, 2004. a double-blind, placebo-controlled, crossover laboratory school 73. Ramtvedt BE, Roinas E, Aabech HS, et al. Clinical gains from study in children with attention-deficit/hyperactivity disorder. including both dextroamphetamine and methylphenidate in J Am Acad Child Adolesc Psychiatry 43(11):1422–1429, 2004. stimulant trials. J Child Adolesc Psychopharmacol 23(9):597–604, 53. McGough JJ, Wigal SB, Abikoff H, et al. A randomized, double- 2013. blind, placebo-controlled, laboratory classroom assessment of 74. Aagaard L, Hansen EH. Adverse drug reaction labelling for methylphenidate transdermal system in children with ADHD. atomoxetine, methylphenidate and modafinil: comparison J Atten Disord 9(3):476–485, 2006. of product information for oral formulations in Australia, 54. Pelham WE, Burrows-Maclean L, Gnagy EM, et al. Transdermal Denmark and the United States. Curr Drug Saf 8(3):162–168, methylphenidate, behavioral, and combined treatment for chil- 2013. dren with ADHD. Exp Clin Psychopharmacol 13(2):111–126, 75. Graham J, Banaschewski T, Buitelaar J, et al. European guidelines 2005. on managing adverse effects of medication for ADHD. Eur Child 55. Pelham WE Jr, Manos MJ, Ezzell CE, et al. A dose-ranging study Adolesc Psychiatry 20(1):17–37, 2011. of a methylphenidate transdermal system in children with 76. Efron D, Jarman F, Barker M. Side effects of methylphenidate ADHD. J Am Acad Child Adolesc Psychiatry 44(6):522–529, 2005. and dexamphetamine in children with attention deficit hyperac- 56. Zhu HJ, Wang JS, Donovan JL, et al. Interactions of attention- tivity disorder: a double-blind, crossover trial. Pediatrics deficit/hyperactivity disorder therapeutic agents with the efflux 100(4):662–666, 1997. transporter P-glycoprotein. Eur J Pharmacol 578(2–3):148–158, 77. Barkley RA, McMurray MB, Edelbrock CS, et al. Side effects of 2008. methylphenidate in children with attention deficit hyperactivity 57. Childress A, Sallee FR. The use of methylphenidate hydrochlo- disorder: A systemic, placebo-controlled evaluation. Pediatrics ride extended-release oral suspension for the treatment of 86(2):184–192, 1990. ADHD. Expert Rev Neurother 13(9):979–988, 2013. 78. Swanson JM, Elliott GR, Greenhill LL, et al. Effects of stimulant 58. Wigal SB, Childress AC, Belden HW, et al. NWP06, an extended- medication on growth rates across 3 years in the MTA follow-up. release oral suspension of methylphenidate, improved attention- J Am Acad Child Adolesc Psychiatry 46(8):1015–1027, 2007. [Epub deficit/hyperactivity disorder symptoms compared with placebo 2007/08/02]. in a laboratory classroom study. J Child Adolesc Psychopharmacol 79. Biederman J, Spencer TJ, Monuteaux MC, et al. A naturalistic 23(1):3–10, 2013. 10-year prospective study of height and weight in children with 59. Ahmann PA, Theye FW, Berg R, et al. Placebo-controlled evalu- attention-deficit hyperactivity disorder grown up: sex and treat- ation of amphetamine mixture-dextroamphetamine salts and ment effects. J Pediatr 157(4):635–640, 40 e1, 2010. amphetamine salts (Adderall): efficacy rate and side effects. Pedi 80. O’Brien LM, Holbrook CR, Mervis CB, et al. Sleep and neuro atrics 107(1):E10, 2001. behavioral characteristics of 5- to 7-year-old children with 60. Spencer T, Biederman J, Wilens T, et al. Efficacy of a mixed parentally reported symptoms of attention-deficit/hyperactivity amphetamine salts compound in adults with attention-deficit/ disorder. Pediatrics 111(3):554–563, 2003. hyperactivity disorder. Arch Gen Psychiatryiatry 58(8):775–782, 81. Corkum P, Moldofsky H, Hogg-Johnson S, et al. Sleep problems 2001. in children with attention-deficit/hyperactivity disorder: impact 61. McCracken JT, Biederman J, Greenhill LL, et al. Analog class- of subtype, comorbidity, and stimulant medication. J Am Acad room assessment of a once-daily mixed amphetamine formula- Child Adolesc Psychiatry 38(10):1285–1293, 1999. tion, SLI381 (Adderall XR), in children with ADHD. J Am Acad 82. Mick E, Biederman J, Jetton J, et al. Sleep disturbances associated Child Adolesc Psychiatry 42(6):673–683, 2003. with attention deficit hyperactivity disorder: the impact of psy- 62. Biederman J, Lopez FA, Boellner SW, et al. A randomized, chiatric comorbidity and pharmacotherapy. J Child Adolesc Psy double-blind, placebo-controlled, parallel-group study of SLI381 chopharmacol 10(3):223–231, 2000.

83. Owens JA, Maxim R, Nobile C, et al. Parental and self-report of 104. Ring BJ, Gillespie JS, Eckstein JA, et al. Identification of the sleep in children with attention-deficit/hyperactivity disorder. human cytochromes P450 responsible for atomoxetine metabo- 49 Arch Pediatr Adolesc Med 154(6):549–555, 2000. lism. Drug Metab Dispos 30(3):319–323, 2002. 84. Schwartz G, Amor LB, Grizenko N, et al. Actigraphic monitoring 105. Witcher JW, Long A, Smith B, et al. Atomoxetine pharmacokinet- during sleep of children with ADHD on methylphenidate and ics in children and adolescents with attention deficit hyperactivity placebo. J Am Acad Child Adolesc Psychiatry 43(10):1276–1282, disorder. J Child Adolesc Psychopharmacol 13(1):53–63, 2003. 2004. 106. Sauer JM, Ponsler GD, Mattiuz EL, et al. Disposition and meta- 85. Stein MA. Unravelling sleep problems in treated and untreated bolic fate of atomoxetine hydrochloride: the role of CYP2D6 in children with ADHD. [Comment]. J Child Adolesc Psychopharma human disposition and metabolism. Drug Metab Dispos col 9(3):157–168, 1999. 31(1):98–107, 2003. 86. Barrett JR, Tracy DK, Giaroli G. To sleep or not to sleep: a sys- 107. Sauer JM, Ring BJ, Witcher JW. Clinical pharmacokinetics of tematic review of the literature of pharmacological treatments of atomoxetine. Clin Pharmacokinet 44(6):571–590, 2005. insomnia in children and adolescents with attention-deficit/ 108. Belle DJ, Ernest CS, Sauer JM, et al. Effect of potent CYP2D6 hyperactivity disorder. J Child Adolesc Psychopharmacol 23(10): inhibition by paroxetine on atomoxetine pharmacokinetics. 640–647, 2013. J Clin Pharmacol 42(11):1219–1227, 2002. 87. Surman CB, Roth T. Impact of stimulant pharmacotherapy on 109. Michelson D, Faries D, Wernicke J, et al. Atomoxetine in the sleep quality: post hoc analyses of 2 large, double-blind, rand- treatment of children and adolescents with attention-deficit/ omized, placebo-controlled trials. J Clin Psychiatry 72(7):903– hyperactivity disorder: a randomized, placebo-controlled, dose- 908, 2011. response study. Pediatrics 108(5):E83, 2001. 