Out Of The Pipeline

Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treating children and adolescents with bipolar mania or schizophrenia. Specifically, the SGA is indicated for treating schizophrenia in patients age 13 to 17 and as monotherapy in short-term treatment of manic or mixed episodes of bipolar I disorder in patients age 10 to 17 (Table 1).

Risperidone also is approved for:

• schizophrenia in adults
• acute mania or mixed episodes associated with bipolar I disorder in adults, alone or in combination with lithium or valproate
• irritability associated with autistic disorder in patients age 5 to 16.

Table 1

Risperidone: Fast facts

Clinical implications

Risperidone is widely used off-label to treat irritability in children with pervasive developmental disorders,^1,2 aggressive behaviors associated with conduct disorder,³ psychotic disorders,⁴ and bipolar disorder.⁵ It also has been used off-label to treat pediatric schizophrenia and bipolar disorder for many years.

These 2 new indications give clinicians additional support for using SGAs in children and adolescents with these serious psychiatric disorders.

How it works

Risperidone’s therapeutic activity in schizophrenia seems to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of risperidone’s other therapeutic effects.

Pharmacokinetics

In children, the half-lives of risperidone and its major active metabolite 9-hydroxyrisperidone are 3±2.3 hours and 22±46 hours, respectively.⁶ The pharmacologic activity of 9-hydroxyrisperidone is similar to that of risperidone.

Risperidone is extensively metabolized in the liver by the cytochrome P-450 (CYP) 2D6 enzyme system. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by CYP 2D6. Food does not affect the rate or extent of the drug’s absorption.⁶

Efficacy studies

In schizophrenia. Approval of the indication for pediatric schizophrenia was based on data from 2 short-term (6 and 8 weeks) randomized, double-blind, controlled trials involving a total of 416 patients age 13 to 17 who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute episode at enrollment.⁷ In one study, patients received risperidone, 1 to 3 mg/d, 4 to 6 mg/d, or placebo. In the other study, dosages were 0.15 to 0.6 mg/d or 1.5 to 6 mg/d. Except for patients in the 0.15 to 0.6 mg group (who initially received 0.05 mg/d), most patients started risperidone at 0.5 mg/d. In both trials, starting dosages were titrated to the target range in approximately 7 days.

Outcomes were measured as changes in total Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale scores. The multi-item PANSS inventory measures positive and negative schizophrenia symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. The PSP gauges personal and social functioning in socially useful activities (work and study), personal and social relationships, self-care, and disturbing/ aggressive behaviors.

Risperidone, 1 to 6 mg/d, improved schizophrenia symptoms significantly more than placebo, as measured by PANSS scores. Doses >3 mg/d did not show greater efficacy than lower doses, as evaluated by PANSS and PSP scores.

Adverse reactions experienced by >5% of patients treated with risperidone included somnolence, parkinsonism, tremor, dystonia, dizziness, akathisia, increased salivation, and anxiety.⁷

In bipolar I disorder. Risperidone’s efficacy for short-term treatment of mania in children and adolescents was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multi-center study of 169 patients age 10 to 17 who were experiencing a manic or mixed episode of bipolar I disorder.⁷ Patients were randomly assigned to risperidone, 0.5 to 2.5 mg/d or 3 to 6 mg/d, or placebo. All patients were started at 0.5 mg/d and this dose was titrated to the target dosage range in 7 days.

Risperidone, 0.5 to 6 mg/d, significantly decreased the total Young Mania Rating Scale score—a measure of the severity of elevated mood, increased motor activity energy, sexual interest, sleep, irritability, speech (rate/amount), language (thought disorder, content, disruptive), aggressive behavior, appearance, and insight. No evidence of increased efficacy was observed at doses >2.5 mg/d. In this trial, symptoms reported by >5% of patients included fatigue, dizziness, dystonia, parkinsonism, akathisia, abdominal pain, dyspepsia, nausea, vomiting, and diarrhea.⁷

Pediatric dosing. Based on these studies, the recommended starting dose for children and adolescents is 0.5 mg/d, with titration in 0.5-to 1-mg increments to targets of:

• 3 mg/d for schizophrenia
• 2.5 mg/d for bipolar mania (Table 2).⁷

Table 2

Recommended dosing of risperidone
for pediatric schizophrenia and bipolar mania

Tolerability studies

In long-term studies, the most commonly reported adverse events associated with risperidone in children and adolescents have been rhinitis, abdominal pain, increased saliva, body pain, gynecomastia, and weight increase.⁸ Specific adverse effects that pose long-term concerns are:

• tardive dyskinesia (TD)
• weight gain
• increased prolactin levels

Tardive dyskinesia. In clinical trials that included 1,885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 2 patients (0.1%) were reported to have TD, which resolved when risperidone was discontinued.⁷ To monitor for TD, administer the Abnormal Involuntary Movement Scale at baseline and every 6 months while using risperidone in pediatric patients.

Weight gain. In long-term, open-label trials, patients with autistic or other psychiatric disorders gained an average 7.5
kg after 12 months of risperidone treatment. Most of the weight gain occurred in the first 6 months.⁹ Expected normal weight gain in children is 3 to 3.5 kg/year adjusted for age, based on Centers for Disease Control and Prevention normative data.

Follow the American Diabetes Association guidelines¹⁰ for monitoring metabolic parameters during antipsychotic
treatment, and intervene if clinically significant weight gain occurs.

In a 16-week, placebo-controlled study,¹¹ metformin reversed weight gain associated with SGAs in children and adolescents. Metformin’s potential side effects include hypoglycemia, diarrhea, nausea/vomiting, and (rarely) lactic acidosis, but no adverse events were attributed to metformin.

Increased prolactin. As in adults, risperidone elevates serum prolactin in children and adolescents. All pediatric risperidone trials—of autism,² disruptive behavior disorders in children with subaverage intelligence,⁹ schizophrenia,⁷ and bipolar mania—have shown increased serum prolactin. Risperidone’s long-term effects on growth and sexual maturation have not been fully evaluated, but hyperprolactinemia may inhibit reproductive function.

Findling et al¹² analyzed data from 5 clinical trials (total 700 patients) in which children and adolescents age 5 to 15 years with subaverage IQs and conduct or other disruptive behavior disorders received risperidone for up to 55 weeks. Mean prolactin levels rose from 7.8 ng/mL
at baseline to 29.4 ng/mL at weeks 4 to 7, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (n=358) and 13.0 ng/mL at weeks 52 to 55 (n=42). Girls returned to a mean value within the normal range (≤30 ng/mL) by weeks 8 to 12, and boys were close to normal values (≤18 ng/mL) by weeks 16 to 24.

The researchers concluded that serum prolactin levels in children tend to rise and peak within the first 1 to 2 months of risperidone treatment and then steadily decline to values within or very close to normal range by 3 to 5 months.

The biological significance of chronic, mild prolactin elevations is unknown.¹³ Children entering puberty appear to be at highest risk for elevated prolactin and clinical symptoms while treated with risperidone.¹⁴ Therefore, ask all adolescents treated with risperidone about increases in breast size and galactorrhea. Switch those who develop these symptoms to an SGA that does not increase serum prolactin.

Contraindications. Risperidone is contraindicated in patients with a known hypersensitivity to the drug.

Related resources

• Risperdal prescribing information. www.risperdal.com/risperdal/shared/pi/risperdal.pdf.

Drug brand names

• Lithium • Eskalith, Lithobid
• Risperidone • Risperdal
• Metformin • Glucophage, Fortamet
• Valproate • Depakote

Disclosures

Dr. Kowatch receives research support from Bristol-Meyers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a consultant for Creative Educational Concepts, Child and Adolescent Bipolar Foundation, Abbott Laboratories, and sanofi-aventis, and a speaker for Abbott Laboratories and AstraZeneca.

Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treating children and adolescents with bipolar mania or schizophrenia. Specifically, the SGA is indicated for treating schizophrenia in patients age 13 to 17 and as monotherapy in short-term treatment of manic or mixed episodes of bipolar I disorder in patients age 10 to 17 (Table 1).

Risperidone also is approved for:

• schizophrenia in adults
• acute mania or mixed episodes associated with bipolar I disorder in adults, alone or in combination with lithium or valproate
• irritability associated with autistic disorder in patients age 5 to 16.

Table 1

Risperidone: Fast facts

Clinical implications

Risperidone is widely used off-label to treat irritability in children with pervasive developmental disorders,^1,2 aggressive behaviors associated with conduct disorder,³ psychotic disorders,⁴ and bipolar disorder.⁵ It also has been used off-label to treat pediatric schizophrenia and bipolar disorder for many years.

These 2 new indications give clinicians additional support for using SGAs in children and adolescents with these serious psychiatric disorders.

How it works

Risperidone’s therapeutic activity in schizophrenia seems to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of risperidone’s other therapeutic effects.

Pharmacokinetics

In children, the half-lives of risperidone and its major active metabolite 9-hydroxyrisperidone are 3±2.3 hours and 22±46 hours, respectively.⁶ The pharmacologic activity of 9-hydroxyrisperidone is similar to that of risperidone.

Risperidone is extensively metabolized in the liver by the cytochrome P-450 (CYP) 2D6 enzyme system. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by CYP 2D6. Food does not affect the rate or extent of the drug’s absorption.⁶

Efficacy studies

In schizophrenia. Approval of the indication for pediatric schizophrenia was based on data from 2 short-term (6 and 8 weeks) randomized, double-blind, controlled trials involving a total of 416 patients age 13 to 17 who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute episode at enrollment.⁷ In one study, patients received risperidone, 1 to 3 mg/d, 4 to 6 mg/d, or placebo. In the other study, dosages were 0.15 to 0.6 mg/d or 1.5 to 6 mg/d. Except for patients in the 0.15 to 0.6 mg group (who initially received 0.05 mg/d), most patients started risperidone at 0.5 mg/d. In both trials, starting dosages were titrated to the target range in approximately 7 days.

Outcomes were measured as changes in total Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale scores. The multi-item PANSS inventory measures positive and negative schizophrenia symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. The PSP gauges personal and social functioning in socially useful activities (work and study), personal and social relationships, self-care, and disturbing/ aggressive behaviors.

