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

Key Points

Attention-deficit/hyperactivity disorder (ADHD) is a common disorder in children, adolescents, and adults.
While the phenotype of ADHD changes across the life span, ADHD persists in many children, adolescents, and adults.
Formulations of stimulant and non-stimulant medications are Food and Drug Administration-approved as pharmacological treatments for ADHD in children, adolescents, and adults.
Co-morbid psychiatric and learning disorders are common in patients with ADHD across the life span.
When treating ADHD and co-morbid disorders, clinicians must prioritize and treat the most severe condition first, and regularly re-assess the symptoms of ADHD and the co-morbid disorder.

Overview

Attention-deficit/hyperactivity disorder (ADHD) is a common 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. The classic triad of impaired attention, impulsivity, and excessive motor activity characterizes ADHD, although many patients may manifest only inattentive symptoms. ADHD usually persists, to a significant degree, from childhood through adolescence and into adulthood. Most children, adolescents, and adults with ADHD suffer significant functional impairment(s) in multiple domains, as well as co-morbid psychiatric or learning disorders.

Studies demonstrate that ADHD is frequently co-morbid with oppositional defiant disorder (ODD), conduct disorder (CD), multiple anxiety disorders (panic disorder, obsessive-compulsive disorder [OCD], tic disorders), mood disorders (e.g., depression, dysthymia, and bipolar disorder [BPD]), learning disorders (e.g., auditory processing problems and dyslexia), and substance use disorders (SUDs) and often complicates the development of patients with autism spectrum disorders (ASDs). Co-morbid psychiatric, learning, and developmental disorders need to be assessed in all patients with ADHD and the relationship of these symptoms with ADHD delineated.

Before using medications, clinicians should complete a through clinical evaluation that includes a complete history of symptoms, a differential diagnosis, a review of prior assessments/treatments, a medical history, and a description of current physical symptoms (including questions about the physical history, including either a personal or family history of cardiovascular symptoms or problems). Before treatment with medications, it is usually important to measure baseline levels of height, weight, blood pressure, and pulse and to monitor them over the course of treatment (see http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm165858.htm for the most recent recommendations by the Food and Drug Administration [FDA] about monitoring for children and http://www.fda.gov/drugs/drugsafety/ucm279858.htm for the most recent recommendations about monitoring for adults). Clinicians and patients/families should select an initial treatment, either a stimulant or a non-stimulant; decide on a target dose (either absolute or weight-based) titration schedule; and decide how to monitor tolerability and response to treatment (using rating scales, anchor points, or both). Patients should be educated about the importance of adherence, safely maintaining medications (e.g., as in college students), and additional types of treatment (e.g., coaching and organizational help) that may be helpful.

Stimulants

For over 60 years stimulants have been used safely and effectively in the treatment of ADHD and they are among the most well-established treatments in psychiatry. The stimulants most commonly used include methylphenidate (MPH), a mixture of amphetamine salts (MAS) and dextroamphetamine (DEX). The recent development of various novel delivery systems has significantly advanced the pharmacotherapy of ADHD (see Table 49-1 for a list of these medications).