88. Kratochvil CJ, Lake M, Pliszka SR, et al. Pharmacological man- 110. Wilens TE, Hammerness P, Utzinger L, et al. An open study of agement of treatment-induced insomnia in ADHD. J Am Acad adjunct OROS-methylphenidate in children and adolescents Child Adolesc Psychiatry 44(5):499–501, 2005. who are atomoxetine partial responders: I. Effectiveness. J Child 89. Cortese S, Brown TE, Corkum P, et al. Assessment and manage- Adolesc Psychopharmacol 19(5):485–492, 2009. ment of sleep problems in youths with attention-deficit/hyper- 111. Hammerness P, Georgiopoulos A, Doyle RL, et al. An open study activity disorder. J Am Acad Child Adolesc Psychiatry 52(8):784–796, of adjunct OROS-methylphenidate in children who are atomox- 2013. etine partial responders: II. Tolerability and pharmacokinetics. 90. Prince J, Wilens T, Biederman J, et al. Clonidine for sleep distur- J Child Adolesc Psychopharmacol 19(5):493–499, 2009. bances associated with attention-deficit hyperactivity disorder: A 112. Adler LA, Spencer TJ, Milton DR, et al. Long-term, open-label systematic chart review of 62 cases. J Am Acad Child Adolesc study of the safety and efficacy of atomoxetine in adults with Psychiatry 35(5):599–605, 1996. attention-deficit/hyperactivity disorder: an interim analysis. 91. Macchi MM, Bruce JN. Human pineal physiology and functional J Clin Psychiatry 66(3):294–299, 2005. significance of melatonin. Front Neuroendocrinol 25(3–4):177– 113. Kratochvil CJ, Wilens TE, Greenhill LL, et al. Effects of long-term 195, 2004. atomoxetine treatment for young children with attention-deficit/ 92. Smits MG, van Stel HF, van der Heijden K, et al. Melatonin hyperactivity disorder. J Am Acad Child Adolesc Psychiatry improves health status and sleep in children with idiopathic 45(8):919–927, 2006. chronic sleep-onset insomnia: a randomized placebo-controlled 114. Wilens TE, Newcorn JH, Kratochvil CJ, et al. Long-term atomox- trial. J Am Acad Child Adolesc Psychiatry 42(11):1286–1293, 2003. etine treatment in adolescents with attention-deficit/hyperactiv- 93. Tjon Pian Gi CV, Broeren JP, Starreveld JS, et al. Melatonin for ity disorder. J Pediatr 149(1):112–119, 2006. treatment of sleeping disorders in children with attention deficit/ 115. Adler L, Dietrich A, Reimherr FW, et al. Safety and tolerability of hyperactivity disorder: a preliminary open label study. Eur J once versus twice daily atomoxetine in adults with ADHD. Ann Pediatr 162(7–8):554–555, 2003. Clin Psychiatry 18(2):107–113, 2006. 94. Weiss MD, Wasdell MB, Bomben MM, et al. Sleep hygiene and 116. Weiss M, Tannock R, Kratochvil C, et al. A randomized, placebo- melatonin treatment for children and adolescents with ADHD controlled study of once-daily atomoxetine in the school setting and initial insomnia. J Am Acad Child Adolesc Psychiatry 45(5): in children with ADHD. J Am Acad Child Adolesc Psychiatry 512–519, 2006. 44(7):647–655, 2005. 95. Zlotos DP. Recent advances in melatonin receptor ligands. Arch 117. Kelsey DK, Sumner CR, Casat CD, et al. Once-daily atomoxetine Pharm (Weinheim) 338(5–6):229–247, 2005. treatment for children with attention-deficit/hyperactivity disor- 96. Daviss WB, Scott J. A chart review of cyproheptadine for der, including an assessment of evening and morning behavior: stimulant-induced weight loss. J Child Adolesc Psychopharmacol a double-blind, placebo-controlled trial. Pediatrics 114(1):e1–e8, 14(1):65–73, 2004. 2004. 97. Markowitz JS, Morrison SD, DeVane CL. Drug interactions 118. Dunn D, Turgay A, Weiss M, editors: Use of plasma concentra- with psychostimulants. Int Clin Psychopharmacol 14(1):1–18, tion to guide atomoxetine doses in ADHD patients. Program and 1999. abstracts of the American Psychiatric Association Annual Meeting. 98. Markowitz JS, Patrick KS. Pharmaokinetic and pharmacody- Atlanta, GA, 2005. namic drug ineractions in the treatment of ADHD. Clin Pharma 119. Adler LA, Liebowitz M, Kronenberger W, et al. Atomoxetine cokinet 40:753–772, 2001. treatment in adults with attention-deficit/hyperactivity disorder 99. Cohen L, Prince J, Biederman J, et al. Desipramine clearance in and comorbid social anxiety disorder. Depress Anxiety 26(3):212– children and adolescence: Absence of effect of development 221, 2009. and gender. J Am Acad Child Adolesc Psychiatry 38(1):79–85, 120. Heil SH, Holmes HW, Bickel WK, et al. Comparison of the sub- 1999. jective, physiological, and psychomotor effects of atomoxetine 100. Brown TE. Atomoxetine and stimulants in combination for treat- and methylphenidate in light drug users. Drug Alcohol Depend ment of attention deficit hyperactivity disorder: four case reports. 67(2):149–156, 2002. J Child Adolesc Psychopharmacol 14(1):129–136, 2004. 121. Wilens TE, Adler LA, Weiss MD, et al. Atomoxetine treatment of 101. Spencer T, Biederman J, Wilens T, et al. Pharmacotherapy of adults with ADHD and comorbid alcohol use disorders. Drug attention deficit disorder across the life cycle. J Am Acad Child Alcohol Depend 96(1–2):145–154, 2008. Adolesc Psychiatry 35(4):409–432, 1996. 122. Adler L, Wilens T, Zhang S, et al. Retrospective safety analysis of 102. Arnsten AF, Pliszka SR. Catecholamine influences on prefrontal atomoxetine in adult ADHD patients with or without comorbid cortical function: relevance to treatment of attention deficit/ alcohol abuse and dependence. Am J Addict 18(5):393–401, hyperactivity disorder and related disorders. Pharmacol Biochem 2009. Behav 99(2):211–216, 2011. 123. Michelson D, Adler L, Spencer T, et al. Atomoxetine in adults 103. Bymaster FP, Katner JS, Nelson DL, et al. Atomoxetine increases with ADHD: two randomized, placebo-controlled studies. Biol extracellular levels of norepinephrine and dopamine in prefron- Psychiatry 53(2):112–120, 2003. tal cortex of rat: a potential mechanism for efficacy in attention 124. Wernicke JF, Faries D, Girod D, et al. Cardiovascular effects of deficit/hyperactivity disorder. Neuropsychopharmacology 27(5): atomoxetine in children, adolescents, and adults. Drug Saf 699–711, 2002. 26(10):729–740, 2003.