Risperidone, 1 to 6 mg/d, improved schizophrenia symptoms significantly more than placebo, as measured by PANSS scores. Doses >3 mg/d did not show greater efficacy than lower doses, as evaluated by PANSS and PSP scores.

Adverse reactions experienced by >5% of patients treated with risperidone included somnolence, parkinsonism, tremor, dystonia, dizziness, akathisia, increased salivation, and anxiety.⁷

In bipolar I disorder. Risperidone’s efficacy for short-term treatment of mania in children and adolescents was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multi-center study of 169 patients age 10 to 17 who were experiencing a manic or mixed episode of bipolar I disorder.⁷ Patients were randomly assigned to risperidone, 0.5 to 2.5 mg/d or 3 to 6 mg/d, or placebo. All patients were started at 0.5 mg/d and this dose was titrated to the target dosage range in 7 days.

Risperidone, 0.5 to 6 mg/d, significantly decreased the total Young Mania Rating Scale score—a measure of the severity of elevated mood, increased motor activity energy, sexual interest, sleep, irritability, speech (rate/amount), language (thought disorder, content, disruptive), aggressive behavior, appearance, and insight. No evidence of increased efficacy was observed at doses >2.5 mg/d. In this trial, symptoms reported by >5% of patients included fatigue, dizziness, dystonia, parkinsonism, akathisia, abdominal pain, dyspepsia, nausea, vomiting, and diarrhea.⁷

Pediatric dosing. Based on these studies, the recommended starting dose for children and adolescents is 0.5 mg/d, with titration in 0.5-to 1-mg increments to targets of:

• 3 mg/d for schizophrenia
• 2.5 mg/d for bipolar mania (Table 2).⁷

Table 2

Recommended dosing of risperidone
for pediatric schizophrenia and bipolar mania

Tolerability studies

In long-term studies, the most commonly reported adverse events associated with risperidone in children and adolescents have been rhinitis, abdominal pain, increased saliva, body pain, gynecomastia, and weight increase.⁸ Specific adverse effects that pose long-term concerns are:

• tardive dyskinesia (TD)
• weight gain
• increased prolactin levels

Tardive dyskinesia. In clinical trials that included 1,885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 2 patients (0.1%) were reported to have TD, which resolved when risperidone was discontinued.⁷ To monitor for TD, administer the Abnormal Involuntary Movement Scale at baseline and every 6 months while using risperidone in pediatric patients.

Weight gain. In long-term, open-label trials, patients with autistic or other psychiatric disorders gained an average 7.5
kg after 12 months of risperidone treatment. Most of the weight gain occurred in the first 6 months.⁹ Expected normal weight gain in children is 3 to 3.5 kg/year adjusted for age, based on Centers for Disease Control and Prevention normative data.

Follow the American Diabetes Association guidelines¹⁰ for monitoring metabolic parameters during antipsychotic
treatment, and intervene if clinically significant weight gain occurs.

In a 16-week, placebo-controlled study,¹¹ metformin reversed weight gain associated with SGAs in children and adolescents. Metformin’s potential side effects include hypoglycemia, diarrhea, nausea/vomiting, and (rarely) lactic acidosis, but no adverse events were attributed to metformin.

Increased prolactin. As in adults, risperidone elevates serum prolactin in children and adolescents. All pediatric risperidone trials—of autism,² disruptive behavior disorders in children with subaverage intelligence,⁹ schizophrenia,⁷ and bipolar mania—have shown increased serum prolactin. Risperidone’s long-term effects on growth and sexual maturation have not been fully evaluated, but hyperprolactinemia may inhibit reproductive function.

Findling et al¹² analyzed data from 5 clinical trials (total 700 patients) in which children and adolescents age 5 to 15 years with subaverage IQs and conduct or other disruptive behavior disorders received risperidone for up to 55 weeks. Mean prolactin levels rose from 7.8 ng/mL
at baseline to 29.4 ng/mL at weeks 4 to 7, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (n=358) and 13.0 ng/mL at weeks 52 to 55 (n=42). Girls returned to a mean value within the normal range (≤30 ng/mL) by weeks 8 to 12, and boys were close to normal values (≤18 ng/mL) by weeks 16 to 24.

The researchers concluded that serum prolactin levels in children tend to rise and peak within the first 1 to 2 months of risperidone treatment and then steadily decline to values within or very close to normal range by 3 to 5 months.

The biological significance of chronic, mild prolactin elevations is unknown.¹³ Children entering puberty appear to be at highest risk for elevated prolactin and clinical symptoms while treated with risperidone.¹⁴ Therefore, ask all adolescents treated with risperidone about increases in breast size and galactorrhea. Switch those who develop these symptoms to an SGA that does not increase serum prolactin.

Contraindications. Risperidone is contraindicated in patients with a known hypersensitivity to the drug.

Related resources

• Risperdal prescribing information. www.risperdal.com/risperdal/shared/pi/risperdal.pdf.

Drug brand names

• Lithium • Eskalith, Lithobid
• Risperidone • Risperdal
• Metformin • Glucophage, Fortamet
• Valproate • Depakote

Disclosures

Dr. Kowatch receives research support from Bristol-Meyers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a consultant for Creative Educational Concepts, Child and Adolescent Bipolar Foundation, Abbott Laboratories, and sanofi-aventis, and a speaker for Abbott Laboratories and AstraZeneca.

Risperidone is the first second-generation antipsychotic (SGA) to receive FDA approval for treating children and adolescents with bipolar mania or schizophrenia. Specifically, the SGA is indicated for treating schizophrenia in patients age 13 to 17 and as monotherapy in short-term treatment of manic or mixed episodes of bipolar I disorder in patients age 10 to 17 (Table 1).

Risperidone also is approved for:

• schizophrenia in adults
• acute mania or mixed episodes associated with bipolar I disorder in adults, alone or in combination with lithium or valproate
• irritability associated with autistic disorder in patients age 5 to 16.

Table 1

Risperidone: Fast facts

Clinical implications

Risperidone is widely used off-label to treat irritability in children with pervasive developmental disorders,^1,2 aggressive behaviors associated with conduct disorder,³ psychotic disorders,⁴ and bipolar disorder.⁵ It also has been used off-label to treat pediatric schizophrenia and bipolar disorder for many years.

These 2 new indications give clinicians additional support for using SGAs in children and adolescents with these serious psychiatric disorders.

How it works

Risperidone’s therapeutic activity in schizophrenia seems to be mediated through a combination of dopamine type 2 (D2) and serotonin type 2 (5HT2) receptor antagonism. Antagonism at receptors other than D2 and 5HT2 may explain some of risperidone’s other therapeutic effects.

Pharmacokinetics

In children, the half-lives of risperidone and its major active metabolite 9-hydroxyrisperidone are 3±2.3 hours and 22±46 hours, respectively.⁶ The pharmacologic activity of 9-hydroxyrisperidone is similar to that of risperidone.

Risperidone is extensively metabolized in the liver by the cytochrome P-450 (CYP) 2D6 enzyme system. The main metabolic pathway is through hydroxylation of risperidone to 9-hydroxyrisperidone by CYP 2D6. Food does not affect the rate or extent of the drug’s absorption.⁶

Efficacy studies

In schizophrenia. Approval of the indication for pediatric schizophrenia was based on data from 2 short-term (6 and 8 weeks) randomized, double-blind, controlled trials involving a total of 416 patients age 13 to 17 who met DSM-IV-TR criteria for schizophrenia and were experiencing an acute episode at enrollment.⁷ In one study, patients received risperidone, 1 to 3 mg/d, 4 to 6 mg/d, or placebo. In the other study, dosages were 0.15 to 0.6 mg/d or 1.5 to 6 mg/d. Except for patients in the 0.15 to 0.6 mg group (who initially received 0.05 mg/d), most patients started risperidone at 0.5 mg/d. In both trials, starting dosages were titrated to the target range in approximately 7 days.

Outcomes were measured as changes in total Positive and Negative Syndrome Scale (PANSS) and Personal and Social Performance (PSP) scale scores. The multi-item PANSS inventory measures positive and negative schizophrenia symptoms, disorganized thoughts, uncontrolled hostility/excitement, and anxiety/depression. The PSP gauges personal and social functioning in socially useful activities (work and study), personal and social relationships, self-care, and disturbing/ aggressive behaviors.

Risperidone, 1 to 6 mg/d, improved schizophrenia symptoms significantly more than placebo, as measured by PANSS scores. Doses >3 mg/d did not show greater efficacy than lower doses, as evaluated by PANSS and PSP scores.

Adverse reactions experienced by >5% of patients treated with risperidone included somnolence, parkinsonism, tremor, dystonia, dizziness, akathisia, increased salivation, and anxiety.⁷

In bipolar I disorder. Risperidone’s efficacy for short-term treatment of mania in children and adolescents was demonstrated in a 3-week, randomized, double-blind, placebo-controlled, multi-center study of 169 patients age 10 to 17 who were experiencing a manic or mixed episode of bipolar I disorder.⁷ Patients were randomly assigned to risperidone, 0.5 to 2.5 mg/d or 3 to 6 mg/d, or placebo. All patients were started at 0.5 mg/d and this dose was titrated to the target dosage range in 7 days.

Risperidone, 0.5 to 6 mg/d, significantly decreased the total Young Mania Rating Scale score—a measure of the severity of elevated mood, increased motor activity energy, sexual interest, sleep, irritability, speech (rate/amount), language (thought disorder, content, disruptive), aggressive behavior, appearance, and insight. No evidence of increased efficacy was observed at doses >2.5 mg/d. In this trial, symptoms reported by >5% of patients included fatigue, dizziness, dystonia, parkinsonism, akathisia, abdominal pain, dyspepsia, nausea, vomiting, and diarrhea.⁷

Pediatric dosing. Based on these studies, the recommended starting dose for children and adolescents is 0.5 mg/d, with titration in 0.5-to 1-mg increments to targets of:

• 3 mg/d for schizophrenia
• 2.5 mg/d for bipolar mania (Table 2).⁷

Table 2

Recommended dosing of risperidone
for pediatric schizophrenia and bipolar mania

Tolerability studies

In long-term studies, the most commonly reported adverse events associated with risperidone in children and adolescents have been rhinitis, abdominal pain, increased saliva, body pain, gynecomastia, and weight increase.⁸ Specific adverse effects that pose long-term concerns are:

• tardive dyskinesia (TD)
• weight gain
• increased prolactin levels

Tardive dyskinesia. In clinical trials that included 1,885 children and adolescents with autistic disorder or other psychiatric disorders treated with risperidone, 2 patients (0.1%) were reported to have TD, which resolved when risperidone was discontinued.⁷ To monitor for TD, administer the Abnormal Involuntary Movement Scale at baseline and every 6 months while using risperidone in pediatric patients.

