Floyd R. Sallee, MD, PhD

Guanfacine extended release (GXR)—a selective α-2 adrenergic agonist FDA-approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)—has demonstrated efficacy for inattentive and hyperactive/impulsive symptom domains in 2 large trials lasting 8 and 9 weeks.^1,2 GXR’s once-daily formulation may increase adherence and deliver consistent control of symptoms across a full day ( Table 1 ).

Table 1

Guanfacine extended release: Fast facts

Clinical implications

GXR exhibits enhancement of noradrenergic pathways through selective direct receptor action in the prefrontal cortex.³ This mechanism of action is different from that of other FDA-approved ADHD medications. GXR can be used alone or in combination with stimulants or atomoxetine for treating complex ADHD, such as cases accompanied by oppositional features and emotional dysregulation or characterized by partial stimulant response.

How it works

Guanfacine—originally developed as an immediate-release (IR) antihypertensive—reduces sympathetic tone, causing centrally mediated vasodilation and reduced heart rate. Although GXR’s mechanism of action in ADHD is not known, the drug is a selective α-2A receptor agonist thought to directly engage postsynaptic receptors in the prefrontal cortex (PFC), an area of the brain believed to play a major role in attentional and organizational functions that preclinical research has linked to ADHD.³

The postsynaptic α-2A receptor is thought to play a central role in the optimal functioning of the PFC as illustrated by the “inverted U hypothesis of PFC activation.”⁴ In this model, cyclic adenosine monophosphate (cAMP) levels build within the prefrontal cortical neurons and cause specific ion channels—hyperpolarization-activated cyclic nucleotide gated (HCN) channels—to open on dendritic spines of these neurons.⁵ Activation of HCN channels effectively reduces membrane resistance, cutting off synaptic inputs and disconnecting PFC network connections. Because α-2A receptors are located in proximity to HCN channels, their stimulation by GXR closes HCN channels, inhibits further production of cAMP, and reestablishes synaptic function and the resulting network connectivity.⁵ Blockade of α-2A receptors by yohimbine reverses this process, eroding network connectivity, and in monkeys has been demonstrated to impair working memory,⁶ damage inhibition/impulse control, and produce locomotor hyperactivity.

Direct stimulation by GXR of the postsynaptic α-2A receptors is thought to:

• strengthen working memory
• reduce susceptibility to distraction
• improve attention regulation
• improve behavioral inhibition
• enhance impulse control.⁷

Pharmacokinetics

GXR offers enhanced pharmaceutics relative to IR guanfacine. IR guanfacine exhibits poor absorption characteristics—peak plasma concentration is achieved too rapidly and then declines precipitously, with considerable inter-individual variation.

GXR’s once-daily formulation is implemented by a proprietary enteric-coated sustained release mechanism⁸ that is meant to:

• control absorption
• provide a broad but flat plasma concentration profile
• reduce inter-individual variation of guanfacine exposure.

Compared with IR guanfacine, GXR exhibits delayed time of maximum concentration (Tmax) and reduced maximum concentration (Cmax). Therapeutic concentrations can be sustained over longer periods with reduced peak-to-trough fluctuation,⁸ which tends to improve tolerability and symptom control throughout the day. The convenience of once-daily dosing also may increase adherence.

GXR’s pharmacokinetic characteristics do not change with dose, but high-fat meals will increase absorption of the drug—Cmax increases by 75% and area under the plasma concentration time curve increases by 40%. Because GXR primarily is metabolized through cytochrome P450 (CYP) 3A4, CYP3A4 inhibitors such as ketoconazole will increase guanfacine plasma concentrations and elevate the risk of adverse events such as bradycardia, hypotension, and sedation. Conversely, CYP3A4 inducers such as rifampin will significantly reduce total guanfacine exposure. Coadministration of valproic acid with GXR can result in increased valproic acid levels, producing additive CNS side effects.

Efficacy

GXR reduced both inattentive and hyperactive/impulsive symptoms in 2 phase III, forced-dose, parallel-design, randomized, placebo-controlled trials ( Table 2 ). In the first trial,¹ 345 children age 6 to 17 received placebo or GXR, 2 mg, 3 mg, or 4 mg once daily for 8 weeks. In the second study,² 324 children age 6 to 17 received placebo or GXR, 1 mg, 2 mg, 3 mg, or 4 mg, once daily for 9 weeks; the 1-mg dose was given only to patients weighing <50 kg (<110 lbs).

In both trials, doses were increased in increments of 1 mg/week, and investigators evaluated participants’ ADHD signs and symptoms once a week using the clinician administered and scored ADHD Rating Scale-IV (ADHD-RS-IV). The primary outcome was change in total ADHD-RS-IV score from baseline to endpoint.