TABLE 49-1

Available FDA-approved Treatments for Attention-Deficit/Hyperactivity Disorder

Generic Name (Brand Name)	Formulation and Mechanism	Duration of Activity	How Supplied	Usual Absolute and (Weight-based) Dosing Range	FDA-approved Maximum Dose for ADHD
MPH (Ritalin) *	Tablet of 50 : 50 racemic mixture d,l-threo-MPH	3–4 hours	5, 10, and 20 mg tablets	(0.3–2 mg/kg/day)	60 mg/day
Dex-MPH (Focalin) *	Tablet of d-threo-MPH	3–5 hours	2.5, 5, and 10 mg tablets (2.5 mg Focalin equivalent to 5 mg Ritalin)	(0.15–1 mg/kg/day)	20 mg/day
MPH (Methylin) *	Tablet of 50 : 50 racemic mixture d,l-threo-MPH	3–4 hours	5, 10, and 20 mg tablets	(0.3–2 mg/kg/day)	60 mg/day
MPH-SR (Ritalin-SR) *	Wax-based matrix tablet of 50 : 50 racemic mixture d,l-threo-MPH	3–8 hours Variable	20 mg tablets (amount absorbed appears to vary)	(0.3–2 mg/kg/day)	60 mg/day
MPH (Metadate ER) *	Wax-based matrix tablet of 50 : 50 racemic mixture d,l-threo-MPH	3–8 hours Variable	10 and 20 mg tablets (amount absorbed appears to vary)	(0.3–2 mg/kg/day)	60 mg/day
MPH (Methylin ER) *	Hydroxypropyl methylcellulose base tablet of 50 : 50 racemic mixture d,l-threo-MPH; no preservatives	8 hours	10 and 20 mg tablets	(0.3–2 mg/kg/day)	60 mg/day
			2.5, 5, and 10 mg chewable tablets
			5 mg/5 ml and 10 mg/5 ml oral solution
MPH (Ritalin LA) *	Two types of beads give bimodal delivery (50% immediate-release and 50% delayed-release) of 50 : 50 racemic mixture d,l-threo-MPH	8 hours	20, 30, and 40 mg capsules; can be sprinkled	(0.3–2 mg/kg/day)	60 mg/day
D-MPH (Focalin XR)	Two types of beads give bimodal delivery (50% immediate-release and 50% delayed-release) of d-threo-MPH	12 hours	5, 10, 15, 20, 25, 30, 35, and 40 mg capsules	0.15–1 mg/kg/day	30 mg/day in youth; 40 mg/day in adults
MPH (Metadate CD) *	Two types of beads give bimodal delivery (30% immediate-release and 70% delayed-release) of 50 : 50 racemic mixture d,l-threo-MPH	8 hours	20 mg capsule; can be sprinkled	(0.3–2 mg/kg/day)	60 mg/day
MPH (Daytrana) *	MPH transdermal system	12 hours (patch worn for 9 hours)	10, 15, 20, and 30 mg patches	0.3–2 mg/kg/day	30 mg/day
MPH (Concerta) *	Osmotic pressure system delivers 50 : 50 racemic mixture d,l-threo-MPH	12 hours	18, 27, 36, and 54 mg caplets	(0.3–2 mg/kg/day)	72 mg/day
MPH (Quillivant XR)	Extended-release liquid	12 hours	25 mg/5 ml	(0.3–2 mg/kg/day)	60 mg/day
AMPH † (Dexedrine Tablets)	d-AMPH tablet	4–5 hours	5 mg tablets	(0.15–1 mg/kg/day)	40 mg/day
AMPH † (Dextrostat)	d-AMPH tablet	4–5 hours	5 and 10 mg tablets	(0.15–1 mg/kg/day)	40 mg/day
AMPH † (Dexedrine Spansules)	Two types of beads in a 50 : 50 mixture short and delayed-absorption of d-AMPH	8 hours	5, 10, and 15 mg capsules	(0.15–1 mg/kg/day)	40 mg/day
Mixed salts of AMPH † (Adderall)	Tablet of d,l-AMPH isomers (75% d-AMPH and 25% l-AMPH)	4–6 hours	5, 7.5, 10, 12.5, 15, 20, and 30 mg tablets	(0.15–1 mg/kg/day)	40 mg/day
Mixed salts of AMPH * ‡ (Adderall-XR)	Two types of beads give bimodal delivery (50% immediate-release and 50% delayed-release) of 75 : 25 racemic mixture d,l-AMPH	At least 8 hours (but appears to last much longer in certain patients)	5, 10, 15, 20, 25, and 30 mg capsules; can be sprinkled	(0.15–1 mg/kg/day)	30 mg/day in children
Mixed salts of AMPH * ‡ (Adderall-XR)			5, 10, 15, 20, 25, and 30 mg capsules; can be sprinkled	(0.15–1 mg/kg/day)	Recommended dose is 20 mg/day in adults
Lisdexamfetamine (Vyvanase) *	Tablets of dextroamphetamine and L-lysine	12 hours	30, 50, and 70 mg tablets		70 mg/day
Atomoxetine * ‡ (Strattera)	Capsule of atomoxetine	5 hour plasma half-life but CNS effects appear to last much longer	10, 18, 25, 40, 60, and 80 mg capsules	1.2 mg/kg/day	1.4 mg/kg/day or 100 mg
Guanfacine ER ^** (Intuniv)	Extended-release tablet of guanfacine	Labeled for once-daily dosing	1,2,3 & 4 mg tablets	Up to 4 mg per day	Up to 4 mg per day
Clonidine ER ^** (Kapvay)	Extended-release tablet of clonidine	Labeled for twice-daily dosing	0.1 mg tablet	0.1–0.2 mg twice daily	Up to 0.4 mg daily