Weight gain. In long-term, open-label trials, patients with autistic or other psychiatric disorders gained an average 7.5
kg after 12 months of risperidone treatment. Most of the weight gain occurred in the first 6 months.⁹ Expected normal weight gain in children is 3 to 3.5 kg/year adjusted for age, based on Centers for Disease Control and Prevention normative data.

Follow the American Diabetes Association guidelines¹⁰ for monitoring metabolic parameters during antipsychotic
treatment, and intervene if clinically significant weight gain occurs.

In a 16-week, placebo-controlled study,¹¹ metformin reversed weight gain associated with SGAs in children and adolescents. Metformin’s potential side effects include hypoglycemia, diarrhea, nausea/vomiting, and (rarely) lactic acidosis, but no adverse events were attributed to metformin.

Increased prolactin. As in adults, risperidone elevates serum prolactin in children and adolescents. All pediatric risperidone trials—of autism,² disruptive behavior disorders in children with subaverage intelligence,⁹ schizophrenia,⁷ and bipolar mania—have shown increased serum prolactin. Risperidone’s long-term effects on growth and sexual maturation have not been fully evaluated, but hyperprolactinemia may inhibit reproductive function.

Findling et al¹² analyzed data from 5 clinical trials (total 700 patients) in which children and adolescents age 5 to 15 years with subaverage IQs and conduct or other disruptive behavior disorders received risperidone for up to 55 weeks. Mean prolactin levels rose from 7.8 ng/mL
at baseline to 29.4 ng/mL at weeks 4 to 7, then progressively decreased to 16.1 ng/mL at weeks 40 to 48 (n=358) and 13.0 ng/mL at weeks 52 to 55 (n=42). Girls returned to a mean value within the normal range (≤30 ng/mL) by weeks 8 to 12, and boys were close to normal values (≤18 ng/mL) by weeks 16 to 24.

The researchers concluded that serum prolactin levels in children tend to rise and peak within the first 1 to 2 months of risperidone treatment and then steadily decline to values within or very close to normal range by 3 to 5 months.

The biological significance of chronic, mild prolactin elevations is unknown.¹³ Children entering puberty appear to be at highest risk for elevated prolactin and clinical symptoms while treated with risperidone.¹⁴ Therefore, ask all adolescents treated with risperidone about increases in breast size and galactorrhea. Switch those who develop these symptoms to an SGA that does not increase serum prolactin.

Contraindications. Risperidone is contraindicated in patients with a known hypersensitivity to the drug.

Related resources

• Risperdal prescribing information. www.risperdal.com/risperdal/shared/pi/risperdal.pdf.

Drug brand names

• Lithium • Eskalith, Lithobid
• Risperidone • Risperdal
• Metformin • Glucophage, Fortamet
• Valproate • Depakote

Disclosures

Dr. Kowatch receives research support from Bristol-Meyers Squibb, Stanley Research Foundation, National Institute of Mental Health, and National Institute of Child Health and Human Development. He is a consultant for Creative Educational Concepts, Child and Adolescent Bipolar Foundation, Abbott Laboratories, and sanofi-aventis, and a speaker for Abbott Laboratories and AstraZeneca.

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.

In recent clinical trials, a new intramuscular (IM) form of the second-generation antipsychotic (SGA) aripiprazole has controlled agitation in adults with schizophrenia or bipolar mania without causing significant side effects (Table 1).^1-3

Table 1

IM aripiprazole: Fast facts

Clinical implications

Rapid intervention is critical to protecting the patient and caregivers when violent and/or destructive behavior accompanies agitation. IM aripiprazole substantially reduced agitation within 45 to 60 minutes of dosing in randomized, double-blind, placebo-controlled studies.^1-3

How it works

Whereas other SGAs have relatively little effect on D₂ (dopamine) receptors and relatively high 5-HT_2A (serotonin) receptor affinities, aripiprazole appears to work via partial D₂ receptor agonism. The medication:

• blocks D₂ receptors in brain regions where dopamine is overactive in schizophrenia, such as the mesolimbic pathway. This produces an antipsychotic effect.
• maintains or moderately boosts dopamine activity as needed in regions such as the nigrostriatal pathway. This reduces the risk of motor side effects and might improve negative and cognitive schizophrenia symptoms.

Aripiprazole is a partial 5-HT_1A receptor agonist and—like other SGAs—a 5-HT_2A receptor antagonist. These receptor subtypes have been implicated in antipsychotic action. In particular, partial 5-HT_1A receptor agonism is thought to help:

• reduce anxiety
• lessen depressive, negative, and cognitive symptoms
• decrease extrapyramidal symptom (EPS) liability.⁴

Aripiprazole also has moderate affinity for histaminic and alpha-adrenergic receptors and no appreciable effect on cholinergic muscarinic receptors.^5-8

Pharmacokinetics

IM aripiprazole’s activity has been attributed to its parent drug and to a lesser extent its major metabolite, dehydroaripiprazole. Both moieties act on D₂ receptors, and dehydroaripiprazole accounts for 40% of the parent drug’s exposure in plasma.

Mean elimination half-lives for aripiprazole and dehydroaripiprazole are approximately 75 and 94 hours, respectively, allowing for daily administration. Both active moieties reach steady-state concentration within 14 days of dosing. Because aripiprazole accumulation is predictable after a single dose and its pharmacokinetics are dose-proportional at steady state, higher doses are not always more effective and could increase side-effect risk.

Aripiprazole is metabolized mainly through the liver by cytochrome P-450 2D6 and 3A4 isozymes. This requires careful monitoring when prescribing the drug concomitantly with:

• agents that induce CYP 3A4—such as carbamazepine—which could diminish aripiprazole’s effectiveness by increasing its clearance and decreasing aripiprazole blood levels
• CYP 3A4 inhibitors such as ketoconazole or CYP 2D6 inhibitors such as quinidine, fluoxetine, or paroxetine, which can inhibit aripiprazole elimination⁹ and increase the risk of adverse events.

Similarly, aripiprazole could be efficacious at lower-than-therapeutic dosages when taken with medications that raise aripiprazole blood levels.

Efficacy

In 3 randomized, placebo-controlled, double-blind trials, IM aripiprazole reduced agitation in inpatients with schizophrenia, schizoaffective disorder, or type I bipolar disorder with manic or mixed episodes, with or without psychotic features.

In each trial, IM aripiprazole was as effective as comparable dosages of haloperidol or lorazepam IM preparations. Patients were moderately to severely agitated based on Positive and Negative Syndrome Scale Excited Component (PANSS-EC) assessments, which gauged impulse control, tension, hostility, uncooperativeness, and excitement.

Patients could receive up to 3 injections within 24 hours but had to wait ≥2 hours for the second injection so that investigators could record follow-up PANSS-EC scores. Clinical Global Impression of Improvement (CGI-I) scale scores were a key secondary measure.

Examination of population subsets in the studies showed no differential response based on age, race, or gender.

Tran-Johnson et al¹followed 357 patients with schizophreniform disorders, schizophrenia, or schizoaffective disorders.

Two hours after initial injection, mean PANSS-EC scores decreased approximately 3 points with placebo and 4 to 6.5 points among patients receiving 7.5 mg of IM haloperidol or 5.25, 9.75, or 15 mg of IM aripiprazole. Agitation improved significantly after 45 minutes among patients receiving 9.75 mg of IM aripiprazole, compared with 105 minutes in the IM haloperidol group.

Prevalence of EPS across 24 hours with haloperidol was 19.3%, compared with an average 5.2% among all IM aripiprazole groups, suggesting that IM aripiprazole carries a substantially lower EPS risk.

Andrezina et al²followed 448 patients with schizophrenia or schizoaffective disorder. Two hours after injection, patients in both treatment groups showed much greater improvement compared with placebo based on mean PANSS-EC score decreases and mean CGI-I scores (Table 2).

Prevalence of EPS was 1.7% with IM aripiprazole, 2.3% with placebo, and 12.6% with IM haloperidol. Prevalence of EPS-related adverse events was 0% with IM aripiprazole, 1.6% with placebo, and 16.5% with IM haloperidol.

Zimbroff et al³ gave IM aripiprazole, 9.75 or 15 mg; IM lorazepam, 2 mg; or placebo to 301 patients with type I bipolar disorder with manic or mixed episodes.

Two hours later, all 3 treatment groups showed significantly greater agitation improvement as shown by PANSS-EC scores, compared with placebo (Table 3).

Across 2 hours, oversedation—defined as an Agitation-Calmness Evaluation Scale score of 8 or 9—was less prevalent among patients receiving IM aripiprazole, 9.75 mg (6.7%), compared with IM aripiprazole, 15 mg (17.3%), or IM lorazepam (19.1%).

Table 2

Agitation, symptom improvement 2 hours after aripiprazole or haloperidol injection

Table 3

Agitation improvement 2 hours after aripiprazole or lorazepam injection

Safety and tolerability

IM aripiprazole was well tolerated in clinical trials and did not cause excessive sedation¹⁰ or injection-site pain.^1-3

Most frequently reported adverse events were headache (12% with IM aripiprazole vs 7% with placebo), nausea (9% vs 3%), dizziness (8% vs 5%), and somnolence (7% vs 4%).

Prevalence of akathisia or dystonia among all IM aripiprazole groups in the 3 trials was 2% and

No clinically significant ECG abnormalities were reported among the aripiprazole groups.^1-3,11

Dosing

Start at 9.75 mg every 2 hours as needed, but do not exceed 30 mg/d across 24 hours. Controlled studies have not evaluated efficacy or safety of more-frequent injections or safety of total daily doses >30 mg.