In both trials, patients taking GXR demonstrated statistically signifcant improvements in ADHD-RS-IV score starting 1 to 2 weeks after they began receiving once-daily GXR:

• In the first trial, the mean reduction in ADHD-RS-IV total score at endpoint was –16.7 for GXR compared with –8.9 for placebo (P < .0001).
• In the second, the reduction was –19.6 for GXR and –12.2 for placebo (P=.004).

Placebo-adjusted least squares mean changes from baseline were statistically significant for all GXR doses in the randomized treatment groups in both studies.

Secondary efficacy outcome measures included the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R) and the Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R).

Significant improvements were seen on both scales. On the CPRS-R, parents reported significant improvement across a full day (as measured at 6 PM, 8 PM, and 6 AM the next day). On the CTRS-R—which was used only in the first trial—teachers reported significant improvement throughout the school day (as measured at 10 AM and 2 PM).

Treating oppositional symptoms. In a collateral study,⁹ GXR was evaluated in complex ADHD patients age 6 to 12 who exhibited oppositional symptoms. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners’ Parent Rating Scale-Revised: Long Form (CPRS-R:L) score.

All subjects randomized to GXR started on a dose of 1 mg/d—which could be titrated by 1 mg/week during the 5-week, dose-optimization period to a maximum of 4 mg/d—and were maintained at their optimal doses for 3 additional weeks. Among the 217 subjects enrolled, 138 received GXR and 79, placebo.

Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were –10.9 in the GXR group compared with –6.8 in the placebo group (P < .001; effect size 0.590). The GXR-treated group showed a significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint compared with the placebo group (–23.8 vs –11.4, respectively, P < .001; effect size 0.916).

Table 2

Randomized, controlled trials supporting GXR’s effectiveness
for treating ADHD symptoms

Tolerability

In the phase III trials, the most commonly reported drug-related adverse reactions (occurring in ≥2% of patients) were:

• somnolence (38%)
• headache (24%)
• fatigue (14%)
• upper abdominal pain (10%)
• nausea, lethargy, dizziness, hypotension/decreased blood pressure, irritability (6% for each)
• decreased appetite (5%)
• dry mouth (4%)
• constipation (3%).

Many of these adverse reactions appear to be dose-related, particularly somnolence, sedation, abdominal pain, dizziness, and hypotension/decreased blood pressure.

Overall, GXR was well tolerated; clinicians rated most events as mild to moderate. Twelve percent of GXR patients discontinued the clinical studies because of adverse events, compared with 4% in the placebo groups. The most common adverse reactions leading to discontinuation were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in 1% of patients) included hypotension/decreased blood pressure, headache, and dizziness.

Open-label safety trial. Sallee et al¹⁰ conducted a longer-term, open-label, flexible-dose safety continuation study of 259 GXR-treated patients (mean exposure 10 months), some of whom also received a psychostimulant. Common adverse reactions (occurring in ≥5% of subjects) included somnolence (45%), headache (26%), fatigue (16%), upper abdominal pain (11%), hypotension/decreased blood pressure (10%), vomiting (9%), dizziness (7%), nausea (7%), weight gain (7%), and irritability (6%).¹⁰ In a subset of patients, the onset of sedative events typically occurred within the first 3 weeks of GXR treatment and then declined with maintenance to a frequency of approximately 16%. The rates of somnolence, sedation, or fatigue were lowest among patients who also received a psychostimulant ( Figure ).

Distribution of GXR doses before the end of this study was 37% of patients on 4 mg, 33% on 3 mg, 27% on 2 mg, and 3% on 1 mg, suggesting a preference for maintenance doses of 3 to 4 mg/d. The most frequent adverse reactions leading to discontinuation were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included hypotension/decreased blood pressure, sedation, headache, and lethargy. Serious adverse reactions in the longer-term study in >1 patient included syncope (2%) and convulsion (0.4%).

Figure: Incidence of somnolence, sedation, and fatigue in study patients receiving GXR
with or without psychostimulants

In the longer-term, open-label safety study,¹⁰ maximum decreases in systolic and diastolic blood pressure occurred in the first month of treatment; decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects but was not dose-dependent. Guanfacine IR can increase QT interval but not in a dose-dependent fashion.

Dosing

The approved dose range for GXR is 1 to 4 mg once daily in the morning. Initiate treatment at 1 mg/d, and adjust the dose in increments of no more than 1 mg/week, evaluating the patient weekly. GXR maintenance therapy is frequently in the range of 2 to 4 mg/d.

Because adverse events such as hypotension, bradycardia, and sedation are dose-related, evaluate benefit and risk using mg/kg range approximation. GXR efficacy on a weight-adjusted (mg/kg) basis is consistent across a dosage range of 0.01 to 0.17 mg/kg/d. Clinically relevant improvements are usually observed beginning at doses of 0.05 to 0.08 mg/kg/d. In clinical trials, efficacy increased with increasing weight-adjusted dose (mg/kg), so if GXR is well-tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit up to the maximum of 4 mg/d.