125. Habel LA, Cooper WO, Sox CM, et al. ADHD medications and 147. Scahill L, editor: Controlled clinical trial of guanfacine in ADHD risk of serious cardiovascular events in young and middle-aged youth with tic disorders. Boca Raton, 2000, NCDEU. adults. JAMA 306(24):2673–2683, 2011. 148. Scahill L, Chappell PB, Kim YS, et al. A placebo-controlled study 126. Cooper WO, Habel LA, Sox CM, et al. ADHD drugs and serious of guanfacine in the treatment of children with tic disorders cardiovascular events in children and young adults. N Engl J Med and attention deficit hyperactivity disorder. Am J Psychiatry 365(20):1896–1904, 2011. 158(7):1067–1074, 2001. 127. Lim JR, Faught PR, Chalasani NP, et al. Severe liver injury after 149. Horrigan JP, Barnhill LJ. Guanfacine and secondary mania in initiating therapy with atomoxetine in two children. J Pediatr children. J Affect Disord 54(3):309–314, 1999. 148(6):831–834, 2006. 150. Sallee F, Connor DF, Newcorn JH. A review of the rationale and 128. Roden DM, Nadeau JHJ, Primm RK. Electrophysiologic and clinical utilization of alpha2-adrenoceptor agonists for the treat- hemodynamic effects of chronic oral therapy with the alpha2- ment of attention-deficit/hyperactivity and related disorders. agonists clonidine and tiamenidine in hypertensive volunteers. J Child Adolesc Psychopharmacol 23(5):308–319, 2013. Clin Pharmacol Ther 43:648–654, 1988. 151. Haavik J, Halmoy A, Lundervold AJ, et al. Clinical assessment 129. Buccafusco JJ. Neuropharmacologic and behavioral actions of and diagnosis of adults with attention-deficit/hyperactivity dis- clonidine: Interactions with central neurotransmitters. Int Rev order. Expert Rev Neurother 10(10):1569–1580, 2010. Neurobiology 33:55–107, 1992. 152. Adler LA, Reingold LS, Morrill MS, et al. Combination pharma- 130. Hunt RD, Inderaa RB, Cohen DJ. The therapeutic effect of clo- cotherapy for adult ADHD. Curr Psychiatry Rep 8(5):409–415, nidine and attention deficit disorder with hyperactivity: A com- 2006. parison with placebo and methylphenidate. Psychopharmacol Bull 153. Nissen SE. ADHD drugs and cardiovascular risk. N Engl J Med 22(1):229–236, 1986. 354(14):1445–1448, 2006. 131. Connor DF, Fletcher KE, Swanson JM. A meta-analysis of cloni- 154. Hammerness PG, Perrin JM, Shelley-Abrahamson R, et al. dine for symptoms of attention-deficit hyperactivity disorder. Cardiovascular risk of stimulant treatment in pediatric attention- J Am Acad Child Adolesc Psychiatry 38(12):1551–1559, 1999. deficit/hyperactivity disorder: update and clinical recommen 132. Connor DF, Barkley RA, Davis HT. A pilot study of methylphe- dations. J Am Acad Child Adolesc Psychiatry 50(10):978–990, nidate, clonidine, or the combination in ADHD comorbid with 2011. aggressive oppositional defiant or conduct disorder. Clin Pediatr 155. Liberthson RR. Sudden death from cardiac causes in children (Phila) 39(1):15–25, 2000. and young adults. N Engl J Med 334(16):1039–1044, 1996. 133. Hazell PL, Stuart JE. A randomized controlled trial of clonidine 156. Biederman J, Spencer TJ, Wilens TE, et al. Treatment of ADHD added to psychostimulant medication for hyperactive and with stimulant medications: response to Nissen perspective in aggressive children. J Am Acad Child Adolesc Psychiatry 42(8):886– the New England Journal of Medicine. J Am Acad Child Adolesc 894, 2003. Psychiatry 45(10):1147–1150, 2006. 134. Schvehla TJ, Mandoki MW, Sumner GS. Clonidine therapy for 157. Wilens TE, Prince JB, Spencer TJ, et al. Stimulants and sudden comorbid attention deficit hyperactivity disorder and conduct death: what is a physician to do? Pediatrics 118(3):1215–1219, disorder: Preliminary findings in a children’s inpatient unit. 2006. South Med J 87(7):692–695, 1994. 158. Wilens TE, Zusman RM, Hammerness PG, et al. An open-label 135. Singer HV, Brown J, Quaskey S, et al. The treatment of attention- study of the tolerability of mixed amphetamine salts in adults deficit hyperactivity disorder in Tourette’s syndrome: A double- with attention-deficit/hyperactivity disorder and treated primary blind placebo controlled study with clonidine and desipramine. essential hypertension. J Clin Psychiatry 67(5):696–702, 2006. Pediatrics 95:74–81, 1995. 159. Connor DF, Glatt SJ, Lopez ID, et al. Psychopharmacology and 136. Steingard R, Biederman J, Spencer T, et al. Comparison of cloni- aggression. I: A meta-analysis of stimulant effects on overt/covert dine response in the treatment of attention deficit hyperactivity aggression-related behaviors in ADHD. J Am Acad Child Adolesc disorder with and without comorbid tic disorders. J Am Acad Psychiatry 41(3):253–261, 2002. Child Adolesc Psychiatry 32:350–353, 1993. 160. Ross RG. Psychotic and manic-like symptoms during stimulant 137. Wilens TE, Biederman J, Spencer T. Clonidine for sleep distur- treatment of attention deficit hyperactivity disorder. Am J Psy bances associated with attention deficit hyperactivity disorder. chiatry 163(7):1149–1152, 2006. J Am Acad Child Adolesc Psychiatry 33:424–426, 1994. 161. Conners CK, Casat CD, Gualtieri CT, et al. Bupropion hydro- 138. Donnelly CL. Pharmacologic treatment approaches for children chloride in attention deficit disorder with hyperactivity. J Am and adolescents with posttraumatic stress disorder. Child Adolesc Acad Child Adolesc Psychiatry 35(10):1314–1321, 1996. Psychiatr Clin N Am 12(2):251–269, 2003. 162. Barrickman L, Perry P, Allen A, et al. Bupropion versus methyl- 139. Klein-Schwartz W. Trends and toxic effects from pediatric cloni- phenidate in the treatment of attention-deficit hyperactivity dis- dine exposures. Arch Pediatr Adolesc Med 156(4):392–396, 2002. order. J Am Acad Child Adolesc Psychiatry 34(5):649–657, 1995. 140. Leckman JF, Ort S, Caruso KA, et al. Rebound phenomena 163. Casat CD, Pleasants DZ, Fleet JVW. A double blind trial of in Tourette’s syndrome after abrupt withdrawal of clonidine: bupropion in children with attention deficit disorder. Psychop Behavioral, cardiovascular, and neurochemical effects. Arch Gen harmacol Bull 23:120–122, 1987. Psychiatryiatry 43:1168–1176, 1986. 164. Wilens TE, Spencer TJ, Biederman J, et al. A controlled clinical 141. Nami R, Bianchini C, Fiorella G, et al. Comparison of effects of trial of bupropion for attention deficit hyperactivity disorder in guanfacine and clonidine on blood pressure, heart rate, urinary adults. Am J Psychiatry 158(2):282–288, 2001. catecholamines, and cyclic nucleotides during and after admin- 165. Wender PH, Reimherr FW. Bupropion treatment of attention istration to patients with mild to moderate hypertension. J Car deficit hyperactivity disorder in adults. Am J Psychiatry 147:1018– diovasc Pharmacol 5(4):546–551, 1983. 1020, 1990. 142. Jaffe R, Livshits T, Bursztyn M. Adverse interaction between clo- 166. Wilens TE, Haight BR, Horrigan JP, et al. Bupropion XL in adults nidine and verapamil. Ann Pharmacother 28:881–883, 1994. with attention-deficit/hyperactivity disorder: a randomized, 143. Wilens TE, Spencer TJ, Swanson JM, et al. Combining methyl- placebo-controlled study. Biol Psychiatry 57(7):793–801, 2005. phenidate and clonidine: a clinically sound medication option. 167. Reimherr FW, Hedges DW, Strong RE, et al. Bupropion SR in J Am Acad Child Adolesc Psychiatry 38(5):614–619, discussion adults with ADHD: a short-term, placebo-controlled trial. Neu 9–22, 1999. ropsychiatric Dis Treatment 1(3):245–251, 2005. 144. Childress AC, Sallee FR. Revisiting clonidine: an innovative 168. Upadhyaya HP, Brady KT, Wang W. Bupropion SR in adolescents add-on option for attention-deficit/hyperactivity disorder. Drugs with comorbid ADHD and nicotine dependence: a pilot study. Today (Barc) 48(3):207–217, 2012. J Am Acad Child Adolesc Psychiatry 43(2):199–205, 2004. 145. Gutgesell H, Atkins D, Barst R, et al. Cardiovascular monitoring of 169. Solhkhah R, Wilens TE, Daly J, et al. Bupropion SR for the treat- children and adolescents receiving psychotropic drugs, Dallas, 1999, ment of substance-abusing outpatient adolescents with American Heart Association, pp 979–982. attention-deficit/hyperactivity disorder and mood disorders. 146. Arnsten AF. The use of alpha-2A adrenergic agonists for the treat- J Child Adolesc Psychopharmacol 15(5):777–786, 2005. ment of attention-deficit/hyperactivity disorder. Expert Rev Neu 170. Riggs P, editor: Preliminary findings on a controlled trial of pemoline rother 10(10):1595–1605, 2010. for adolescents with ADHD and substance abuse. Scientific