Try a lower dose (5.25 mg) for patients who are elderly or small in body size or have reacted adversely to other antipsychotics. If necessary, give another 5.25 mg in 2 hours. If the patient is still agitated 2 hours after the second dose, consider a third dose at 9.75 mg. Again, do not exceed 30 mg over 24 hours. Obtain lower doses by administering a portion of the vial.

Transitioning to oral Tx

If IM aripiprazole reduces psychotic symptoms as well as acute behaviors, switch the patient to oral aripiprazole once the risk of violence has diminished.¹² If psychosis does not improve with IM aripiprazole, weigh clinical factors before choosing an oral antipsychotic.

Only one controlled trial¹² has examined transitioning from IM aripiprazole to an oral antipsychotic. In the randomized study, 448 patients receiving IM aripiprazole, 9.75 mg; IM haloperidol, 6.5 mg; or placebo for agitation secondary to schizophrenia or schizoaffective disorder were transitioned to the oral preparation of the drug they were receiving: aripiprazole, 10 to 15 mg/d, or haloperidol, 7.5 to 10 mg/d. Placebo-group patients transitioned to oral aripiprazole.

Over 4 days, both oral treatments provided continued efficacy, suggesting that:

• patients receiving IM aripiprazole can be conveniently switched to the oral preparation
• IM and oral aripiprazole are equally safe.

Oral and IM aripiprazole doses are equivalent and the pharmacokinetics are comparable. For example, a patient receiving 20 mg/d of IM aripiprazole can take 20 mg of oral aripiprazole within 24 hours of the last injection.

Related resources

• Allen MH, Currier GW, Carpenter D, et al. Expert consensus guidelines: treatment of behavioral emergencies. J Psychiatr Pract 2005;11(suppl 1):5-108.
• Currier GW, Citrome LL, Zimbroff DL, et al. Intramuscular aripiprazole in the control of agitation. J Psychiatr Pract 2007;13:159-69.

Drug brand names

• Aripiprazole IM • Abilify
• Carbamazepine • Tegretol, others
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Ketoconazole • Nizoral
• Lorazepam • Ativan
• Paroxetine • Paxil
• Quinidine • Quinaglute

Disclosure

Dr. Josiassen was principal investigator and Dr. Shaughnessy a co-investigator on a pre-approval clinical trial of IM aripiprazole. Both have conducted sponsor- and investigator-initiated studies for AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, Janssen, Novartis Pharmaceuticals Corp., Organon, Otsuka America Pharmaceuticals, Otsuka Maryland Research Institute, Pfizer, and Yamanuchi.

Acknowledgments

This article was supported in part by the Arthur P. Noyes Research Foundation.

The authors thank Margit Kacso, Cara Bendler, Dawn Filmyer, and Jon Weinstein for their technical and editorial assistance in preparing this article.

Varenicline tartrate—the first nicotine-free medication FDA-approved for smoking cessation in nearly a decade (Table 1)—has helped patients stop smoking and remain smoke-free for up to 1 year in clinical trials. Its selective action on the receptor subtype that makes tobacco enjoyable offers a novel approach to antismoking therapy.

Table 1

Varenicline: Fast facts

How it works

Unlike other FDA-approved smoking cessation treatments such as nicotine replacement therapy and sustained-release bupropion, varenicline selectively targets the α4β2 nicotinic acetylcholine receptor (nAChR),¹ which helps mediate nicotine’s reinforcing effects.^2-4 By targeting this receptor subtype, varenicline ultimately diminishes these effects in the mesocorticolimbic dopamine system—the brain’s “reward center.”

As a partial α4β2 nAChR agonist, varenicline offers a two-pronged approach to smoking cessation:¹

• During abstinence, varenicline stimulates low-level dopamine release by binding to α4β2 receptors located on dopamine neurons. This action, which compensates for loss of exogenous nicotine after quitting, can help counteract craving and other signs and symptoms of nicotine withdrawal caused by dopamine depletion.
• If the patient resumes smoking, varenicline makes tobacco less pleasurable by competitively binding at the α4β2 receptor.^1,5

Pharmacokinetics

Varenicline is rapidly absorbed across the gut mucosa and reaches maximum concentration in approximately 4 hours. After repeated dosing, the drug reaches steady-state concentrations within 4 days, and its elimination half-life is 17 to 24 hours.

Because varenicline’s simple benzazepine structure lacks bulky moieties that would promote hepatic biotransformation,⁵ 90% of the drug is excreted through the kidneys. To date, no clinically relevant drug-drug interactions have been reported.⁶

Efficacy

Varenicline showed a dose-dependent effect in phase-2 clinical trials,^7,8 with 1 mg bid providing optimal efficacy and tolerability. Compared with placebo, varenicline was significantly more effective in initiating:

• continuous abstinence for ≥4 weeks during active treatment, confirmed by measuring carbon monoxide (CO) in exhaled breath
• long-term abstinence, evidenced by self-report and exhaled CO ≤10 ppm at 24 and 52 weeks.^7,8

Odds ratios calculated for patients who stayed smoke-free for ≥4 weeks during 7 to 12 weeks of active treatment suggest that smokers who use varenicline, 1 mg bid, are approximately 4 to 8 times more likely to achieve short-term abstinence during this active treatment period than those who received placebo.^7,8

In phase-3 trials,^9-11 patients were also followed for up to 1 year and received brief, standardized counseling along with medication or placebo—as recommended in the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence.¹²

12-week treatment trials.^9,10 A total of 2,052 adults in two randomized, double-blind trials received varenicline, sustained-release (SR) bupropion, or placebo for 12 weeks. Based on phase-2 trial results—which showed that varenicline was better tolerated after a 1-week dosage titration period—varenicline was given at:

• 0.5 mg/d for days 1 through 3
• 0.5 mg bid for days 4 through 7
• 1 mg bid through week 12.

Bupropion SR was given at 150 mg/d for days 1 through 3, then 150 mg bid through week 12.

Patients were then followed for up to 40 weeks after drug discontinuation. Patients had been smoking ≥10 cigarettes/day at baseline and were motivated to stop smoking.

Overall, varenicline was associated with higher short- and long-term abstinence rates compared with bupropion SR or placebo (Table 2), although the comparison with bupropion SR was not statistically significant (P=0.057) for weeks 9 through 52 in one study.⁹ As in the phase-2 studies, abstinence was confirmed by measuring CO in exhaled breath.

Compared with placebo, varenicline also reduced cravings and other signs and symptoms of tobacco withdrawal as measured with the Brief Questionnaire of Smoking Urges and Minnesota Nicotine Withdrawal Scale.^9,10

Relapse prevention study. Tonstad et al¹¹ investigated whether extended varenicline treatment prolongs smoking abstinence. A total of 1,210 patients who quit smoking after 12 weeks of open-label varenicline treatment continued taking varenicline at 1 mg bid or were switched to placebo during a 3-month, double-blind phase.

Compared with placebo, rates of continuous smoking abstinence were significantly higher among the varenicline group during the double-blind active treatment phase (70.5% vs. 49.6%) and for 6 months after drug discontinuation (43.6% vs. 36.9%).¹¹ These data suggest that an extended varenicline regimen might promote long-term abstinence.^6,13

Table 2

Smoking abstinence* rates among patients
during varenicline phase-3 clinical trials

Tolerability

Overall, varenicline was safe and well tolerated in clinical trials.

Nausea was the most commonly reported adverse event in fixed-dose, placebo-controlled studies.⁶ Although approximately 3% of patients stopped varenicline prematurely because of upset stomach,⁶ most rated their nausea as mild to moderate and reported reduced nausea with continued varenicline use. For patients with intolerable nausea, consider reducing the dosage.

Sleep disturbance, constipation, flatulence, and vomiting were twice as prevalent among the varenicline groups compared with placebo.⁶ Overall treatment discontinuation rates were similar with varenicline, 1 mg bid, and placebo (12% vs. 10%) in 12-week phase-2 and phase-3 clinical trials.⁶

To improve tolerability, the FDA recommends splitting varenicline into twice-daily doses.^6,13

Dosing

Start varenicline at 0.5 mg/d for 3 days, 0.5 mg bid for the next 4 days, then 1 mg bid through week 12. To improve tolerability, advise patients to take varenicline after eating and with a full glass of water.

Setting a target quit date (TQD) is a critical element of smoking cessation treatment. Schedule the TQD for the same day the patient begins 1 mg bid varenicline dosing so that the medication is approaching maximal steady-state concentrations during the quit attempt to help counter withdrawal. Allow patients to continue smoking during the 1-week titration period, but stress the importance of trying to quit on the TQD.

Because varenicline is primarily eliminated through the kidneys, limit dosages to 0.5 mg bid in patients with severe renal impairment (estimated creatinine clearance 6,13

Varenicline has not been studied in patients with substance use and other psychiatric disorders—patients who account for most of a psychiatrist’s caseload and whose nicotine dependence is difficult to treat. Even so, the medication’s lack of discernible drug-drug interactions and selectivity of α4β2 nAChR action make varenicline worth considering for these patients.

Varenicline also has not been tested or approved for use in adolescent or pregnant smokers; research is needed on how the medication works in these patients.

Role of behavioral treatment

The Clinical Practice Guideline, Treating Tobacco Use and Dependence¹² suggests combining antismoking pharmacotherapy with counseling to maximize outcome. To that end, varenicline’s manufacturer has developed a personalized behavioral support program for patients taking the medication.¹⁴ Adjunctive therapy via the Internet, telephone, or direct mail can complement other extra-treatment supports—such as toll-free quit lines and classes offered through health organizations—and more-formal, intensive behavioral interventions.

Related resources

• Varenicline Web site. www.chantix.com.
• World Health Organization. Causes of death. In: Epidemiology and burden of disease. Geneva: World Health Organization, 2003.
• Fiore MC, Bailey WC, Cohen SJ, et al. Clinical practice guideline. Treating tobacco use and dependence. Rockville, MD: U.S. Department of Health and Human Services, 2000. www.surgeongeneral.gov/tobacco/treating_tobacco_use.pdf.