Instruct patients to swallow GXR whole because crushing, chewing, or otherwise breaking the tablet’s enteric coating will markedly enhance guanfacine release.

Abruptly discontinuing GXR is associated with infrequent, transient elevations in blood pressure above the patient’s baseline (ie, rebound). To minimize these effects, GXR should be gradually tapered in decrements of no more than 1 mg every 3 to 7 days. Isolated missed doses of GXR generally are not a problem, but ≥2 consecutive missed doses may warrant reinitiation of the titration schedule.

Related resource

• Guanfacine extended release (Intuniv) prescribing information. www.intuniv.com/documents/INTUNIV_Full_Prescribing_Information.pdf.

Drug brand names

• Atomoxetine • Strattera
• Guanfacine extended release • Intuniv
• Guanfacine immediate release • Tenex
• Ketoconazole • Nizoral
• Rifampin • Rifadin, Rimactane
• Valproic acid • Depakene, Depakote

Disclosure

Dr. Sallee receives grant/research support from the National Institutes of Health. He is a consultant to Otsuka, Nextwave, and Sepracor and a consultant to and speaker for Shire. Dr. Sallee is a consultant to, shareholder of, and member of the board of directors of P2D Inc. and a principal in Satiety Solutions.

Guanfacine extended release (GXR)—a selective α-2 adrenergic agonist FDA-approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)—has demonstrated efficacy for inattentive and hyperactive/impulsive symptom domains in 2 large trials lasting 8 and 9 weeks.^1,2 GXR’s once-daily formulation may increase adherence and deliver consistent control of symptoms across a full day ( Table 1 ).

Table 1

Guanfacine extended release: Fast facts

Clinical implications

GXR exhibits enhancement of noradrenergic pathways through selective direct receptor action in the prefrontal cortex.³ This mechanism of action is different from that of other FDA-approved ADHD medications. GXR can be used alone or in combination with stimulants or atomoxetine for treating complex ADHD, such as cases accompanied by oppositional features and emotional dysregulation or characterized by partial stimulant response.

How it works

Guanfacine—originally developed as an immediate-release (IR) antihypertensive—reduces sympathetic tone, causing centrally mediated vasodilation and reduced heart rate. Although GXR’s mechanism of action in ADHD is not known, the drug is a selective α-2A receptor agonist thought to directly engage postsynaptic receptors in the prefrontal cortex (PFC), an area of the brain believed to play a major role in attentional and organizational functions that preclinical research has linked to ADHD.³

The postsynaptic α-2A receptor is thought to play a central role in the optimal functioning of the PFC as illustrated by the “inverted U hypothesis of PFC activation.”⁴ In this model, cyclic adenosine monophosphate (cAMP) levels build within the prefrontal cortical neurons and cause specific ion channels—hyperpolarization-activated cyclic nucleotide gated (HCN) channels—to open on dendritic spines of these neurons.⁵ Activation of HCN channels effectively reduces membrane resistance, cutting off synaptic inputs and disconnecting PFC network connections. Because α-2A receptors are located in proximity to HCN channels, their stimulation by GXR closes HCN channels, inhibits further production of cAMP, and reestablishes synaptic function and the resulting network connectivity.⁵ Blockade of α-2A receptors by yohimbine reverses this process, eroding network connectivity, and in monkeys has been demonstrated to impair working memory,⁶ damage inhibition/impulse control, and produce locomotor hyperactivity.

Direct stimulation by GXR of the postsynaptic α-2A receptors is thought to:

• strengthen working memory
• reduce susceptibility to distraction
• improve attention regulation
• improve behavioral inhibition
• enhance impulse control.⁷

Pharmacokinetics

GXR offers enhanced pharmaceutics relative to IR guanfacine. IR guanfacine exhibits poor absorption characteristics—peak plasma concentration is achieved too rapidly and then declines precipitously, with considerable inter-individual variation.

GXR’s once-daily formulation is implemented by a proprietary enteric-coated sustained release mechanism⁸ that is meant to:

• control absorption
• provide a broad but flat plasma concentration profile
• reduce inter-individual variation of guanfacine exposure.

Compared with IR guanfacine, GXR exhibits delayed time of maximum concentration (Tmax) and reduced maximum concentration (Cmax). Therapeutic concentrations can be sustained over longer periods with reduced peak-to-trough fluctuation,⁸ which tends to improve tolerability and symptom control throughout the day. The convenience of once-daily dosing also may increase adherence.

GXR’s pharmacokinetic characteristics do not change with dose, but high-fat meals will increase absorption of the drug—Cmax increases by 75% and area under the plasma concentration time curve increases by 40%. Because GXR primarily is metabolized through cytochrome P450 (CYP) 3A4, CYP3A4 inhibitors such as ketoconazole will increase guanfacine plasma concentrations and elevate the risk of adverse events such as bradycardia, hypotension, and sedation. Conversely, CYP3A4 inducers such as rifampin will significantly reduce total guanfacine exposure. Coadministration of valproic acid with GXR can result in increased valproic acid levels, producing additive CNS side effects.