* 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.

Pharmacodynamic Properties of Stimulants

Stimulants increase intra-synaptic concentrations of dopamine (DA) and norepinephrine (NE). MPH primarily binds to the DA transporter protein (DAT), blocking the re-uptake of DA, increasing intra-synaptic DA. While amphetamines diminish pre-synaptic re-uptake of DA by binding to DAT, these compounds also travel into the DA neuron, promoting release of DA from reserpine-sensitive vesicles in the pre-synaptic neuron. In addition, stimulants (amphetamine > MPH) increase levels of NE and serotonin (5-HT) in the inter-neuronal space. Although group studies comparing MPH and amphetamines generally demonstrate similar efficacy, their pharmacodynamic differences may explain why a particular patient may respond to, or tolerate, one stimulant preferentially over another. It is necessary to appreciate that while the efficacy of amphetamine and MPH is similar, their potency differs, such that 5 mg of amphetamine is approximately equally potent to 10 mg of MPH.

Methylphenidate

As originally formulated, MPH was produced as an equal mixture of d,l-threo-MPH and d,l-erythro-MPH. The erythro isomers of MPH appear to produce side effects, and thus MPH is now manufactured as an equal racemic mixture of d,l-threo-MPH. Behavioral effects of immediate-release MPH peak 1 to 2 hours after administration, and tend to dissipate within 3 to 5 hours. After oral administration immediate-release MPH is readily absorbed, reaching peak plasma concentration in 1.5 to 2.5 hours, and has an elimination half-life of 2.5–3.5 hours. After oral administration, but prior to reaching the plasma, the enzyme carboxylesterase (CES-1), which is located in the walls of the stomach and liver, extensively metabolizes MPH via hydrolysis and de-esterification, with little oxidation. Individual differences in CES-1's hydrolyzing activity may result in variable metabolism and serum MPH levels. While generic MPH has a similar pharmacokinetic profile to Ritalin, it is more rapidly absorbed and peaks sooner. Due to its wax-matrix preparation, the absorption of the sustained-release MPH preparation (Ritalin-SR) is variable, with peak MPH plasma levels in 1 to 4 hours, a half-life of 2 to 6 hours, and behavioral effects that may last up to 8 hours. The availability of the various new extended-delivery stimulant formulations has greatly curtailed use of MPH-SR.

Concerta (OROS-MPH) uses the Osmotic Releasing Oral System (OROS) technology to deliver a 50 : 50 racemic mixture of d,l-threo-MPH. OROS-MPH, indicated for the treatment of ADHD in children and adolescents, is available in 18, 27, 36, and 54 mg doses and is indicated in doses up to 72 mg daily. The 18 mg caplet of OROS-MPH provides an initial bolus of 4 mg of MPH, delivering the remaining MPH in an ascending pattern, such that peak concentrations are generally reached around 8 hours after dosing; it is labeled for 12 hours of coverage. A single morning dose of 18, 27, 36, 54,or 72 mg of OROS-MPH is approximately bioequivalent to 5, 7.5, 10,15,or 20 mg of immediate-release MPH administered three times daily, respectively. The effectiveness and tolerability of OROS-MPH have been demonstrated in children, adolescents, and adults with ADHD. Data support OROS-MPH's continued efficacy in many of those with ADHD over the course of 24 months of treatment.