proceedings of the American Academy of Child and Adolescent Psy treatment for adults with ADHD. J Atten Disord 2012. [Epub chiatry; Honolulu, 2001. 2012/05/24]. 49 171. Daviss WB, editor: Wellbutrin SR for adolescents with ADHD and 191. Swanson JM, Greenhill LL, Lopez FA, et al. Modafinil film-coated depression. American Academy of Child and Adolescent Psychia- tablets in children and adolescents with attention-deficit/hyper- try; Chicago, IL, 1999, Solvay Pharmaceuticals, Inc. activity disorder: results of a randomized, double-blind, placebo- 172. Biederman J, Wilens T, Mick E, et al. Psychoactive substance use controlled, fixed-dose study followed by abrupt discontinuation. disorders in adults with attention deficit hyperactivity disorder J Clin Psychiatry 67(1):137–147, 2006. (ADHD): effects of ADHD and psychiatric comorbidity. Am J 192. Greenhill LL, Biederman J, Boellner SW, et al. A randomized, Psychiatry 152(11):1652–1658, 1995. double-blind, placebo-controlled study of modafinil film-coated 173. Haney M, Ward AS, Comer SD, et al. Bupropion SR worsens tablets in children and adolescents with attention-deficit/hyper- mood during marijuana withdrawal in humans. Source Psycho activity disorder. J Am Acad Child Adolesc Psychiatry 45(5):503– pharmacology. 155(2):171-9, 2001 May. Psychopharmacology 511, 2006. 155(2):171–179, 2001. 193. Biederman J, Swanson JM, Wigal SB, et al. Efficacy and safety of 174. Wilens TE, Prince JB, Spencer T, et al. An open trial of bupropion modafinil film-coated tablets in children and adolescents with for the treatment of adults with attention-deficit/hyperactivity attention-deficit/hyperactivity disorder: results of a randomized, disorder and bipolar disorder. Biol Psychiatry 54(1):9–16, 2003. double-blind, placebo-controlled, flexible-dose study. Pediatrics 175. Wilens TE, Prince JB, Waxmonsky J, et al. An open trial of sus- 116(6):e777–e784, 2005. tained release bupropion for attention-deficit/hyperactivity dis- 194. Hellriegel ET, Arora S, Nelson M, et al. Steady-state pharmacoki- order in adults with ADHD plus substance use disorders. netics and tolerability of modafinil given alone or in combina- J ADHD & Related Disord 1(3):25–35, 2010. tion with methylphenidate in healthy volunteers. J Clin Pharmacol 176. Levin FR, Evans SM, McDowell DM, et al. Bupropion treatment 41(8):895–904, 2001. for cocaine abuse and adult attention-deficit/hyperactivity disor- 195. Wong YN, King SP, Simcoe D, et al. Open-label, single-dose der. J Addict Dis 21(2):1–16, 2002. pharmacokinetic study of modafinil tablets: influence of age and 177. Gelenberg AJ, Bassuk EL, Schoonover SC. The practioner’s guide gender in normal subjects. J Clin Pharmacol 39(3):281–288, to psychoactive drugs, ed 3, New York, 1991, Plenum Medical Book 1999. Company. 196. Vorspan F, Warot D, Consoli A, et al. Mania in a boy treated with 178. Spencer T, Biederman J, Steingard R, et al. Bupropion exacer- modafinil for narcolepsy. Am J Psychiatry 162(4):813–814, 2005. bates tics in children with attention-deficit hyperactivity disorder 197. Rezvani AH, Levin ED. Cognitive effects of nicotine. Biol Psychia and Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry try 49(3):258–267, 2001. 32(1):211–214, 1993. 198. Wilens TE, Verlinden MH, Adler LA, et al. ABT-089, A neuronal 179. Biederman J, Baldessarini RJ, Wright V, et al. A double-blind nicotinic receptor partial agonist, for the treatment of attention- placebo controlled study of desipramine in the treatment of deficit/hyperactivity disorder in adults: Results of a pilot study. ADD: I. Efficacy. J Am Acad Child Adolesc Psychiatry 28(5):777– Biol Psychiatry 2006. 784, 1989. 199. Wilens TE, Biederman J, Spencer TJ, et al. A pilot controlled 180. Wilens T, Biederman J, Prince J, et al. Six-week, double blind, clinical trial of ABT-418, a cholinergic agonist, in the treatment placebo-controlled study of desipramine for adult attention of adults with attention deficit hyperactivity disorder. Am J Psy deficit hyperactivity disorder. Am J Psychiatry 153:1147–1153, chiatry 156(12):1931–1937, 1999. 1996. 200. Apostol G, Abi-Saab W, Kratochvil CJ, et al. Efficacy and safety 181. Prince JB, Wilens TE, Biederman J, et al. A controlled study of of the novel alpha(4)beta(2) neuronal nicotinic receptor partial nortriptyline in children and adolescents with attention deficit agonist ABT-089 in adults with attention-deficit/hyperactivity hyperactivity disorder. J Child Adolesc Psychopharmacol 10(3):193– disorder: a randomized, double-blind, placebo-controlled cross- 204, 2000. over study. Psychopharmacology (Berl) 219(3):715–725, 2012. 182. Spencer T, Biederman J, Coffey B, et al. A double-blind compari- 201. Wilens TE, Gault LM, Childress A, et al. Safety and efficacy of son of desipramine and placebo in children and adolescents ABT-089 in pediatric attention-deficit/hyperactivity disorder: with chronic tic disorder and comorbid attention-deficit/hyper- results from two randomized placebo-controlled clinical trials. activity disorder. Arch Gen Psychiatryiatry 59(7):649–656, 2002. J Am Acad Child Adolesc Psychiatry 50(1):73–84 e1, 2011. 183. Gutgesell H, Atkins D, Barst R, et al. AHA scientific statement: 202. Wilens T, Biederman J, Wong J, et al. Donepezil in ADHD: Case Cardiovascular monitoring of children and adolescents receiving series. J Child Adolesc Psychopharmacol 10(3):217–222, 2000. psychotropic drugs. J Am Acad Child Adolesc Psychiatry 38(8):979– 203. Wilens TE, Waxmonsky J, Scott M, et al. An open trial of adjunc- 982, 1999. tive donepezil in attention-deficit/hyperactivity disorder. J Child 184. Riddle MA, Nelson JC, Kleinman CS, et al. Sudden death in Adolesc Psychopharmacol 15(6):947–955, 2005. children receiving Norpramin: a review of three reported cases 204. Biederman J, Mick E, Faraone S, et al. A double-blind compari- and commentary. J Am Acad Child Adolesc Psychiatry 30(1):104– son of galantamine hydrogen bromide and placebo in adults 108, 1991. with attention-deficit/hyperactivity disorder: a pilot study. J Clin 185. Biederman J, Thisted RA, Greenhill L, et al. Estimation of the Psychopharmacol 26(2):163–166, 2006. association between desipramine and the risk for sudden death 205. Surman CB, Hammerness PG, Petty C, et al. A pilot open label in 5- to 14- year old children. J Clin Psychiatry 56(3):87–93, prospective study of memantine monotherapy in adults with 1995. ADHD. World J Biol Psychiatry 14(4):291–298, 2013. 186. Daly J, Wilens T. The use of tricyclic antidepressants in children 206. Manor I, Ben-Hayun R, Aharon-Peretz J, et al. A randomized, and adolescents. In Pediatric Clinics of North America, Philadel- double-blind, placebo-controlled, multicenter study evaluating phia, 1998, WB Saunders Press, pp 1123–1135. the efficacy, safety, and tolerability of extended-release metadox- 187. Lin JS, Gervasoni D, Hou Y, et al. Effects of amphetamine and ine in adults with attention-deficit/hyperactivity disorder. J Clin modafinil on the sleep/wake cycle during experimental hyper- Psychiatry 73(12):1517–1523, 2012. somnia induced by sleep deprivation in the cat. J Sleep Res 207. Mohammadi MR, Ghanizadeh A, Alaghband-Rad J, et al. Sele- 9(1):89–96, 2000. giline in comparison with methylphenidate in attention deficit 188. Lin JS, Hou Y, Jouvet M. Potential brain neuronal targets for hyperactivity disorder children and adolescents in a double- amphetamine-, methylphenidate-, and modafinil-induced blind, randomized clinical trial. J Child Adolesc Psychopharmacol wakefulness, evidenced by c-focs immunocytochemistry in the 14(3):418–425, 2004. cat. Proc Natl Acad Sci U S A 93:14128–14133, 1996. 208. Akhondzadeh S, Tavakolian R, Davari-Ashtiani R, et al. Sele- 189. Taylor FB, editor: Comparing modafinil to dextroamphetamine in the giline in the treatment of attention deficit hyperactivity disorder treatment of adult ADHD. 153rd Annual Meeting of the American in children: a double blind and randomized trial. Prog Neuropsy Psychiatric Association. Chicago, 2000. chopharmacol Biol Psychiatry 27(5):841–845, 2003. 190. Arnold VK, Feifel D, Earl CQ, et al. A 9-Week, Randomized, 209. Ernst M, Liebenauer L, Jons P, et al. Selegiline in adults with double-blind, placebo-controlled, parallel-group, dose-finding attention deficit hyperactivity disorder: Clinical efficacy and study to evaluate the efficacy and safety of modafinil as safety. Psychopharmacol Bull 32:327–334, 1996.