Drug brand names

• Bupropion SR • Wellbutrin, Zyban
• Varenicline • Chantix

Disclosures

Dr. Anthenelli is a consultant for Alkermes and Cephalon and a speaker and consultant for Pfizer and sanofi-aventis.

The Tri-State Tobacco and Alcohol Research Center receives research grants from Addex, Ortho-McNeil Neurologics, and sanofi-aventis.

Dr. Anthenelli and the Tri-State Tobacco and Alcohol Research Center were members of the Varenicline Study Group.

Acknowledgments

The writing of this article was supported in part by National Institutes of Health Grant Awards Nos. AA013957 and AA013307.

The author thanks Reene Cantwell for her technical assistance in preparing this article.

Varenicline tartrate—the first nicotine-free medication FDA-approved for smoking cessation in nearly a decade (Table 1)—has helped patients stop smoking and remain smoke-free for up to 1 year in clinical trials. Its selective action on the receptor subtype that makes tobacco enjoyable offers a novel approach to antismoking therapy.

Table 1

Varenicline: Fast facts

How it works

Unlike other FDA-approved smoking cessation treatments such as nicotine replacement therapy and sustained-release bupropion, varenicline selectively targets the α4β2 nicotinic acetylcholine receptor (nAChR),¹ which helps mediate nicotine’s reinforcing effects.^2-4 By targeting this receptor subtype, varenicline ultimately diminishes these effects in the mesocorticolimbic dopamine system—the brain’s “reward center.”

As a partial α4β2 nAChR agonist, varenicline offers a two-pronged approach to smoking cessation:¹

• During abstinence, varenicline stimulates low-level dopamine release by binding to α4β2 receptors located on dopamine neurons. This action, which compensates for loss of exogenous nicotine after quitting, can help counteract craving and other signs and symptoms of nicotine withdrawal caused by dopamine depletion.
• If the patient resumes smoking, varenicline makes tobacco less pleasurable by competitively binding at the α4β2 receptor.^1,5

Pharmacokinetics

Varenicline is rapidly absorbed across the gut mucosa and reaches maximum concentration in approximately 4 hours. After repeated dosing, the drug reaches steady-state concentrations within 4 days, and its elimination half-life is 17 to 24 hours.

Because varenicline’s simple benzazepine structure lacks bulky moieties that would promote hepatic biotransformation,⁵ 90% of the drug is excreted through the kidneys. To date, no clinically relevant drug-drug interactions have been reported.⁶

Efficacy

Varenicline showed a dose-dependent effect in phase-2 clinical trials,^7,8 with 1 mg bid providing optimal efficacy and tolerability. Compared with placebo, varenicline was significantly more effective in initiating:

• continuous abstinence for ≥4 weeks during active treatment, confirmed by measuring carbon monoxide (CO) in exhaled breath
• long-term abstinence, evidenced by self-report and exhaled CO ≤10 ppm at 24 and 52 weeks.^7,8

Odds ratios calculated for patients who stayed smoke-free for ≥4 weeks during 7 to 12 weeks of active treatment suggest that smokers who use varenicline, 1 mg bid, are approximately 4 to 8 times more likely to achieve short-term abstinence during this active treatment period than those who received placebo.^7,8

In phase-3 trials,^9-11 patients were also followed for up to 1 year and received brief, standardized counseling along with medication or placebo—as recommended in the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence.¹²

12-week treatment trials.^9,10 A total of 2,052 adults in two randomized, double-blind trials received varenicline, sustained-release (SR) bupropion, or placebo for 12 weeks. Based on phase-2 trial results—which showed that varenicline was better tolerated after a 1-week dosage titration period—varenicline was given at:

• 0.5 mg/d for days 1 through 3
• 0.5 mg bid for days 4 through 7
• 1 mg bid through week 12.

Bupropion SR was given at 150 mg/d for days 1 through 3, then 150 mg bid through week 12.

Patients were then followed for up to 40 weeks after drug discontinuation. Patients had been smoking ≥10 cigarettes/day at baseline and were motivated to stop smoking.

Overall, varenicline was associated with higher short- and long-term abstinence rates compared with bupropion SR or placebo (Table 2), although the comparison with bupropion SR was not statistically significant (P=0.057) for weeks 9 through 52 in one study.⁹ As in the phase-2 studies, abstinence was confirmed by measuring CO in exhaled breath.

Compared with placebo, varenicline also reduced cravings and other signs and symptoms of tobacco withdrawal as measured with the Brief Questionnaire of Smoking Urges and Minnesota Nicotine Withdrawal Scale.^9,10

Relapse prevention study. Tonstad et al¹¹ investigated whether extended varenicline treatment prolongs smoking abstinence. A total of 1,210 patients who quit smoking after 12 weeks of open-label varenicline treatment continued taking varenicline at 1 mg bid or were switched to placebo during a 3-month, double-blind phase.

Compared with placebo, rates of continuous smoking abstinence were significantly higher among the varenicline group during the double-blind active treatment phase (70.5% vs. 49.6%) and for 6 months after drug discontinuation (43.6% vs. 36.9%).¹¹ These data suggest that an extended varenicline regimen might promote long-term abstinence.^6,13

Table 2

Smoking abstinence* rates among patients
during varenicline phase-3 clinical trials

Tolerability

Overall, varenicline was safe and well tolerated in clinical trials.

Nausea was the most commonly reported adverse event in fixed-dose, placebo-controlled studies.⁶ Although approximately 3% of patients stopped varenicline prematurely because of upset stomach,⁶ most rated their nausea as mild to moderate and reported reduced nausea with continued varenicline use. For patients with intolerable nausea, consider reducing the dosage.

Sleep disturbance, constipation, flatulence, and vomiting were twice as prevalent among the varenicline groups compared with placebo.⁶ Overall treatment discontinuation rates were similar with varenicline, 1 mg bid, and placebo (12% vs. 10%) in 12-week phase-2 and phase-3 clinical trials.⁶

To improve tolerability, the FDA recommends splitting varenicline into twice-daily doses.^6,13

Dosing

Start varenicline at 0.5 mg/d for 3 days, 0.5 mg bid for the next 4 days, then 1 mg bid through week 12. To improve tolerability, advise patients to take varenicline after eating and with a full glass of water.

Setting a target quit date (TQD) is a critical element of smoking cessation treatment. Schedule the TQD for the same day the patient begins 1 mg bid varenicline dosing so that the medication is approaching maximal steady-state concentrations during the quit attempt to help counter withdrawal. Allow patients to continue smoking during the 1-week titration period, but stress the importance of trying to quit on the TQD.

Because varenicline is primarily eliminated through the kidneys, limit dosages to 0.5 mg bid in patients with severe renal impairment (estimated creatinine clearance 6,13

Varenicline has not been studied in patients with substance use and other psychiatric disorders—patients who account for most of a psychiatrist’s caseload and whose nicotine dependence is difficult to treat. Even so, the medication’s lack of discernible drug-drug interactions and selectivity of α4β2 nAChR action make varenicline worth considering for these patients.

Varenicline also has not been tested or approved for use in adolescent or pregnant smokers; research is needed on how the medication works in these patients.

Role of behavioral treatment

The Clinical Practice Guideline, Treating Tobacco Use and Dependence¹² suggests combining antismoking pharmacotherapy with counseling to maximize outcome. To that end, varenicline’s manufacturer has developed a personalized behavioral support program for patients taking the medication.¹⁴ Adjunctive therapy via the Internet, telephone, or direct mail can complement other extra-treatment supports—such as toll-free quit lines and classes offered through health organizations—and more-formal, intensive behavioral interventions.

Related resources

• Varenicline Web site. www.chantix.com.
• World Health Organization. Causes of death. In: Epidemiology and burden of disease. Geneva: World Health Organization, 2003.
• Fiore MC, Bailey WC, Cohen SJ, et al. Clinical practice guideline. Treating tobacco use and dependence. Rockville, MD: U.S. Department of Health and Human Services, 2000. www.surgeongeneral.gov/tobacco/treating_tobacco_use.pdf.

Drug brand names

• Bupropion SR • Wellbutrin, Zyban
• Varenicline • Chantix

Disclosures

Dr. Anthenelli is a consultant for Alkermes and Cephalon and a speaker and consultant for Pfizer and sanofi-aventis.

The Tri-State Tobacco and Alcohol Research Center receives research grants from Addex, Ortho-McNeil Neurologics, and sanofi-aventis.

Dr. Anthenelli and the Tri-State Tobacco and Alcohol Research Center were members of the Varenicline Study Group.

Acknowledgments

The writing of this article was supported in part by National Institutes of Health Grant Awards Nos. AA013957 and AA013307.

The author thanks Reene Cantwell for her technical assistance in preparing this article.

Varenicline tartrate—the first nicotine-free medication FDA-approved for smoking cessation in nearly a decade (Table 1)—has helped patients stop smoking and remain smoke-free for up to 1 year in clinical trials. Its selective action on the receptor subtype that makes tobacco enjoyable offers a novel approach to antismoking therapy.

Table 1

Varenicline: Fast facts

How it works

Unlike other FDA-approved smoking cessation treatments such as nicotine replacement therapy and sustained-release bupropion, varenicline selectively targets the α4β2 nicotinic acetylcholine receptor (nAChR),¹ which helps mediate nicotine’s reinforcing effects.^2-4 By targeting this receptor subtype, varenicline ultimately diminishes these effects in the mesocorticolimbic dopamine system—the brain’s “reward center.”

As a partial α4β2 nAChR agonist, varenicline offers a two-pronged approach to smoking cessation:¹

• During abstinence, varenicline stimulates low-level dopamine release by binding to α4β2 receptors located on dopamine neurons. This action, which compensates for loss of exogenous nicotine after quitting, can help counteract craving and other signs and symptoms of nicotine withdrawal caused by dopamine depletion.
• If the patient resumes smoking, varenicline makes tobacco less pleasurable by competitively binding at the α4β2 receptor.^1,5

Pharmacokinetics

Varenicline is rapidly absorbed across the gut mucosa and reaches maximum concentration in approximately 4 hours. After repeated dosing, the drug reaches steady-state concentrations within 4 days, and its elimination half-life is 17 to 24 hours.