Metadate CD (MPH MR), the first available extended-delivery stimulant preparation to employ beaded technology, is available in capsules of 10, 20, 30, 40, 50, and 60 mg, which may be sprinkled. Using Eurand's Diffucaps technology, MPH MR contains two types of coated beads, IR-MPH and extended-release-MPH (ER-MPH). Metadate delivers 30% of d,l-threo-MPH initially, and 70% of d,l-threo-MPH several hours later. MPH MR is designed to simulate twice-daily (BID) dosing of IR MPH providing approximately 8 hours of coverage. The efficacy of MPH MR capsules has been demonstrated, and it is approved for treatment in youth with ADHD in doses of up to 60 mg/day. An extended-delivery tablet form of Metadate (Metadate ER) is also available in doses of 10 and 20 mg.

Ritalin-LA (MPH-ERC), another beaded-stimulant preparation, which may be sprinkled, is available in capsules of 10, 20, 30, and 40 mg, essentially equivalent to 5, 10, 15 and 20 mg of IR-MPH delivered BID. MPH-ERC uses the beaded Spheroidal Oral Drug Absorption System (SODAS) technology to achieve a bi-modal release profile that delivers 50% of its d,l-threo-MPH initially and another bolus approximately 3 to 4 hours later, providing around 8 hours of coverage. The efficacy of MPH-ERC has been demonstrated in youth with ADHD.

The primarily active form of MPH appears to be the d-threo isomer, which is available in both immediate-release tablets (Focalin 2.5, 5, and 10 mg) and, employing the SODAS technology, extended-delivery capsules (Focalin XR 5, 10, 15, and 20 mg). The efficacy of D-MPH is well established in children, adolescents, and adults under open- and double-blind conditions. D-MPH is approved to treat ADHD in children, adolescents, and adults in doses of up to 20 mg per day and has been labeled to provide a 12-hour duration of coverage. Although not definitive, 10 mg of MPH appears to be approximately equivalent to 5 mg of d-MPH, and clinicians can reasonably use this estimate in clinical practice.

The MPH transdermal system (MTS; Daytrana) delivers MPH through the skin via the DOT Matrix transdermal system. The patches are applied once daily and intended to be worn for 9 hours, although in clinical practice they can be worn for shorter and longer periods of time. The MTS usually takes effect within 2 hours and provides coverage for 3 hours after removal. MTS is available in 10, 15, 20, and 30 mg patches. Since the MPH is absorbed through the skin, it does not undergo first-pass metabolism by CES-1 in the liver, resulting in higher plasma MPH levels. Therefore, patients may require lower doses with MTS compared to oral preparations (10 mg of MTS = 15 mg of extended-release oral MPH). MTS may be a particularly useful treatment option for patients who have difficulty swallowing or tolerating oral stimulant formulations or for patients who need flexibility in the duration of medication effect.

Recently an extended-delivery MPH oral suspension formulation became available (MEROS or Quillivant XR 25 mg/5 ml). Although head-to-head trials haven't been published and clinical experience to date is limited, this formulation appears to provide similar efficacy and duration of effect as other extended-delivery MPH preparations. This preparation may be particularly helpful for youth who prefer a liquid preparation or who experience skin reactions to the transdermal patch. Prior to dosing, the manufacturer recommends shaking the contents in the bottle to ensure an even distribution of medication.

Amphetamines

Amphetamine is available in three forms, dextroamphetamine (DEX; Dexedrine), mixed amphetamine salts (MAS; Adderall), and lisdexamfetaminedimesylate (LDX, Vyvanase). DEX tablets achieve peak plasma levels 2 to 3 hours after oral administration, and have a half-life of 4 to 6 hours. Behavioral effects of DEX tablets peak 1 to 2 hours after administration, and last 4 to 5 hours. For DEX spansules, these values are somewhat longer. MAS consist of equal portions of d-amphetamine saccharate, d,l-amphetamine asparate, d-amphetamine sulfate, and d,l-amphetamine sulfate, and a single dose results in a ratio of approximately 3 : 1 d- to l-amphetamine. The two isomers have different pharmacodynamic properties, and some patients with ADHD preferentially respond to one isomer over another. The efficacy of MAS tablets is well established in ADHD youth and adults. An extended-delivery preparation of MAS is available as a capsule containing two types of Micotrol beads (MAS XR; Adderall XR). The beads are present in a 50 : 50 ratio, with immediate-release beads designed to release MAS in a fashion similar to MAS tablets, and delayed-release beads designed to release MAS 4 hours after dosing. The efficacy of MAS XR is well established in children, adolescents, and adults. Furthermore, open treatment with MAS XR appears to be effective in the treatment of many ADHD youths over a 24-month period.