Efficacy

GXR reduced both inattentive and hyperactive/impulsive symptoms in 2 phase III, forced-dose, parallel-design, randomized, placebo-controlled trials ( Table 2 ). In the first trial,¹ 345 children age 6 to 17 received placebo or GXR, 2 mg, 3 mg, or 4 mg once daily for 8 weeks. In the second study,² 324 children age 6 to 17 received placebo or GXR, 1 mg, 2 mg, 3 mg, or 4 mg, once daily for 9 weeks; the 1-mg dose was given only to patients weighing <50 kg (<110 lbs).

In both trials, doses were increased in increments of 1 mg/week, and investigators evaluated participants’ ADHD signs and symptoms once a week using the clinician administered and scored ADHD Rating Scale-IV (ADHD-RS-IV). The primary outcome was change in total ADHD-RS-IV score from baseline to endpoint.

In both trials, patients taking GXR demonstrated statistically signifcant improvements in ADHD-RS-IV score starting 1 to 2 weeks after they began receiving once-daily GXR:

• In the first trial, the mean reduction in ADHD-RS-IV total score at endpoint was –16.7 for GXR compared with –8.9 for placebo (P < .0001).
• In the second, the reduction was –19.6 for GXR and –12.2 for placebo (P=.004).

Placebo-adjusted least squares mean changes from baseline were statistically significant for all GXR doses in the randomized treatment groups in both studies.

Secondary efficacy outcome measures included the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R) and the Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R).

Significant improvements were seen on both scales. On the CPRS-R, parents reported significant improvement across a full day (as measured at 6 PM, 8 PM, and 6 AM the next day). On the CTRS-R—which was used only in the first trial—teachers reported significant improvement throughout the school day (as measured at 10 AM and 2 PM).

Treating oppositional symptoms. In a collateral study,⁹ GXR was evaluated in complex ADHD patients age 6 to 12 who exhibited oppositional symptoms. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners’ Parent Rating Scale-Revised: Long Form (CPRS-R:L) score.

All subjects randomized to GXR started on a dose of 1 mg/d—which could be titrated by 1 mg/week during the 5-week, dose-optimization period to a maximum of 4 mg/d—and were maintained at their optimal doses for 3 additional weeks. Among the 217 subjects enrolled, 138 received GXR and 79, placebo.

Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were –10.9 in the GXR group compared with –6.8 in the placebo group (P < .001; effect size 0.590). The GXR-treated group showed a significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint compared with the placebo group (–23.8 vs –11.4, respectively, P < .001; effect size 0.916).

Table 2

Randomized, controlled trials supporting GXR’s effectiveness
for treating ADHD symptoms

Tolerability

In the phase III trials, the most commonly reported drug-related adverse reactions (occurring in ≥2% of patients) were:

• somnolence (38%)
• headache (24%)
• fatigue (14%)
• upper abdominal pain (10%)
• nausea, lethargy, dizziness, hypotension/decreased blood pressure, irritability (6% for each)
• decreased appetite (5%)
• dry mouth (4%)
• constipation (3%).

Many of these adverse reactions appear to be dose-related, particularly somnolence, sedation, abdominal pain, dizziness, and hypotension/decreased blood pressure.

Overall, GXR was well tolerated; clinicians rated most events as mild to moderate. Twelve percent of GXR patients discontinued the clinical studies because of adverse events, compared with 4% in the placebo groups. The most common adverse reactions leading to discontinuation were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in 1% of patients) included hypotension/decreased blood pressure, headache, and dizziness.

Open-label safety trial. Sallee et al¹⁰ conducted a longer-term, open-label, flexible-dose safety continuation study of 259 GXR-treated patients (mean exposure 10 months), some of whom also received a psychostimulant. Common adverse reactions (occurring in ≥5% of subjects) included somnolence (45%), headache (26%), fatigue (16%), upper abdominal pain (11%), hypotension/decreased blood pressure (10%), vomiting (9%), dizziness (7%), nausea (7%), weight gain (7%), and irritability (6%).¹⁰ In a subset of patients, the onset of sedative events typically occurred within the first 3 weeks of GXR treatment and then declined with maintenance to a frequency of approximately 16%. The rates of somnolence, sedation, or fatigue were lowest among patients who also received a psychostimulant ( Figure ).

Distribution of GXR doses before the end of this study was 37% of patients on 4 mg, 33% on 3 mg, 27% on 2 mg, and 3% on 1 mg, suggesting a preference for maintenance doses of 3 to 4 mg/d. The most frequent adverse reactions leading to discontinuation were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included hypotension/decreased blood pressure, sedation, headache, and lethargy. Serious adverse reactions in the longer-term study in >1 patient included syncope (2%) and convulsion (0.4%).