210. Feigin A, Kurlan R, McDermott MP, et al. A controlled trial 231. Tannock R, Ickowicz A, Schachar R. Differential effects of methyl of deprenyl in children with Tourette’s syndrome and atten phenidate on working memory in ADHD children with and tion deficit hyperactivity disorder. Neurology 46(4):965–968, without comorbid anxiety. J Am Acad Child Adolesc Psychiatry 1996. 34(7):886–896, 1995. 211. Jankovic J. Deprenyl in attention deficit associated with Tourette’s 232. DuPaul GJ, Barkley RA, McMurray MB. Response of children with syndrome. Arch Neurol 50(March 1993):286–288, 1993. ADHD to methylphenidate: Interaction with internalizing symp- 212. Transdermal selegiline (Emsam). Med Lett Drugs Ther 48(1235): toms. J Am Acad Child Adolesc Psychiatry 33(6):894–903, 1994. 41–42, 2006. 233. Diamond I, Tannock R, Schachar R. Response to methylpheni- 213. Rey JM, Sawyer MG, Prior MR. Similarities and differences date in children with ADHD and comorbid anxiety. J Am Acad between aggressive and delinquent children and adolescents in Child Adolesc Psychiatry 38(4):402–409, 1999. a national sample. Aust N Z J Psychiatry 39(5):366–372, 2005. 234. Gadow KD, Nolan EE, Sverd J, et al. Anxiety and depression 214. Burke JD, Loeber R, Birmaher B. Oppositional defiant disorder symptoms and response to methylphenidate in children with and conduct disorder: a review of the past 10 years, part II. J Am attention-deficit hyperactivity disorder and tic disorder. J Clin Acad Child Adolesc Psychiatry 41(11):1275–1293, 2002. Psychopharmacol 22(3):267–274, 2002. 215. Pappadopulos E, Macintyre Ii JC, Crismon ML, et al. Treatment 235. Abikoff H, McGough J, Vitiello B, et al. Sequential pharmaco- recommendations for the use of antipsychotics for aggressive therapy for children with comorbid attention-deficit/hyperactiv- youth (TRAAY). Part II. J Am Acad Child Adolesc Psychiatry ity and anxiety disorders. J Am Acad Child Adolesc Psychiatry 42(2):145–161, 2003. 44(5):418–427, 2005. 216. Schur SB, Sikich L, Findling RL, et al. Treatment recommenda- 236. Kratochvil CJ, Newcorn JH, Arnold LE, et al. Atomoxetine alone tions for the use of antipsychotics for aggressive youth (TRAAY). or combined with fluoxetine for treating ADHD with comorbid Part I: a review. J Am Acad Child Adolesc Psychiatry 42(2):132– depressive or anxiety symptoms. J Am Acad Child Adolesc Psychia 144, 2003. try 44(9):915–924, 2005. 217. Connor DF, Carlson GA, Chang KD, et al. Juvenile maladaptive 237. Geller DA, Biederman J, Faraone S, et al. Re-examining comor- aggression: a review of prevention, treatment, and service con- bidity of Obsessive Compulsive and Attention-Deficit Hyperac- figuration and a proposed research agenda. J Clin Psychiatry tivity Disorder using an empirically derived taxonomy. Eur Child 67(5):808–820, 2006. Adolesc Psychiatry 13(2):83–91, 2004. [Epub 2004/04/23]. 218. Steiner H, Karnik NS. Integrated treatment of aggression in the 238. Geller DA, Biederman J, Faraone S, et al. Developmental aspects context of ADHD in children refractory to stimulant mono- of obsessive compulsive disorder: findings in children, adoles- therapy: a window into the future of child psychopharmacology. cents, and adults. J Nerv Ment Dis 189(7):471–477, 2001. Am J Psychiatry 166(12):1315–1317, 2009. 239. Geller D, Biederman J, Faraone SV, et al. Clinical correlates of 219. Pliszka SR, Crismon ML, Hughes CW, et al. The Texas Children’s obsessive compulsive disorder in children and adolescents Medication Algorithm Project: revision of the algorithm for referred to specialized and non-specialized clinical settings. pharmacotherapy of attention-deficit/hyperactivity disorder. Depress Anxiety 11(4):163–168, 2000. J Am Acad Child Adolesc Psychiatry 45(6):642–657, 2006. 240. Pediatric OCD Treatment Study (POTS) Team. Cognitive- 220. Jensen PS, Hinshaw SP, Kraemer HC, et al. ADHD comorbidity behavior therapy, sertraline, and their combination for children findings from the MTA study: comparing comorbid subgroups. and adolescents with obsessive-compulsive disorder: the Pediat- J Am Acad Child Adolesc Psychiatry 40(2):147–158, 2001. ric OCD Treatment Study (POTS) randomized controlled trial. 221. Newcorn JH, Spencer TJ, Biederman J, et al. Atomoxetine treat- JAMA 292(16):1969–1976, 2004. ment in children and adolescents with attention-deficit/hyper- 241. Group TTsSS. Treatment of ADHD in children with tics: A ran- activity disorder and comorbid oppositional defiant disorder. domized controlled trial. Neurology 58(4):527–536, 2002. J Am Acad Child Adolesc Psychiatry 44(3):240–248, 2005. 242. Gadow K, Sverd J, Sprafkin J, et al. Long-term methylphenidate 222. Spencer TJ, Abikoff HB, Connor DF, et al. Efficacy and safety of therapy in children with comorbid attention-deficit hyperactivity mixed amphetamine salts extended release (adderall XR) in the disorder and chronic multiple tic disorder. Arch Gen Psychiatryia management of oppositional defiant disorder with or without try 56(4):330–336, 1999. comorbid attention-deficit/hyperactivity disorder in school-aged 243. Kurlan R, McDermott MP, Deeley C, et al. Prevalence of tics in children and adolescents: A 4-week, multicenter, randomized, schoolchildren and association with placement in special educa- double-blind, parallel-group, placebo-controlled, forced-dose- tion. Neurology 57(8):1383–1388, 2001. escalation study. Clin Ther 28(3):402–418, 2006. 244. Gadow KD, Nolan EE, Sprafkin J, et al. Tics and psychiatric 223. Biederman J, Spencer TJ, Newcorn JH, et al. Effect of comorbid comorbidity in children and adolescents. Dev Med Child Neurol symptoms of oppositional defiant disorder on responses to 44(5):330–338, 2002. atomoxetine in children with ADHD: a meta-analysis of control- 245. Peterson BS, Pine DS, Cohen P, et al. Prospective, longitudinal led clinical trial data. Psychopharmacology (Berl) 190(1):31–41, study of tic, obsessive-compulsive, and attention-deficit/hyper- 2007. activity disorders in an epidemiological sample. J Am Acad Child 224. Loy JH, Merry SN, Hetrick SE, et al. Atypical antipsychotics for Adolesc Psychiatry 40(6):685–695, 2001. disruptive behaviour disorders in children and youths. Cochrane 246. Castellanos FX, Giedd JN, Elia J, et al. Controlled stimulant Database Syst Rev (9):CD008559, 2012. treatment of ADHD and comorbid tourette’s syndrome: Effects 225. Linton D, Barr AM, Honer WG, et al. Antipsychotic and psycho- of stimulant and dose. J Am Acad Child Adolesc Psychiatry 36(5): stimulant drug combination therapy in attention deficit/ 1–8, 1997. hyperactivity and disruptive behavior disorders: a systematic 247. Kurlan R. Methylphenidate to treat ADHD is not contraindicated review of efficacy and tolerability. Curr Psychiatry Rep 15(5):355, in children with tics. Mov Disord 17(1):5–6, 2002. 2013. 