LDX is FDA-approved for treatment of ADHD in children, adolescents, and adults. LDX is an amphetamine pro-drug in which L-lysine, a naturally occurring amino acid, is covalently linked to d-amphetamine. After oral administration, the pro-drug is metabolically hydrolyzed in the body to release d-amphetamine. LDX appears to reduce abuse liability (e.g., misuse, abuse, and overdose) as intravenously and intra-nasally administered LDX results in similar effects as oral administration. It is available in capsules of 20, 30, 40, 50, 60, and 70 mg that appear to be comparable to MAS XR doses of 10, 15, 20, 25, 30, and 35 mg, respectively.

Clinical Use of Stimulants

Guidelines and recent excellent clinical reviews regarding the use of stimulant medications in children, adolescents, and adults in clinical practice have been published. Treatment with immediate-release preparations generally starts at 5 mg of MPH or amphetamine once daily and is titrated upward every 3 to 5 days until an effect is noted or adverse effects emerge. Typically, the half-life of the short-acting stimulants necessitates at least twice-daily dosing, with the addition of similar or reduced afternoon doses dependent on break-through symptoms. In a typical adult, dosing of immediate-release MPH is generally up to 30 mg three to four times daily or amphetamine 15 to 20 mg three to four times a day. Currently, most adults with ADHD will be treated with a stimulant that has an extended delivery. Since there is no way to determine which stimulant will be best tolerated and most effective, it is wise to consider including trials with extended-delivery preparations of both MPH and amphetamine.

Side Effects of Stimulants

Although generally well tolerated, stimulants can cause clinically significant side effects (including anorexia, nausea, difficulty falling asleep, obsessiveness, headaches, dry mouth, rebound phenomena, anxiety, nightmares, dizziness, irritability, dysphoria, and weight loss). Rates and types of stimulant side effects appear to be similar in ADHD patients, regardless of age. In patients with a current co-morbid mood/anxiety disorder, clinicians should consider whether an adverse effect reflects the co-morbid disorder, a side effect of the treatment, or an exacerbation of the co-morbidity. Moreover, while stimulants can cause these side effects, many ADHD patients experience these problems before treatment; therefore, it is important for clinicians to document these symptoms at baseline. Recommendations about management of some common side effects are listed in Table 49-2 .

TABLE 49-2

Pharmacological Strategies in Challenging Cases of Attention-Deficit/Hyperactivity Disorder

Symptoms	Interventions
Worsening or unchanged ADHD symptoms (inattention, impulsivity, hyperactivity)	Change medication dose (increase or decrease)
	Change timing of dose
	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 syndrome (TS) or use with co-morbid tics or TS	Assess persistence of tics or TS
	If tics abate, re-challenge
	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, irritability, acceleration, agitation	Assess for toxicity or rebound
	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, mood lability, or marked anxiety symptoms	Assess for toxicity or rebound
	Evaluate development or exacerbation of co-morbidity
	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

Growth

The impact of stimulant treatment on growth remains a concern, and the data are conflicting. For instance, in the MTA study, ADHD youth, treated with a stimulant medication continuously over a 24-month period, experienced a deceleration of about 1 cm per year. Despite this slowing, except for those subjects in the lowest percentile for height, these children remained within the normal curves. Recently, Biederman and colleagues reported on growth trajectories in two case-control samples of boys and girls with ADHD compared to controls. Over 10–11 years of follow-up these authors found no significant impact of ADHD or its treatment on growth parameters except in subjects with ADHD and depression, where girls were larger and boys smaller. Despite reassuring data clinicians, parents and patients healthy physical development and these difficulties do not usually pose significant clinical problems for most patients. To effectively address these concerns the AACAP practice parameters for ADHD recommend routine monitoring of height and weight, including serial plotting of growth parameters. Crossing two percentile lines of height and/or weight may indicate a clinically significant change in growth that should be addressed clinically. A variety of options may be considered, including a medication holiday, dose adjustment, a change in medication, and/or consultation. Ultimately impact on growth should be balanced with the overall benefits of treatment.