Figure: Incidence of somnolence, sedation, and fatigue in study patients receiving GXR
with or without psychostimulants

In the longer-term, open-label safety study,¹⁰ maximum decreases in systolic and diastolic blood pressure occurred in the first month of treatment; decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects but was not dose-dependent. Guanfacine IR can increase QT interval but not in a dose-dependent fashion.

Dosing

The approved dose range for GXR is 1 to 4 mg once daily in the morning. Initiate treatment at 1 mg/d, and adjust the dose in increments of no more than 1 mg/week, evaluating the patient weekly. GXR maintenance therapy is frequently in the range of 2 to 4 mg/d.

Because adverse events such as hypotension, bradycardia, and sedation are dose-related, evaluate benefit and risk using mg/kg range approximation. GXR efficacy on a weight-adjusted (mg/kg) basis is consistent across a dosage range of 0.01 to 0.17 mg/kg/d. Clinically relevant improvements are usually observed beginning at doses of 0.05 to 0.08 mg/kg/d. In clinical trials, efficacy increased with increasing weight-adjusted dose (mg/kg), so if GXR is well-tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit up to the maximum of 4 mg/d.

Instruct patients to swallow GXR whole because crushing, chewing, or otherwise breaking the tablet’s enteric coating will markedly enhance guanfacine release.

Abruptly discontinuing GXR is associated with infrequent, transient elevations in blood pressure above the patient’s baseline (ie, rebound). To minimize these effects, GXR should be gradually tapered in decrements of no more than 1 mg every 3 to 7 days. Isolated missed doses of GXR generally are not a problem, but ≥2 consecutive missed doses may warrant reinitiation of the titration schedule.

Related resource

• Guanfacine extended release (Intuniv) prescribing information. www.intuniv.com/documents/INTUNIV_Full_Prescribing_Information.pdf.

Drug brand names

• Atomoxetine • Strattera
• Guanfacine extended release • Intuniv
• Guanfacine immediate release • Tenex
• Ketoconazole • Nizoral
• Rifampin • Rifadin, Rimactane
• Valproic acid • Depakene, Depakote

Disclosure

Dr. Sallee receives grant/research support from the National Institutes of Health. He is a consultant to Otsuka, Nextwave, and Sepracor and a consultant to and speaker for Shire. Dr. Sallee is a consultant to, shareholder of, and member of the board of directors of P2D Inc. and a principal in Satiety Solutions.

Guanfacine extended release (GXR)—a selective α-2 adrenergic agonist FDA-approved for the treatment of attention-deficit/hyperactivity disorder (ADHD)—has demonstrated efficacy for inattentive and hyperactive/impulsive symptom domains in 2 large trials lasting 8 and 9 weeks.^1,2 GXR’s once-daily formulation may increase adherence and deliver consistent control of symptoms across a full day ( Table 1 ).

Table 1

Guanfacine extended release: Fast facts

Clinical implications

GXR exhibits enhancement of noradrenergic pathways through selective direct receptor action in the prefrontal cortex.³ This mechanism of action is different from that of other FDA-approved ADHD medications. GXR can be used alone or in combination with stimulants or atomoxetine for treating complex ADHD, such as cases accompanied by oppositional features and emotional dysregulation or characterized by partial stimulant response.

How it works

Guanfacine—originally developed as an immediate-release (IR) antihypertensive—reduces sympathetic tone, causing centrally mediated vasodilation and reduced heart rate. Although GXR’s mechanism of action in ADHD is not known, the drug is a selective α-2A receptor agonist thought to directly engage postsynaptic receptors in the prefrontal cortex (PFC), an area of the brain believed to play a major role in attentional and organizational functions that preclinical research has linked to ADHD.³

The postsynaptic α-2A receptor is thought to play a central role in the optimal functioning of the PFC as illustrated by the “inverted U hypothesis of PFC activation.”⁴ In this model, cyclic adenosine monophosphate (cAMP) levels build within the prefrontal cortical neurons and cause specific ion channels—hyperpolarization-activated cyclic nucleotide gated (HCN) channels—to open on dendritic spines of these neurons.⁵ Activation of HCN channels effectively reduces membrane resistance, cutting off synaptic inputs and disconnecting PFC network connections. Because α-2A receptors are located in proximity to HCN channels, their stimulation by GXR closes HCN channels, inhibits further production of cAMP, and reestablishes synaptic function and the resulting network connectivity.⁵ Blockade of α-2A receptors by yohimbine reverses this process, eroding network connectivity, and in monkeys has been demonstrated to impair working memory,⁶ damage inhibition/impulse control, and produce locomotor hyperactivity.