248. Palumbo D, Spencer T, Lynch J, et al. Emergence of tics in 226. Olfson M, Blanco C, Liu L, et al. National trends in the outpa- children with ADHD: impact of once-daily OROS methylpheni- tient treatment of children and adolescents with antipsychotic date therapy. J Child Adolesc Psychopharmacol 14(2):185–194, drugs. Arch Gen Psychiatryiatry 63(6):679–685, 2006. 2004. 227. Olfson M, Marcus SC, Corey-Lisle P, et al. Hyperlipidemia fol- 249. Allen AJ, Kurlan RM, Gilbert DL, et al. Atomoxetine treatment lowing treatment with antipsychotic medications. Am J Psychiatry in children and adolescents with ADHD and comorbid tic dis- 163(10):1821–1825, 2006. orders. Neurology 65(12):1941–1949, 2005. 228. Consensus development conference on antipsychotic drugs and 250. Daviss WB. A review of co-morbid depression in pediatric obesity and diabetes. Diabetes Care 27(2):596–601, 2004. ADHD: etiology, phenomenology, and treatment. J Child Adolesc 229. Biederman J, Faraone SV, Keenan K, et al. Familial association Psychopharmacol 18(6):565–571, 2008. between attention deficit disorder and anxiety disorders. Am J 251. McIntyre RS, Kennedy SH, Soczynska JK, et al. Attention-deficit/ Psychiatry 148(2):251–256, 1991. hyperactivity disorder in adults with bipolar disorder or major 230. Urman R, Ickowicz A, Fulford P, et al. An exaggerated cardiovas- depressive disorder: results from the international mood disor- cular response to methylphenidate in ADHD children with ders collaborative project. Prim Care Companion J Clin Psychiatry anxiety. J Child Adolesc Psychopharmacol 5:29–37, 1995. 12(3):2010.

252. Milberger S, Biederman J, Faraone S, et al. Attention deficit 274. Kowatch RA, Youngstrom EA, Horwitz S, et al. Prescription of hyperactivity disorder and comorbid disorders: Issues of overlap- psychiatric medications and polypharmacy in the LAMS cohort. 49 ping symptoms. Am J Psychiatry 152(12):1793–1799, 1995. Psychiatr Serv 64(10):1026–1034, 2013. 253. Biederman J, Faraone S, Mick E, et al. Psychiatric comorbidity 275. Liu HY, Potter MP, Woodworth KY, et al. Pharmacologic treat- among referred juveniles with major depression: fact or artifact? ments for pediatric bipolar disorder: a review and meta-analysis. J Am Acad Child Adolesc Psychiatry 34(5):579–590, 1995. [Epub J Am Acad Child Adolesc Psychiatry 50(8):749–762, e39, 2011. 1995/05/01]. 276. Scheffer RE, Kowatch RA, Carmody T, et al. Randomized, 254. Bostic JQ, Rubin DH, Prince J, et al. Treatment of depression in placebo-controlled trial of mixed amphetamine salts for symp- children and adolescents. J Psychiatr Pract 11(3):141–154, 2005. toms of comorbid ADHD in pediatric bipolar disorder after 255. Dilsaver SC, Henderson-Fuller S, Akiskal HS. Occult mood dis- mood stabilization with divalproex sodium. Am J Psychiatry orders in 104 consecutively presenting children referred for the 162(1):58–64, 2005. treatment of attention-deficit/hyperactivity disorder in a com- 277. McIntyre RS, Alsuwaidan M, Soczynska JK, et al. The effect of munity mental health clinic. J Clin Psychiatry 64(10):1170–1176, lisdexamfetamine dimesylate on body weight, metabolic param- quiz 274–6, 2003. eters, and attention deficit hyperactivity disorder symptomatol- 256. Wilens TE, Biederman J, Wozniak J, et al. Can adults with ogy in adults with bipolar I/II disorder. Hum Psychopharmacol attention-deficit/hyperactivity disorder be distinguished from 28(5):421–427, 2013. those with comorbid bipolar disorder? Findings from a sample 278. Hah M, Chang K. Atomoxetine for the treatment of attention- of clinically referred adults. Biol Psychiatry 54(1):1–8, 2003. deficit/hyperactivity disorder in children and adolescents with 257. Duffy A. The nature of the association between childhood bipolar disorders. J Child Adolesc Psychopharmacol 15(6):996– ADHD and the development of bipolar disorder: a review of 1004, 2005. prospective high-risk studies. Am J Psychiatry 169(12):1247– 279. Jaworowski S, Benarroch F, Gross-Tsur V. Concomitant use of 1255, 2012. atomoxetine and OROS-methylphenidate in a 10-year-old child 258. Biederman J, Faraone SV, Wozniak J, et al. Clinical correlates of suffering from attention-deficit/hyperactivity disorder with bipolar disorder in a large, referred sample of children and ado- comorbid bipolar disorder and Tourette syndrome. J Child lescents. J Psychiatr Res 39(6):611–622, 2005. Adolesc Psychopharmacol 16(3):365–370, 2006. 259. Kowatch RA, Youngstrom EA, Danielyan A, et al. Review and 280. Henderson TA. Mania induction associated with atomoxetine. meta-analysis of the phenomenology and clinical characteristics J Clin Psychopharmacol 24(5):567–568, 2004. of mania in children and adolescents. Bipolar Disord 7(6):483– 281. Henderson TA, Hartman K. Aggression, mania, and hypomania 496, 2005. induction associated with atomoxetine. Pediatrics 114(3):895– 260. Geller B, Tillman R, Craney JL, et al. Four-year prospective 896, 2004. outcome and natural history of mania in children with a prepu- 282. Steinberg S, Chouinard G. A case of mania associated with bertal and early adolescent bipolar disorder phenotype. Arch Gen tomoxetine. Am J Psychiatry 142(12):1517–1518, 1985. Psychiatryiatry 61(5):459–467, 2004. 283. Reichart CG, Nolen WA. Earlier onset of bipolar disorder in 261. Wozniak J, Biederman J, Kwon A, et al. How cardinal are cardinal children by antidepressants or stimulants? An hypothesis. J Affect symptoms in pediatric bipolar disorder? An examination of Disord 78(1):81–84, 2004. clinical correlates. Biol Psychiatry 58(7):583–588, 2005. 284. Faedda GL, Baldessarini RJ, Glovinsky IP, et al. Treatment- 262. Birmaher B, Axelson D, Goldstein B, et al. Four-year longitudinal emergent mania in pediatric bipolar disorder: a retrospective course of children and adolescents with bipolar spectrum disor- case review. J Affect Disord 82(1):149–158, 2004. ders: the Course and Outcome of Bipolar Youth (COBY) study. 285. Carlson GA, Loney J, Salisbury H, et al. Stimulant treatment in Am J Psychiatry 166(7):795–804, 2009. young boys with symptoms suggesting childhood mania: a 263. Mick E, Spencer T, Wozniak J, et al. Heterogeneity of irritability report from a longitudinal study. J Child Adolesc Psychopharmacol in attention-deficit/hyperactivity disorder subjects with and 10(3):175–184, 2000. without mood disorders. Biol Psychiatry 58(7):576–582, 2005. 286. Galanter CA, Carlson GA, Jensen PS, et al. Response to methyl- 264. Diagnostic and statistical manual of mental disorders, ed 5, phenidate in children with attention deficit hyperactivity Washington, DC, 2013, American Psychiatric Press. disorder and manic symptoms in the multimodal treatment 265. Copeland WE, Angold A, Costello EJ, et al. Prevalence, comor- study of children with attention deficit hyperactivity disorder bidity, and correlates of DSM-5 proposed disruptive mood dys- titration trial. J Child Adolesc Psychopharmacol 13(2):123–136, regulation disorder. Am J Psychiatry 170(2):173–179, 2013. 2003. 