Sleep

Parents often report sleep disturbances in their children with ADHD before and during treatment. Various strategies (including improving sleep hygiene, making behavioral modifications, adjusting timing or type of stimulant, and switching to an alternative ADHD treatment) have been suggested to help make it easier for patients with ADHD to fall asleep. Complementary pharmacological treatments to consider include the following: melatonin (1 to 3 mg), clonidine (0.1 to 0.3 mg), diphenhydramine (25 to 50 mg), trazodone (25 to 50 mg), and mirtazapine (3.75 to 15 mg). Recently, interest in the use of melatonin, a hormone secreted by the pineal gland that helps regulate circadian rhythms, to address sleep problems in children has been growing. Melatonin used alone and in conjunction with sleep hygiene techniques appears to improve sleep in youths with ADHD. In these two well-designed but small studies, the most concerning adverse events included migraine (n = 1), nightmares (n = 1), and aggression (n = 1). Although not yet studied, another consideration is ramelteon, a synthetic melatonin receptor agonist.

Appetite Suppression

Patients treated with stimulants often experience a dose-related reduction in appetite, and in some cases weight loss. Although appetite suppression often decreases over time, clinicians should give guidance on improving the patient's nutritional options with higher caloric intake to balance the consequences of decreased food intake. While appetite suppression is a common side effect of stimulants, little research has been done studying remedies. Cyproheptadine, in doses of 4 to 8 mg, has recently been reported to improve appetite in ADHD patients with stimulant-associated appetite suppression.

Medication Interactions with Stimulants

The interactions of stimulants with other prescription and non-prescription medications are generally mild and not a major source of concern. Concomitant use of sympathomimetic agents (e.g., pseudoephedrine) may potentiate the effects of both medications. Likewise, excessive intake of caffeine may potentially compromise the effectiveness of the stimulants and exacerbate sleep difficulties. Although data on the co-administration of stimulants with tricyclic antidepressants (TCAs) suggest little interaction between these compounds, careful monitoring is warranted when prescribing stimulants with either TCAs or anticonvulsants. Although administering stimulants with ATMX is common in clinical practice, and appears to be safe, well tolerated, and effective based on clinical experience, to date only small samples have been studied; therefore, patients taking this combination should be monitored closely. In fact, co-administration of stimulants with MAOIs is the only true contraindication.

Despite the increasing use of stimulants for patients with ADHD, many of them may not respond, experience untoward side effects, or manifest co-morbidity, which stimulants may exacerbate or be ineffective in treating. Over the last 10 years ATMX has been systematically evaluated and is FDA-approved for the treatment of ADHD in children, adolescents, and adults.

Atomoxetine

Unlike the stimulants, atomoxetine (ATMX; Strattera) is unscheduled; therefore, clinicians can prescribe refills. ATMX acts by blocking the NE re-uptake pump on the pre-synaptic membrane, thus increasing the availability of intra-synaptic NE, with little affinity for other monoamine transporters or neurotransmitter receptors. In addition to prominent effects of ATMX on NE re-uptake inhibition, pre-clinical data also show that the noradrenergic pre-synaptic re-uptake protein regulates DA in the frontal lobes and that by blocking this protein ATMX increases DA in the frontal lobes. ATMX is rapidly absorbed following oral administration; food does not appear to affect absorption, and C _max occurs 1 to 2 hours after dosing. While the plasma half-life appears to be around 5 hours, the central nervous system (CNS) effects appear to last over 24 hours. ATMX is metabolized primarily in the liver to 4-hydroxyatomoxetine by the cytochrome (CYP) P450 2D6 enzyme. Although patients identified as “poor metabolizers” (i.e., with low 2D6 activity) appear to generally tolerate ATMX, these patients seem to have more side effects, and a reduction in dose may be necessary. Therefore, in patients who are taking medications that are strong 2D6 inhibitors (e.g., fluoxetine, paroxetine, quinidine), it may be necessary to reduce the dose of ATMX. Clinically, ATMX is often prescribed in conjunction with stimulants. Although the safety, tolerability, and efficacy of this combination have not been fully studied, reports suggest that this combination is well tolerated and effective. Therefore, although the full safety of administering stimulants and ATMX together has not been fully established, there are good data from which to extrapolate, and clinicians must balance the risks and benefits in each patient.