Direct stimulation by GXR of the postsynaptic α-2A receptors is thought to:

• strengthen working memory
• reduce susceptibility to distraction
• improve attention regulation
• improve behavioral inhibition
• enhance impulse control.⁷

Pharmacokinetics

GXR offers enhanced pharmaceutics relative to IR guanfacine. IR guanfacine exhibits poor absorption characteristics—peak plasma concentration is achieved too rapidly and then declines precipitously, with considerable inter-individual variation.

GXR’s once-daily formulation is implemented by a proprietary enteric-coated sustained release mechanism⁸ that is meant to:

• control absorption
• provide a broad but flat plasma concentration profile
• reduce inter-individual variation of guanfacine exposure.

Compared with IR guanfacine, GXR exhibits delayed time of maximum concentration (Tmax) and reduced maximum concentration (Cmax). Therapeutic concentrations can be sustained over longer periods with reduced peak-to-trough fluctuation,⁸ which tends to improve tolerability and symptom control throughout the day. The convenience of once-daily dosing also may increase adherence.

GXR’s pharmacokinetic characteristics do not change with dose, but high-fat meals will increase absorption of the drug—Cmax increases by 75% and area under the plasma concentration time curve increases by 40%. Because GXR primarily is metabolized through cytochrome P450 (CYP) 3A4, CYP3A4 inhibitors such as ketoconazole will increase guanfacine plasma concentrations and elevate the risk of adverse events such as bradycardia, hypotension, and sedation. Conversely, CYP3A4 inducers such as rifampin will significantly reduce total guanfacine exposure. Coadministration of valproic acid with GXR can result in increased valproic acid levels, producing additive CNS side effects.

Efficacy

GXR reduced both inattentive and hyperactive/impulsive symptoms in 2 phase III, forced-dose, parallel-design, randomized, placebo-controlled trials ( Table 2 ). In the first trial,¹ 345 children age 6 to 17 received placebo or GXR, 2 mg, 3 mg, or 4 mg once daily for 8 weeks. In the second study,² 324 children age 6 to 17 received placebo or GXR, 1 mg, 2 mg, 3 mg, or 4 mg, once daily for 9 weeks; the 1-mg dose was given only to patients weighing <50 kg (<110 lbs).

In both trials, doses were increased in increments of 1 mg/week, and investigators evaluated participants’ ADHD signs and symptoms once a week using the clinician administered and scored ADHD Rating Scale-IV (ADHD-RS-IV). The primary outcome was change in total ADHD-RS-IV score from baseline to endpoint.

In both trials, patients taking GXR demonstrated statistically signifcant improvements in ADHD-RS-IV score starting 1 to 2 weeks after they began receiving once-daily GXR:

• In the first trial, the mean reduction in ADHD-RS-IV total score at endpoint was –16.7 for GXR compared with –8.9 for placebo (P < .0001).
• In the second, the reduction was –19.6 for GXR and –12.2 for placebo (P=.004).

Placebo-adjusted least squares mean changes from baseline were statistically significant for all GXR doses in the randomized treatment groups in both studies.

Secondary efficacy outcome measures included the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R) and the Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R).

Significant improvements were seen on both scales. On the CPRS-R, parents reported significant improvement across a full day (as measured at 6 PM, 8 PM, and 6 AM the next day). On the CTRS-R—which was used only in the first trial—teachers reported significant improvement throughout the school day (as measured at 10 AM and 2 PM).

Treating oppositional symptoms. In a collateral study,⁹ GXR was evaluated in complex ADHD patients age 6 to 12 who exhibited oppositional symptoms. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners’ Parent Rating Scale-Revised: Long Form (CPRS-R:L) score.

All subjects randomized to GXR started on a dose of 1 mg/d—which could be titrated by 1 mg/week during the 5-week, dose-optimization period to a maximum of 4 mg/d—and were maintained at their optimal doses for 3 additional weeks. Among the 217 subjects enrolled, 138 received GXR and 79, placebo.

Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were –10.9 in the GXR group compared with –6.8 in the placebo group (P < .001; effect size 0.590). The GXR-treated group showed a significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint compared with the placebo group (–23.8 vs –11.4, respectively, P < .001; effect size 0.916).

Table 2

Randomized, controlled trials supporting GXR’s effectiveness
for treating ADHD symptoms

Tolerability

In the phase III trials, the most commonly reported drug-related adverse reactions (occurring in ≥2% of patients) were:

• somnolence (38%)
• headache (24%)
• fatigue (14%)
• upper abdominal pain (10%)
• nausea, lethargy, dizziness, hypotension/decreased blood pressure, irritability (6% for each)
• decreased appetite (5%)
• dry mouth (4%)
• constipation (3%).

Many of these adverse reactions appear to be dose-related, particularly somnolence, sedation, abdominal pain, dizziness, and hypotension/decreased blood pressure.