266. Axelson D, Findling RL, Fristad MA, et al. Examining the pro- 287. Biederman J, Mick E, Prince J, et al. Systematic chart review of posed disruptive mood dysregulation disorder diagnosis in chil- the pharmacologic treatment of comorbid attention deficit dren in the Longitudinal Assessment of Manic Symptoms study. hyperactivity disorder in youth with bipolar disorder. J Child J Clin Psychiatry 73(10):1342–1350, 2012. Adolesc Psychopharmacol 9(4):247–256, 1999. 267. Arnold LE, Mount K, Frazier T, et al. Pediatric bipolar disorder 288. Wilens TE, Biederman J, Mick E, et al. Attention deficit hyperac- and ADHD: family history comparison in the LAMS clinical tivity disorder (ADHD) is associated with early onset substance sample. J Affect Disord 141(2–3):382–389, 2012. use disorders. J Nerv Ment Dis 185(8):475–482, 1997. 268. Barkley RA. Differential diagnosis of adults with ADHD: the 289. Wilens TE, Martelon M, Joshi G, et al. Does ADHD predict role of executive function and self-regulation. J Clin Psychiatry substance-use disorders? A 10-year follow-up study of young 71(7):e17, 2010. adults with ADHD. J Am Acad Child Adolesc Psychiatry 50(6):543– 269. Biederman J, Mick E, Faraone SV, et al. A prospective follow-up 553, 2011. study of pediatric bipolar disorder in boys with attention-deficit/ 290. Milberger S, Biederman J, Faraone S, et al. ADHD is associated hyperactivity disorder. J Affect Disord 82(Suppl. 1):S17–S23, with early initiation of cigarette smoking in children and 2004. adolescents. J Am Acad Child Adolesc Psychiatry 36:37–43, 270. Nierenberg AA, Miyahara S, Spencer T, et al. Clinical and diag- 1997. nostic implications of lifetime attention-deficit/hyperactivity 291. Pomerleau CS, Downey KK, Snedecor SM, et al. Smoking pat- disorder comorbidity in adults with bipolar disorder: data from terns and abstinence effects in smokers with no ADHD, child- the first 1000 STEP-BD participants. Biol Psychiatry 57(11):1467– hood ADHD, and adult ADHD symptomatology. Addict Behav 1473, 2005. 28(6):1149–1157, 2003. 271. Simon NM, Otto MW, Weiss RD, et al. Pharmacotherapy for 292. Pomerleau O, Downey K, Stelson F, et al. Cigarette smoking in bipolar disorder and comorbid conditions: baseline data from adult patients diagnosed with attention deficit hyperactivity dis- STEP-BD. J Clin Psychopharmacol 24(5):512–520, 2004. order. J Subst Abuse 7:373–378, 1995. 272. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines 293. Wilens TE. Impact of ADHD and its treatment on substance for children and adolescents with bipolar disorder. J Am Acad abuse in adults. J Clin Psychiatry 65(Suppl. 3):38–45, 2004. Child Adolesc Psychiatry 44(3):213–235, 2005. 294. Wilens TE, Vitulano M, Upadhyaya H, et al. Cigarette smoking 273. Practice guideline for the treatment of patients with bipolar associated with attention deficit hyperactivity disorder. J Pediatr disorder (revision). Am J Psychiatry 159(4 Suppl.):1–50, 2002. 153(3):414–419, 2008.

295. Biederman J, Faraone SV, Spencer TJ, et al. Gender differences in 310. Johnston K, Dittner A, Bramham J, et al. Attention deficit hyper- a sample of adults with attention deficit hyperactivity disorder. activity disorder symptoms in adults with autism spectrum dis- Psychiatric Res 53:13–29, 1994. orders. Autism 6(4):225–236, 2013. 296. Wilens T, Faraone S, Biederman J, et al. Does stimulant therapy 311. Rommelse NN, Franke B, Geurts HM, et al. Shared heritability of attention-deficit/hyperactivity disorder beget later substance of attention-deficit/hyperactivity disorder and autism spectrum abuse? A meta-analytic review of the literature. Pediatrics disorder. Eur Child Adolesc Psychiatry 19(3):281–295, 2010. 111(1):179–185, 2003. 312. Handen B, Feldman H, Lurier A, et al. Efficacy of methylpheni- 297. Biederman J, Monuteaux MC, Spencer T, et al. Stimulant therapy date among preschool children with develpomental disabilities and risk for subsequent substance use disorders in male adults and ADHD. J Am Acad Child Adolesc Psychiatry 38(7):805–812, with ADHD: a naturalistic controlled 10-year follow-up study. 1999. Am J Psychiatry 165(5):597–603, 2008. 313. Quintana H, Birmaher B, Stedge D, et al. Use of methylpheni- 298. Katusic SK, Barbaresi WJ, Colligan RC, et al. Psychostimulant date in the treatment of children with autistic disorder. J Autism treatment and risk for substance abuse among young adults with Dev Disord, 25(3):283–294, 1995. a history of attention-deficit/hyperactivity disorder: a population- 314. Research Units on Pediatric Psychopharmacology Autism based, birth cohort study. J Child Adolesc Psychopharmacol 15(5): Network. Randomized, controlled, crossover trial of methylphe- 764–776, 2005. nidate in pervasive developmental disorders with hyperactivity. 299. Barkley RA, Fischer M, Smallish L, et al. Does the treatment of Arch Gen Psychiatryiatry 62(11):1266–1274, 2005. attention-deficit/hyperactivity disorder with stimulants contrib- 315. Pearson DA, Santos CW, Aman MG, et al. Effects of extended ute to drug use/abuse? A 13-year prospective study. Pediatrics release methylphenidate treatment on ratings of attention- 111(1):97–109, 2003. deficit/hyperactivity disorder (ADHD) and associated behavior 300. Wilens TE, Biederman J. Alcohol, drugs, and attention-deficit/ in children with autism spectrum disorders and ADHD symp- hyperactivity disorder: a model for the study of addictions in toms. J Child Adolesc Psychopharmacol 23(5):337–351, 2013. youth. J Psychopharmacol 20(4):580–588, 2006. 316. Jou RJ, Handen BL, Hardan AY. Retrospective assessment of 301. Wilens TE, Morrison NR. Substance-use disorders in adolescents atomoxetine in children and adolescents with pervasive and adults with ADHD: focus on treatment. Neuropsychiatry developmental disorders. J Child Adolesc Psychopharmacol 15(2): 2(4):301–312, 2012. 325–330, 2005. 302. McCabe SE, Knight JR, Teter CJ, et al. Non-medical use of pre- 317. van der Meer JM, Harfterkamp M, van de Loo-Neus G, et al. A scription stimulants among US college students: prevalence and randomized, double-blind comparison of atomoxetine and correlates from a national survey. Addiction 100(1):96–106, placebo on response inhibition and interference control in chil- 2005. dren and adolescents with autism spectrum disorder and comor- 303. McCabe SE, Teter CJ, Boyd CJ. The use, misuse and diversion of bid attention-deficit/hyperactivity disorder symptoms. J Clin prescription stimulants among middle and high school students. Psychopharmacol 33(6):824–827, 2013. Subst Use Misuse 39(7):1095–1116, 2004. 318. Benvenuto A, Battan B, Porfirio MC, et al. Pharmacotherapy of 304. Upadhyaya HP, Rose K, Wang W, et al. Attention-deficit/hyper- autism spectrum disorders. Brain Dev 35(2):119–127, 2013. activity disorder, medication treatment, and substance use pat- 319. Siegel M. Psychopharmacology of autism spectrum disorder: terns among adolescents and young adults. J Child Adolesc evidence and practice. Child Adolesc Psychiatr Clin N Am Psychopharmacol 15(5):799–809, 2005. 