Because varenicline’s simple benzazepine structure lacks bulky moieties that would promote hepatic biotransformation,⁵ 90% of the drug is excreted through the kidneys. To date, no clinically relevant drug-drug interactions have been reported.⁶

Efficacy

Varenicline showed a dose-dependent effect in phase-2 clinical trials,^7,8 with 1 mg bid providing optimal efficacy and tolerability. Compared with placebo, varenicline was significantly more effective in initiating:

• continuous abstinence for ≥4 weeks during active treatment, confirmed by measuring carbon monoxide (CO) in exhaled breath
• long-term abstinence, evidenced by self-report and exhaled CO ≤10 ppm at 24 and 52 weeks.^7,8

Odds ratios calculated for patients who stayed smoke-free for ≥4 weeks during 7 to 12 weeks of active treatment suggest that smokers who use varenicline, 1 mg bid, are approximately 4 to 8 times more likely to achieve short-term abstinence during this active treatment period than those who received placebo.^7,8

In phase-3 trials,^9-11 patients were also followed for up to 1 year and received brief, standardized counseling along with medication or placebo—as recommended in the U.S. Department of Health and Human Services Clinical Practice Guideline, Treating Tobacco Use and Dependence.¹²

12-week treatment trials.^9,10 A total of 2,052 adults in two randomized, double-blind trials received varenicline, sustained-release (SR) bupropion, or placebo for 12 weeks. Based on phase-2 trial results—which showed that varenicline was better tolerated after a 1-week dosage titration period—varenicline was given at:

• 0.5 mg/d for days 1 through 3
• 0.5 mg bid for days 4 through 7
• 1 mg bid through week 12.

Bupropion SR was given at 150 mg/d for days 1 through 3, then 150 mg bid through week 12.

Patients were then followed for up to 40 weeks after drug discontinuation. Patients had been smoking ≥10 cigarettes/day at baseline and were motivated to stop smoking.

Overall, varenicline was associated with higher short- and long-term abstinence rates compared with bupropion SR or placebo (Table 2), although the comparison with bupropion SR was not statistically significant (P=0.057) for weeks 9 through 52 in one study.⁹ As in the phase-2 studies, abstinence was confirmed by measuring CO in exhaled breath.

Compared with placebo, varenicline also reduced cravings and other signs and symptoms of tobacco withdrawal as measured with the Brief Questionnaire of Smoking Urges and Minnesota Nicotine Withdrawal Scale.^9,10

Relapse prevention study. Tonstad et al¹¹ investigated whether extended varenicline treatment prolongs smoking abstinence. A total of 1,210 patients who quit smoking after 12 weeks of open-label varenicline treatment continued taking varenicline at 1 mg bid or were switched to placebo during a 3-month, double-blind phase.

Compared with placebo, rates of continuous smoking abstinence were significantly higher among the varenicline group during the double-blind active treatment phase (70.5% vs. 49.6%) and for 6 months after drug discontinuation (43.6% vs. 36.9%).¹¹ These data suggest that an extended varenicline regimen might promote long-term abstinence.^6,13

Table 2

Smoking abstinence* rates among patients
during varenicline phase-3 clinical trials

Tolerability

Overall, varenicline was safe and well tolerated in clinical trials.

Nausea was the most commonly reported adverse event in fixed-dose, placebo-controlled studies.⁶ Although approximately 3% of patients stopped varenicline prematurely because of upset stomach,⁶ most rated their nausea as mild to moderate and reported reduced nausea with continued varenicline use. For patients with intolerable nausea, consider reducing the dosage.

Sleep disturbance, constipation, flatulence, and vomiting were twice as prevalent among the varenicline groups compared with placebo.⁶ Overall treatment discontinuation rates were similar with varenicline, 1 mg bid, and placebo (12% vs. 10%) in 12-week phase-2 and phase-3 clinical trials.⁶

To improve tolerability, the FDA recommends splitting varenicline into twice-daily doses.^6,13

Dosing

Start varenicline at 0.5 mg/d for 3 days, 0.5 mg bid for the next 4 days, then 1 mg bid through week 12. To improve tolerability, advise patients to take varenicline after eating and with a full glass of water.

Setting a target quit date (TQD) is a critical element of smoking cessation treatment. Schedule the TQD for the same day the patient begins 1 mg bid varenicline dosing so that the medication is approaching maximal steady-state concentrations during the quit attempt to help counter withdrawal. Allow patients to continue smoking during the 1-week titration period, but stress the importance of trying to quit on the TQD.

Because varenicline is primarily eliminated through the kidneys, limit dosages to 0.5 mg bid in patients with severe renal impairment (estimated creatinine clearance 6,13

Varenicline has not been studied in patients with substance use and other psychiatric disorders—patients who account for most of a psychiatrist’s caseload and whose nicotine dependence is difficult to treat. Even so, the medication’s lack of discernible drug-drug interactions and selectivity of α4β2 nAChR action make varenicline worth considering for these patients.

Varenicline also has not been tested or approved for use in adolescent or pregnant smokers; research is needed on how the medication works in these patients.

Role of behavioral treatment

The Clinical Practice Guideline, Treating Tobacco Use and Dependence¹² suggests combining antismoking pharmacotherapy with counseling to maximize outcome. To that end, varenicline’s manufacturer has developed a personalized behavioral support program for patients taking the medication.¹⁴ Adjunctive therapy via the Internet, telephone, or direct mail can complement other extra-treatment supports—such as toll-free quit lines and classes offered through health organizations—and more-formal, intensive behavioral interventions.

Related resources

• Varenicline Web site. www.chantix.com.
• World Health Organization. Causes of death. In: Epidemiology and burden of disease. Geneva: World Health Organization, 2003.
• Fiore MC, Bailey WC, Cohen SJ, et al. Clinical practice guideline. Treating tobacco use and dependence. Rockville, MD: U.S. Department of Health and Human Services, 2000. www.surgeongeneral.gov/tobacco/treating_tobacco_use.pdf.

Drug brand names

• Bupropion SR • Wellbutrin, Zyban
• Varenicline • Chantix

Disclosures

Dr. Anthenelli is a consultant for Alkermes and Cephalon and a speaker and consultant for Pfizer and sanofi-aventis.

The Tri-State Tobacco and Alcohol Research Center receives research grants from Addex, Ortho-McNeil Neurologics, and sanofi-aventis.

Dr. Anthenelli and the Tri-State Tobacco and Alcohol Research Center were members of the Varenicline Study Group.

Acknowledgments

The writing of this article was supported in part by National Institutes of Health Grant Awards Nos. AA013957 and AA013307.

The author thanks Reene Cantwell for her technical assistance in preparing this article.

Paliperidone, a second-generation antipsychotic (SGA), was awaiting FDA approval for treating schizophrenia (Table 1) at press time. FDA issued an approvable letter September 29.

The long-acting oral medication can be given once daily, without the plasma level peaks and troughs associated with other SGAs.

Table 1

Paliperidone: Fast facts

Clinical implications

Paliperidone—the active metabolite of risperidone (9-hydroxy risperidone)—produces the same effects as its parent compound. Because it is metabolized less by the liver, however, paliperidone will likely have a lower risk of drug-drug interactions than risperidone.

Paliperidone can help patients with hallucinations, delusions, and other florid psychotic symptoms. Once-daily dosing could also make it easier for patients with schizophrenia to adhere to treatment.

Paliperidone caused relatively few side effects in clinical trials, indicating that the drug could be started at therapeutic dosages. A 6-mg dose reaches clinically effective plasma levels in approximately 22 hours; a higher dosage might take less time.

How it works

As with all antipsychotics, paliperidone blocks dopamine uptake (D2 receptors) and—as with other newer SGAs—it has a high affinity for 5-HT (serotonin) receptors. This serotonergic action may help modulate side effects.

Paliperidone has shown antipsychotic effectiveness at 3 to 15 mg/d, and a 6-mg dosage is no more likely to cause extrapyramidal symptoms (EPS) or other adverse events than olanzapine, 10 mg/d, or placebo.^1-3 This finding suggests that 6 mg/d might be a suitable starting dosage for most patients.

Clinical findings

Efficacy. The drug showed efficacy for treating acute schizophrenia in three randomized, double-blind, controlled trials.

In a 6-week study,¹ 444 patients who were experiencing acute schizophrenia episodes and had Positive and Negative Syndrome Scale (PANSS) scores between 70 and 120 received paliperidone, 6 or 12 mg/d, olanzapine, 10 mg/d, or placebo. The study was powered to compare paliperidone and placebo; the olanzapine group was included to confirm study sensitivity.

Mean baseline total and negative symptom PANSS scores improved twice as much among the paliperidone and olanzapine groups compared with placebo (Table 2). Personal and Social Performance (PSP) scale scores also improved significantly among patients receiving paliperidone, 6 mg/d. The PSP scale gauges function, ability to perform socially useful activities such as self-care and work, and disturbing and aggressive behavior.

In two similarly designed, 6-week studies (N=1,248),^2,3 paliperidone at 3, 6, 9, or 12 mg/d produced statistically significant improvement in total and negative symptom PANSS scores and PSP scale scores compared with placebo.

Table 2

Mean PANSS score reductions among patients taking paliperidone, olanzapine, or placebo

Relapse prevention. Kramer et al⁴ measured paliperidone’s ability to prevent or delay schizophrenia recurrence among 205 patients experiencing an episode. Participants had been diagnosed with schizophrenia at least 1 year earlier and had PANSS total scores between 70 and 120. Patients with substance dependence or other axis I disorders were excluded.

Over an 8-week run-in period, patients were hospitalized for 2 weeks and started on open-label paliperidone, 9 mg/d; dosages then were titrated to 3 to 15 mg/d depending on efficacy and tolerability. Once stable for 2 weeks, subjects were discharged and maintained on paliperidone for 6 weeks, then were randomized to a double-blind phase during which they received a similar dosage of paliperidone or placebo. Regimen duration varied during the double-blind phase.