Overall, GXR was well tolerated; clinicians rated most events as mild to moderate. Twelve percent of GXR patients discontinued the clinical studies because of adverse events, compared with 4% in the placebo groups. The most common adverse reactions leading to discontinuation were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in 1% of patients) included hypotension/decreased blood pressure, headache, and dizziness.

Open-label safety trial. Sallee et al¹⁰ conducted a longer-term, open-label, flexible-dose safety continuation study of 259 GXR-treated patients (mean exposure 10 months), some of whom also received a psychostimulant. Common adverse reactions (occurring in ≥5% of subjects) included somnolence (45%), headache (26%), fatigue (16%), upper abdominal pain (11%), hypotension/decreased blood pressure (10%), vomiting (9%), dizziness (7%), nausea (7%), weight gain (7%), and irritability (6%).¹⁰ In a subset of patients, the onset of sedative events typically occurred within the first 3 weeks of GXR treatment and then declined with maintenance to a frequency of approximately 16%. The rates of somnolence, sedation, or fatigue were lowest among patients who also received a psychostimulant ( Figure ).

Distribution of GXR doses before the end of this study was 37% of patients on 4 mg, 33% on 3 mg, 27% on 2 mg, and 3% on 1 mg, suggesting a preference for maintenance doses of 3 to 4 mg/d. The most frequent adverse reactions leading to discontinuation were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included hypotension/decreased blood pressure, sedation, headache, and lethargy. Serious adverse reactions in the longer-term study in >1 patient included syncope (2%) and convulsion (0.4%).

Figure: Incidence of somnolence, sedation, and fatigue in study patients receiving GXR
with or without psychostimulants

In the longer-term, open-label safety study,¹⁰ maximum decreases in systolic and diastolic blood pressure occurred in the first month of treatment; decreases were less pronounced over time. Syncope occurred in 1% of pediatric subjects but was not dose-dependent. Guanfacine IR can increase QT interval but not in a dose-dependent fashion.

Dosing

The approved dose range for GXR is 1 to 4 mg once daily in the morning. Initiate treatment at 1 mg/d, and adjust the dose in increments of no more than 1 mg/week, evaluating the patient weekly. GXR maintenance therapy is frequently in the range of 2 to 4 mg/d.

Because adverse events such as hypotension, bradycardia, and sedation are dose-related, evaluate benefit and risk using mg/kg range approximation. GXR efficacy on a weight-adjusted (mg/kg) basis is consistent across a dosage range of 0.01 to 0.17 mg/kg/d. Clinically relevant improvements are usually observed beginning at doses of 0.05 to 0.08 mg/kg/d. In clinical trials, efficacy increased with increasing weight-adjusted dose (mg/kg), so if GXR is well-tolerated, doses up to 0.12 mg/kg once daily may provide additional benefit up to the maximum of 4 mg/d.

Instruct patients to swallow GXR whole because crushing, chewing, or otherwise breaking the tablet’s enteric coating will markedly enhance guanfacine release.

Abruptly discontinuing GXR is associated with infrequent, transient elevations in blood pressure above the patient’s baseline (ie, rebound). To minimize these effects, GXR should be gradually tapered in decrements of no more than 1 mg every 3 to 7 days. Isolated missed doses of GXR generally are not a problem, but ≥2 consecutive missed doses may warrant reinitiation of the titration schedule.

Related resource

• Guanfacine extended release (Intuniv) prescribing information. www.intuniv.com/documents/INTUNIV_Full_Prescribing_Information.pdf.

Drug brand names

• Atomoxetine • Strattera
• Guanfacine extended release • Intuniv
• Guanfacine immediate release • Tenex
• Ketoconazole • Nizoral
• Rifampin • Rifadin, Rimactane
• Valproic acid • Depakene, Depakote

Disclosure

Dr. Sallee receives grant/research support from the National Institutes of Health. He is a consultant to Otsuka, Nextwave, and Sepracor and a consultant to and speaker for Shire. Dr. Sallee is a consultant to, shareholder of, and member of the board of directors of P2D Inc. and a principal in Satiety Solutions.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.

Methylphenidate and other amphetamine-based agents are mainstays in treating attention-deficit/hyperactivity disorder (ADHD). Although these stimulants are considered safe, their potentially addictive properties have concerned clinicians, adult patients, and parents of children and adolescents with ADHD.

Table

Atomoxetine: fast facts

Atomoxetine—a nonaddictive, nonstimulant medication—has demonstrated efficacy in placebo-controlled trials.