21(4):957–973, 2012. 305. Volkow ND, Wang GJ, Ma Y, et al. Expectation enhances the 320. Kaplan G, McCracken JT. Psychopharmacology of autism spec- regional brain metabolic and the reinforcing effects of stimu- trum disorders. Pediatr Clin North Am 59(1):175–187, xii, 2012. lants in cocaine abusers. J Neurosci 23(36):11461–11468, 2003. 321. Schubert R. Attention deficit disorder and epilepsy. Pediatr Neurol 306. Swanson JM, Volkow ND. Serum and brain concentrations of 32(1):1–10, 2005. methylphenidate: implications for use and abuse. Neurosci Biobe 322. Tan M, Appleton R. Attention deficit and hyperactivity disorder, hav Rev 27(7):615–621, 2003. methylphenidate, and epilepsy. Arch Dis Child 90(1):57–59, 307. Fein D, Dixon P, Paul J, et al. Brief report: pervasive developmen- 2005. tal disorder can evolve into ADHD: case illustrations. J Autism 323. Fosi T, Lax-Pericall MT, Scott RC, et al. Methylphenidate treat- Dev Disord 35(4):525–534, 2005. ment of attention deficit hyperactivity disorder in young people 308. Kotte A, Joshi G, Fried R, et al. Autistic traits in children with with learning disability and difficult-to-treat epilepsy: Evidence and without ADHD. Pediatrics 132(3):e612–e622, 2013. of clinical benefit. Epilepsia 54(12):2071–2081, 2013. 309. Goldstein S, Schwebach AJ. The comorbidity of Pervasive Devel- 324. Santos K, Palmini A, Radziuk AL, et al. The impact of methyl- opmental Disorder and Attention Deficit Hyperactivity Disorder: phenidate on seizure frequency and severity in children with results of a retrospective chart review. J Autism Dev Disord attention-deficit-hyperactivity disorder and difficult-to-treat epi- 34(3):329–339, 2004. lepsies. Dev Med Child Neurol 655(7):654–660, 2013.

MULTIPLE CHOICE QUESTIONS multiple domains, as well as co-morbid psychiatric and/or learning disorders. 49 Select the appropriate answer. Several types of studies inform us about ADHD and co-mor- Q1 Which of the following disorders is LEAST likely to be bid psychiatric disorders, including cross-sectional clinical and co-morbid with attention-deficit/hyperactivity disorder? epidemiological studies of ADHD in children and adults; family-genetic studies (which study the distribution of psychi- ○ Conduct disorder atric disorders in adoptive and biological families of ADHD ○ Major depression children and adults); prospective longitudinal follow-up studies (that observe the development of ADHD in patients ○ Obsessive-compulsive disorder from childhood through adolescence and into adulthood); ○ Oppositional defiant disorder and studies of referred ADHD adults. These studies demonstrate that ADHD is frequently co-morbid with oppositional ○ Schizophrenia defiant disorder (ODD), conduct disorder (CD), multiple anxiety disorders (panic disorder, obsessive-compulsive disorder [OCD], tic disorders), mood disorders (e.g., depression, Q2 Stimulants are thought to be effective in ADHD because dysthymia, and bipolar disorder [BPD]), learning disorders of their ability to increase intrasynaptic concentrations (e.g., auditory processing problems, and dyslexia), and sub- of norepinephrine (NE) and what other stance use disorders (SUDs). These studies demonstrate that neurotransmitter? ADHD is not a feature of, or a precursor to, these co-morbid conditions and that these co-morbid disorders are not the ○ Acetylcholine result of methodological artifacts. Moreover, some of these ○ Cholecystokinin co-morbid disorders segregate independently of ADHD (e.g., CD, BPD, and anxiety disorders), while others co-segregate ○ Dopamine within families (e.g., depression). ○ Glutamate Q2 The answer is: Dopamine. ○ Serotonin Stimulants increase intrasynaptic concentrations of dopamine Q3 Which of the following agents for the treatment of (DA) and norepinephrine (NE). Methylphenidate (MPH) pri- ADHD was removed from the market in 2005? marily binds to the dopamine transporter protein (DAT), blocking the reuptake of DA, increasing intrasynaptic DA from ○ Atomoxetine reserpine insensitive DA pools. While amphetamines diminish presynaptic reuptake of DA by binding to DAT, these com- ○ Clonidine pounds also travel into the DA neuron, cause release of DA ○ Dextroamphetamine from vesicles into the cytoplasm, prevent re-packaging of DA from the cytoplasm into the vesicles and promoting release of ○ Methylphenidate DA from reserpine-sensitive vesicles in the presynaptic neuron. ○ Pemoline In addition, stimulants (amphetamine more than MPH) increase levels of NE and serotonin (5-HT) in the interneuro- Q4 True or False. Stimulants may have a mild negative nal, space although compared to their effects on DA these impact on growth velocity in youths with ADHD. effects are relatively minor. Although group studies comparing MPH and amphetamines generally demonstrate similar effi- ○ True cacy, their pharmacodynamic differences may explain why a ○ False particular patient may respond to, or tolerate, one stimulant preferentially over another. It is necessary to appreciate that Q5 True or False. Stimulant treatment results in nearly while the efficacy of amphetamine and MPH is similar, their a two-fold reduction in the risk for substance abuse potency differs, such that 5 mg of amphetamine is approxi- among youths treated with a stimulant for ADHD, as mately equivalent to 10 mg of MPH. compared to youths receiving no pharmacotherapy for their ADHD. Q3 The answer is: Pemoline. ○ True Pemoline (Cylert) is a central nervous system (CNS) stimulant that is structurally different from both methylphenidate ○ False (MPH) and amphetamine and that seems to enhance central dopaminergic transmission. Although a variety of studies have demonstrated pemoline’s efficacy, the overall risk of liver toxicity appears to be 10 to 25 times the background risk; there- MULTIPLE CHOICE ANSWERS fore the Food and Drug Administration (FDA) concluded that the risks of this medication outweighed the benefits and Q1 The answer is: Schizophrenia. pemoline was removed from the market in the United States Attention-deficit/hyperactivity disorder (ADHD) is a common on October 24, 2005 (www.fda.gov/cder/drug/InfoSheets/ psychiatric condition shown to occur in 3% to 10% of school- HCP/pemolineHCP.htm). Although pemoline will remain age children worldwide and in up to 4% of adults. The classic available from pharmacies and wholesalers until supplies are triad of impaired attention, impulsivity, and excessive motor exhausted, clinicians are advised to transition patients to alter- activity characterizes ADHD, although many patients may native treatments. manifest only inattentive symptoms. ADHD usually persists, Q4 The answer is: True. to a significant degree, from childhood through adolescence and into adulthood. Most children, adolescents, and adults The impact of stimulant treatment on growth remains a with ADHD suffer significant functional impairment(s) in concern, and the data are conflicting. For instance, ADHD