The study was stopped after 2 months when an interim analysis showed significant efficacy for paliperidone. Among patients who relapsed, mean time to relapse was 68 days among patients taking paliperidone (n=14, 25%), compared with 25 days in the placebo group (n=29, 53%).

Recurrence was defined as:

• psychiatric hospitalization
• total PANSS score ≥40 at randomization decreased by 25% for 2 days, or total PANSS score
• Clinical Global Impression of Severity (CGI-S) score ≥3 at randomization increased to ≥4 for 2 days, or CGI-S score ≥4 at randomization rose to ≥5
• individual-item PANSS baseline score ≥3 increased to ≥5 for 2 days, or baseline score ≥4 rose to ≥6
• self injury, suicidal or homicidal thoughts, or clinically significant aggressive behavior.

A final analysis showed a 22% relapse rate among patients taking paliperidone vs. 52% of the placebo group. Paliperidone was associated with improvements in PANSS, CGI-S, PSP, and quality of life measures at all dosages.

Safety

Compared with placebo, mean prolactin levels in the long-term study were four times as high among men (40 vs. 10 ng/mL) and five times as high among women (100 vs. 20 ng/mL) who received paliperidone at any dosage.⁴ Also, EPS such as dystonia and hyperkinesis were more prevalent at 12 mg/d (10%) than at 6 mg/d (5%).^1,2

During paliperidone therapy, patients should be asked if they are experiencing abnormal movements, sexual dysfunction, breast enlargement, or irregular menstruation (women). If so, decrease the dosage by 3 mg and monitor for side effects and clinical efficacy.

Among other reported adverse effects in the efficacy studies:

• somnolence was less prevalent among patients receiving either paliperidone, 3 to 12 mg/d, or placebo (13%) than among those receiving olanzapine, 10 mg/d (25%)³
• tachycardia was more prevalent among the paliperidone and olanzapine groups (14% to 20%) compared with placebo (0%)^1-3
• headache prevalence (10% to 20%) was similar in all groups^1-3
• mean body weight changes after 6 weeks were more pronounced in the olanzapine group (1.3±2.8 kg) than among patients receiving placebo (–0.7±2.4 kg) or paliperidone at 6 mg/d (0.2±2.4 kg), 9 mg/d (0.6±2.7 kg), or 12 mg/d (0.6±2.6 kg).²

In the relapse prevention study,⁴ potential neuroleptic malignant syndrome was reported in 1 patient taking paliperidone 3 days after the patient withdrew from the study. The patient had received paliperidone for 19 days and was treated for EPS with an unknown medication during the run-in period. Medical status returned to normal at endpoint except for elevated creatine kinase.

Discontinuation rates in the relapse prevention study’s double-blind phase were greater among the paliperidone group (n=20, 19%) compared with placebo (n=8, 8%).⁴ The reasons paliperidone group patients withdrew consent were not available.

Related resources

• Karlsson P, Dencker E, Nyberg S, et al. Pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy and safety profile of paliperidone extended-release in healthy subjects. Poster presented at: Winter Workshop on Schizophrenia (WWS); February 5-11, 2006; Davos, Switzerland.

Drug brand names

• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosures

Dr. Simpson receives grant support from AstraZeneca Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, and Johnson & Johnson. He is a consultant to Janssen Pharmaceutica, Johnson & Johnson, Merck and Co., and Pfizer, and is a speaker for Janssen Pharmaceutica and Pfizer.

Paliperidone, a second-generation antipsychotic (SGA), was awaiting FDA approval for treating schizophrenia (Table 1) at press time. FDA issued an approvable letter September 29.

The long-acting oral medication can be given once daily, without the plasma level peaks and troughs associated with other SGAs.

Table 1

Paliperidone: Fast facts

Clinical implications

Paliperidone—the active metabolite of risperidone (9-hydroxy risperidone)—produces the same effects as its parent compound. Because it is metabolized less by the liver, however, paliperidone will likely have a lower risk of drug-drug interactions than risperidone.

Paliperidone can help patients with hallucinations, delusions, and other florid psychotic symptoms. Once-daily dosing could also make it easier for patients with schizophrenia to adhere to treatment.

Paliperidone caused relatively few side effects in clinical trials, indicating that the drug could be started at therapeutic dosages. A 6-mg dose reaches clinically effective plasma levels in approximately 22 hours; a higher dosage might take less time.

How it works

As with all antipsychotics, paliperidone blocks dopamine uptake (D2 receptors) and—as with other newer SGAs—it has a high affinity for 5-HT (serotonin) receptors. This serotonergic action may help modulate side effects.

Paliperidone has shown antipsychotic effectiveness at 3 to 15 mg/d, and a 6-mg dosage is no more likely to cause extrapyramidal symptoms (EPS) or other adverse events than olanzapine, 10 mg/d, or placebo.^1-3 This finding suggests that 6 mg/d might be a suitable starting dosage for most patients.

Clinical findings

Efficacy. The drug showed efficacy for treating acute schizophrenia in three randomized, double-blind, controlled trials.

In a 6-week study,¹ 444 patients who were experiencing acute schizophrenia episodes and had Positive and Negative Syndrome Scale (PANSS) scores between 70 and 120 received paliperidone, 6 or 12 mg/d, olanzapine, 10 mg/d, or placebo. The study was powered to compare paliperidone and placebo; the olanzapine group was included to confirm study sensitivity.

Mean baseline total and negative symptom PANSS scores improved twice as much among the paliperidone and olanzapine groups compared with placebo (Table 2). Personal and Social Performance (PSP) scale scores also improved significantly among patients receiving paliperidone, 6 mg/d. The PSP scale gauges function, ability to perform socially useful activities such as self-care and work, and disturbing and aggressive behavior.

In two similarly designed, 6-week studies (N=1,248),^2,3 paliperidone at 3, 6, 9, or 12 mg/d produced statistically significant improvement in total and negative symptom PANSS scores and PSP scale scores compared with placebo.

Table 2

Mean PANSS score reductions among patients taking paliperidone, olanzapine, or placebo

Relapse prevention. Kramer et al⁴ measured paliperidone’s ability to prevent or delay schizophrenia recurrence among 205 patients experiencing an episode. Participants had been diagnosed with schizophrenia at least 1 year earlier and had PANSS total scores between 70 and 120. Patients with substance dependence or other axis I disorders were excluded.

Over an 8-week run-in period, patients were hospitalized for 2 weeks and started on open-label paliperidone, 9 mg/d; dosages then were titrated to 3 to 15 mg/d depending on efficacy and tolerability. Once stable for 2 weeks, subjects were discharged and maintained on paliperidone for 6 weeks, then were randomized to a double-blind phase during which they received a similar dosage of paliperidone or placebo. Regimen duration varied during the double-blind phase.

The study was stopped after 2 months when an interim analysis showed significant efficacy for paliperidone. Among patients who relapsed, mean time to relapse was 68 days among patients taking paliperidone (n=14, 25%), compared with 25 days in the placebo group (n=29, 53%).

Recurrence was defined as:

• psychiatric hospitalization
• total PANSS score ≥40 at randomization decreased by 25% for 2 days, or total PANSS score
• Clinical Global Impression of Severity (CGI-S) score ≥3 at randomization increased to ≥4 for 2 days, or CGI-S score ≥4 at randomization rose to ≥5
• individual-item PANSS baseline score ≥3 increased to ≥5 for 2 days, or baseline score ≥4 rose to ≥6
• self injury, suicidal or homicidal thoughts, or clinically significant aggressive behavior.

A final analysis showed a 22% relapse rate among patients taking paliperidone vs. 52% of the placebo group. Paliperidone was associated with improvements in PANSS, CGI-S, PSP, and quality of life measures at all dosages.

Safety

Compared with placebo, mean prolactin levels in the long-term study were four times as high among men (40 vs. 10 ng/mL) and five times as high among women (100 vs. 20 ng/mL) who received paliperidone at any dosage.⁴ Also, EPS such as dystonia and hyperkinesis were more prevalent at 12 mg/d (10%) than at 6 mg/d (5%).^1,2

During paliperidone therapy, patients should be asked if they are experiencing abnormal movements, sexual dysfunction, breast enlargement, or irregular menstruation (women). If so, decrease the dosage by 3 mg and monitor for side effects and clinical efficacy.

Among other reported adverse effects in the efficacy studies:

• somnolence was less prevalent among patients receiving either paliperidone, 3 to 12 mg/d, or placebo (13%) than among those receiving olanzapine, 10 mg/d (25%)³
• tachycardia was more prevalent among the paliperidone and olanzapine groups (14% to 20%) compared with placebo (0%)^1-3
• headache prevalence (10% to 20%) was similar in all groups^1-3
• mean body weight changes after 6 weeks were more pronounced in the olanzapine group (1.3±2.8 kg) than among patients receiving placebo (–0.7±2.4 kg) or paliperidone at 6 mg/d (0.2±2.4 kg), 9 mg/d (0.6±2.7 kg), or 12 mg/d (0.6±2.6 kg).²

In the relapse prevention study,⁴ potential neuroleptic malignant syndrome was reported in 1 patient taking paliperidone 3 days after the patient withdrew from the study. The patient had received paliperidone for 19 days and was treated for EPS with an unknown medication during the run-in period. Medical status returned to normal at endpoint except for elevated creatine kinase.

Discontinuation rates in the relapse prevention study’s double-blind phase were greater among the paliperidone group (n=20, 19%) compared with placebo (n=8, 8%).⁴ The reasons paliperidone group patients withdrew consent were not available.

Related resources

• Karlsson P, Dencker E, Nyberg S, et al. Pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy and safety profile of paliperidone extended-release in healthy subjects. Poster presented at: Winter Workshop on Schizophrenia (WWS); February 5-11, 2006; Davos, Switzerland.

Drug brand names

• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosures

Dr. Simpson receives grant support from AstraZeneca Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, and Johnson & Johnson. He is a consultant to Janssen Pharmaceutica, Johnson & Johnson, Merck and Co., and Pfizer, and is a speaker for Janssen Pharmaceutica and Pfizer.

Paliperidone, a second-generation antipsychotic (SGA), was awaiting FDA approval for treating schizophrenia (Table 1) at press time. FDA issued an approvable letter September 29.