HOW IT WORKS

Atomoxetine enhances synaptic concentrations of norepinephrine via the presynaptic transporter. The agent has a strong affinity with norepinephrine transporters, modest affinity with serotonin transporters, and no affinity with dopamine transporters.¹

When applied directly to the prefrontal cortex, however, atomoxetine has been shown to increase both extracellular norepinephrine and dopamine. Sustained levels of norepinephrine and dopamine in the prefrontal cortex may explain why atomoxetine works well beyond its 5.3-hour biologic half-life.¹

In contrast, methylphenidate has shown high affinity with dopamine transporters. It produces intense, brief prefrontal increases in norepinephrine and dopamine and sustained dopamine increases in the nucleus accumbens and striatum.² This might explain methylphenidate’s rewarding properties and its association with stereotypic motor activity and tics. By comparison, atomoxetine has a lower abuse potential and does not affect basal ganglia motor output.³

Atomoxetine’s pharmacokinetics have been evaluated in more than 400 children and adolescents. Its half-life, clearance (0.35 L/hr/kg), and volume of distribution are similar across age groups, and the dose-plasma concentration relationship is linear, suggesting that dosing can be reliably adjusted according to weight. Atomoxetine is rapidly absorbed, food does not appreciably affect absorption, and peak plasma concentrations are achieved within 1 to 2 hours. The drug is distributed mostly in total body water and is highly protein bound.

Atomoxetine is metabolized primarily through the cytochrome P (CYP)-450 2D6 pathway. The major metabolite is 4-hydroxyatomoxetine, which is equipotent to atomoxetine as a norepinephrine transporter inhibitor.

WHAT RESEARCHERS SAY

In an 8-week study, 297 patients ages 8 to 18 received a divided fixed dosage of atomoxetine (0.5, 1.2 or 1.8 mg/kg/d) or placebo. The 1.2 and 1.8 mg/kg/d dosages were more effective than placebo and were equally effective against hyperactivity/impulsivity and inattention symptoms. The 0.5 mg/kg/d dosage was not much more effective than placebo.⁴

In a 6-week, placebo-controlled study, 85 subjects ages 6 to 16 who received a single dose of atomoxetine each morning (mean dosage 1.3 mg/kg/d) achieved favorable outcomes based on investigator, parent, and teacher ratings and on an ADHD Rating Scale (ADHD-RS) primary outcome measure. The treatment effect size (0.71) was similar to that found in the twice-daily dosing studies, suggesting that single-daily dosing is effective.⁵

Box

Two controlled, comparison studies involving 291 subjects ages 7 to 13 with ADHD found that atomoxetine (mean final dosage 1.6 mg/kg/d) compares favorably to methylphenidate with similar effect sizes across ADHD symptom domains (unpublished data). Limited published data indicate that randomized, open-label atomoxetine and methylphenidate are similarly effective across ADHD symptom domains in children.⁶

Atomoxetine also was shown to improve ADHD symptoms in two placebo-controlled trials involving a total of 536 adults (mean daily divided dose 95 mg).⁷ Inattention, hyperactivity, and impulsivity—as measured with the Conners Adult ADHD Rating Scale—were reduced among both treatment groups.

DOSING AND ADMINISTRATION

No age- or gender-related differences in response to atomoxetine have been reported, although dosing varies with age and weight (Box).

The agent should be used cautiously in patients with cardiovascular or cerebrovascular disease, as side effects include slight elevation of pulse and blood pressure. Atomoxetine also may exacerbate urinary retention or hesitation in some adults. The drug may impair sexual function; at least 7% of men in placebo-controlled trials experienced erectile disturbance, and 3% experienced impotence.⁷

In children and adolescents, gastrointestinal discomfort, asthenia, fatigue, mild appetite decreases, and slight weight loss were reported adverse effects.⁵ Nausea and vomiting were the most troublesome acute side effects in children, with most episodes lasting 1 to 2 days.⁵

CLINICAL IMPLICATIONS

Atomoxetine may help patients with ADHD who respond inadequately or do not respond to stimulants. Its lack of abuse potential suggests it may be useful in adults with comorbid substance use disorders. Atomoxetine also does not appear to exacerbate insomnia—a potential benefit for ADHD patients with poor sleep quality.

Given its pharmacologic profile, the agent will reduce the impact of comorbidities (such as anxiety and depression) common to adults with ADHD. Research is needed to determine its role in treating more complicated pathologies, such as ADHD with comorbid bipolar disorder.

Whereas some stimulants require multiple daily dosing, atomoxetine is administered once daily. This could save clinicians time by reducing the need for refills, out-of-visit prescribing, and monthly patient visits (our pediatric practice writes 20 to 40 stimulant refills per day)and enhance convenience for patients.

Related resources

• Spencer T, Biederman J, Wilens T, et al. Effectiveness and tolerability of tomoxetine in adults with attention deficit hyperactivity disorder. Am J Psychiatry 1998;155:693-5.

Drug Brand Names

• Methylphenidate • Concerta, Ritalin

Disclosure

The author receives research/grant support from and is a consultant to and speaker for Eli Lilly and Co. He also receives research/grant support from Shire Pharmaceuticals and Johnson & Johnson, and is a consultant to Abbott Laboratories, Merck and Co., Pfizer Inc., and Organon.