Clinical Use of Atomoxetine

ATMX should be initiated at 0.5 mg/kg/day and after a few days increased to a target dose of 1.2 mg/kg/day. Although ATMX has been studied in doses of up to 2 mg/kg/day, current dosing guidelines recommend a maximum dosage of 1.4 mg/kg/day. Although some patients have an early response, it may take up to 10 weeks to see the full benefits of ATMX treatment. In the initial trials, ATMX was dosed BID (typically after breakfast and after dinner); however, recent studies have demonstrated its efficacy and tolerability in many patients dosed once a day. Although the effects of ATMX dosed once daily in the morning or at bedtime appear to be similar (with a mean dose of 1.25 mg/kg/morning or 1.26 mg/kg/night), once-daily ATMX appears to be best tolerated when dosed in the evening. To date, plasma levels of ATMX have not been used to guide dosing. However, Dunn and colleagues found that patients with a plasma level of ATMX greater than 800 ng/ml had more robust responses, although patients treated with higher doses also experienced more side effects.

ATMX may be particularly useful when anxiety, mood symptoms, or tics co-occur with ADHD. For example, a large, 14-week multi-site study of ATMX in adults with ADHD and social anxiety disorder reported clinically significant effects on both ADHD and on anxiety. Although untested, because of its lack of abuse liability, ATMX may be particularly of use in adults with current substance use issues. For instance, Wilens and associates demonstrated in a 12-week controlled trial that treatment with ATMX in recently abstinent alcoholics was associated with improved ADHD and reduced drinking, although absolute abstinent rates were unaffected. Moreover, ATMX has not been reported to have significant or serious drug interactions with alcohol or marijuana.

Side Effects of Atomoxetine

Although generally well tolerated, the most common side effects in children and adolescents taking ATMX include reduced appetite, dyspepsia, and dizziness, although height and weight in long-term use appear to be on target. In adults, ATMX treatment may be associated with dry mouth, insomnia, nausea, decreased appetite, constipation, decreased libido, dizziness, and sweating. Furthermore, some men taking ATMX may have difficulty attaining or maintaining erections. Several easy strategies can be used to manage ATMX's side effects. When patients experience nausea, the dose of ATMX should be divided and administered with food. Sedation is often transient, but may be helped by either administering the dose at night or by dividing the dose. If mood swings occur, patients should be evaluated and their diagnosis reassessed.

Although ATMX treatment is associated with mean increases in heart rate of 6 beats per minute, and increases in systolic and diastolic blood pressure of 1.5 mm Hg, the impact of ATMX on the cardiovascular system appears to be minimal. Extensive electrocardiogram (ECG) monitoring indicates that ATMX has no apparent effect on QTc intervals, and ECG monitoring outside of routine medical care does not appear to be necessary. Adults should have their vital signs checked prior to initiating treatment with ATMX and periodically thereafter.

Concerns have been raised that treatment with ATMX may increase the risk of hepatitis. During post-marketing surveillance, two patients (out of 3 million exposures) developed hepatitis during treatment with ATMX. Patients and families should contact their doctors if they develop pruritus, jaundice, dark urine, right upper quadrant tenderness, or unexplained “flu-like” symptoms.

The FDA issued a public health advisory, and the manufacturer later added a black box warning regarding the development of suicidal ideation in patients treated with ATMX. Similar to the selective serotonin re-uptake inhibitors (SSRIs), there was a slight increase in suicidal thinking in controlled trials. Parents and caregivers should be made aware of any such occurrences and should monitor unexpected changes in mood or behavior.

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