The long-acting oral medication can be given once daily, without the plasma level peaks and troughs associated with other SGAs.

Table 1

Paliperidone: Fast facts

Clinical implications

Paliperidone—the active metabolite of risperidone (9-hydroxy risperidone)—produces the same effects as its parent compound. Because it is metabolized less by the liver, however, paliperidone will likely have a lower risk of drug-drug interactions than risperidone.

Paliperidone can help patients with hallucinations, delusions, and other florid psychotic symptoms. Once-daily dosing could also make it easier for patients with schizophrenia to adhere to treatment.

Paliperidone caused relatively few side effects in clinical trials, indicating that the drug could be started at therapeutic dosages. A 6-mg dose reaches clinically effective plasma levels in approximately 22 hours; a higher dosage might take less time.

How it works

As with all antipsychotics, paliperidone blocks dopamine uptake (D2 receptors) and—as with other newer SGAs—it has a high affinity for 5-HT (serotonin) receptors. This serotonergic action may help modulate side effects.

Paliperidone has shown antipsychotic effectiveness at 3 to 15 mg/d, and a 6-mg dosage is no more likely to cause extrapyramidal symptoms (EPS) or other adverse events than olanzapine, 10 mg/d, or placebo.^1-3 This finding suggests that 6 mg/d might be a suitable starting dosage for most patients.

Clinical findings

Efficacy. The drug showed efficacy for treating acute schizophrenia in three randomized, double-blind, controlled trials.

In a 6-week study,¹ 444 patients who were experiencing acute schizophrenia episodes and had Positive and Negative Syndrome Scale (PANSS) scores between 70 and 120 received paliperidone, 6 or 12 mg/d, olanzapine, 10 mg/d, or placebo. The study was powered to compare paliperidone and placebo; the olanzapine group was included to confirm study sensitivity.

Mean baseline total and negative symptom PANSS scores improved twice as much among the paliperidone and olanzapine groups compared with placebo (Table 2). Personal and Social Performance (PSP) scale scores also improved significantly among patients receiving paliperidone, 6 mg/d. The PSP scale gauges function, ability to perform socially useful activities such as self-care and work, and disturbing and aggressive behavior.

In two similarly designed, 6-week studies (N=1,248),^2,3 paliperidone at 3, 6, 9, or 12 mg/d produced statistically significant improvement in total and negative symptom PANSS scores and PSP scale scores compared with placebo.

Table 2

Mean PANSS score reductions among patients taking paliperidone, olanzapine, or placebo

Relapse prevention. Kramer et al⁴ measured paliperidone’s ability to prevent or delay schizophrenia recurrence among 205 patients experiencing an episode. Participants had been diagnosed with schizophrenia at least 1 year earlier and had PANSS total scores between 70 and 120. Patients with substance dependence or other axis I disorders were excluded.

Over an 8-week run-in period, patients were hospitalized for 2 weeks and started on open-label paliperidone, 9 mg/d; dosages then were titrated to 3 to 15 mg/d depending on efficacy and tolerability. Once stable for 2 weeks, subjects were discharged and maintained on paliperidone for 6 weeks, then were randomized to a double-blind phase during which they received a similar dosage of paliperidone or placebo. Regimen duration varied during the double-blind phase.

The study was stopped after 2 months when an interim analysis showed significant efficacy for paliperidone. Among patients who relapsed, mean time to relapse was 68 days among patients taking paliperidone (n=14, 25%), compared with 25 days in the placebo group (n=29, 53%).

Recurrence was defined as:

• psychiatric hospitalization
• total PANSS score ≥40 at randomization decreased by 25% for 2 days, or total PANSS score
• Clinical Global Impression of Severity (CGI-S) score ≥3 at randomization increased to ≥4 for 2 days, or CGI-S score ≥4 at randomization rose to ≥5
• individual-item PANSS baseline score ≥3 increased to ≥5 for 2 days, or baseline score ≥4 rose to ≥6
• self injury, suicidal or homicidal thoughts, or clinically significant aggressive behavior.

A final analysis showed a 22% relapse rate among patients taking paliperidone vs. 52% of the placebo group. Paliperidone was associated with improvements in PANSS, CGI-S, PSP, and quality of life measures at all dosages.

Safety

Compared with placebo, mean prolactin levels in the long-term study were four times as high among men (40 vs. 10 ng/mL) and five times as high among women (100 vs. 20 ng/mL) who received paliperidone at any dosage.⁴ Also, EPS such as dystonia and hyperkinesis were more prevalent at 12 mg/d (10%) than at 6 mg/d (5%).^1,2

During paliperidone therapy, patients should be asked if they are experiencing abnormal movements, sexual dysfunction, breast enlargement, or irregular menstruation (women). If so, decrease the dosage by 3 mg and monitor for side effects and clinical efficacy.

Among other reported adverse effects in the efficacy studies:

• somnolence was less prevalent among patients receiving either paliperidone, 3 to 12 mg/d, or placebo (13%) than among those receiving olanzapine, 10 mg/d (25%)³
• tachycardia was more prevalent among the paliperidone and olanzapine groups (14% to 20%) compared with placebo (0%)^1-3
• headache prevalence (10% to 20%) was similar in all groups^1-3
• mean body weight changes after 6 weeks were more pronounced in the olanzapine group (1.3±2.8 kg) than among patients receiving placebo (–0.7±2.4 kg) or paliperidone at 6 mg/d (0.2±2.4 kg), 9 mg/d (0.6±2.7 kg), or 12 mg/d (0.6±2.6 kg).²

In the relapse prevention study,⁴ potential neuroleptic malignant syndrome was reported in 1 patient taking paliperidone 3 days after the patient withdrew from the study. The patient had received paliperidone for 19 days and was treated for EPS with an unknown medication during the run-in period. Medical status returned to normal at endpoint except for elevated creatine kinase.

Discontinuation rates in the relapse prevention study’s double-blind phase were greater among the paliperidone group (n=20, 19%) compared with placebo (n=8, 8%).⁴ The reasons paliperidone group patients withdrew consent were not available.

Related resources

• Karlsson P, Dencker E, Nyberg S, et al. Pharmacokinetics, dopamine D2 and serotonin 5-HT2A receptor occupancy and safety profile of paliperidone extended-release in healthy subjects. Poster presented at: Winter Workshop on Schizophrenia (WWS); February 5-11, 2006; Davos, Switzerland.

Drug brand names

• Olanzapine • Zyprexa
• Risperidone • Risperdal

Disclosures

Dr. Simpson receives grant support from AstraZeneca Pharmaceuticals, GlaxoSmithKline, Janssen Pharmaceutica, and Johnson & Johnson. He is a consultant to Janssen Pharmaceutica, Johnson & Johnson, Merck and Co., and Pfizer, and is a speaker for Janssen Pharmaceutica and Pfizer.

When prescribing methylphenidate to children with attention-deficit/hyperactivity disorder (ADHD), psychiatrists have had two options:

• immediate-release oral methylphenidate, which works for 3 to 5 hours, necessitating multiple daily doses
• extended-release oral methylphenidate, which can prevent irritability and other rebound symptoms caused by multiple daily dosing.¹ Because its effects last 12 hours, however, once-daily dosing with this formulation is inflexible.

A new option—a transdermal methylphenidate patch FDA-approved for treating ADHD in children ages 6 to 12 (Table 1)—offers flexible methylphenidate coverage based on response to or need for the medication.

Table 1

Transdermal methylphenidate: Fast facts

Clinical implications

The transdermal patch allows dosing to be tailored—or changed day to day as needed—to maximize effectiveness and reduce side-effect risk. The manufacturer recommends that the patch be worn for 9 hours daily, but it can be removed sooner if children experience appetite loss, insomnia, or other adverse effects with 9 hours of exposure to methylphenidate.

Minimizing daily exposure to methylphenidate can also reduce the risk of long-term effects. Findings from one large, randomized clinical trial² suggest that chronic exposure to high-dose stimulant medications might suppress growth in height and weight, although other data indicate that initial height reductions found in children receiving methylphenidate for ADHD were no longer significant in adulthood.³

The patch also could benefit youths who have trouble following dosing schedules and young children who are unable to swallow pills.

How it works

The patch contains methylphenidate dispersed in an acrylic multipolymeric adhesive that is further dispersed in a silicone adhesive.⁴ The methylphenidate within the acrylic adhesive flows into the skin, then into the bloodstream. The patch is worn on the hip—where it is covered by clothing and unlikely to be dislodged—and changed daily.

The patch comes in four sizes—12.5, 18.75, 25, and 37.5 cm²—which, respectively, deliver 10, 15, 20, and 30 mg of methylphenidate over 9 hours.⁴ Methylphenidate concentration is the same for all four sizes, so patch size and duration of use determine dose delivery.

In clinical trials, therapeutic effect was seen 2 hours after patch placement and continued through 12 hours.⁵ Methylphenidate is delivered continuously while the patch is in place and for as long as 2 hours after it is removed.

Pharmacokinetics

Methylphenidate, a known CNS stimulant, blocks norepinephrine and dopamine reuptake in the presynaptic neuron, thereby releasing more of these neuro-transmitters into the extraneuronal space.⁴ Methylphenidate’s precise therapeutic action in ADHD is not known.

Methylphenidate is a racemic mixture of d- and l-enantiomers, the first of which is believed to be more active. Whereas the liver removes the l-enantiomer from oral methylphenidate, the transdermal formulation bypasses the liver and preserves the l-enantiomer, thus increasing exposure to racemic methylphenidate. This means that optimal dosages of transdermal methylphenidate (10 to 30 mg/d) may be lower compared with the oral formulation^5-7 (Table 2).

Methylphenidate’s d-enantiomer has a mean 3- to 4-hour elimination half-life, approximately twice that of the l-enantiomer. This is why transdermal methylphenidate continues to exert therapeutic effect several hours after the patch is removed.⁵

Table 2

Transdermal methylphenidate dosage delivery in children ages 6 to 12

Efficacy

Results from randomized, double-blind, placebo-controlled trials support short-term use of transdermal methylphenidate in ADHD. The following studies recruited children ages 6 to 12 with the disorder.

Dose-ranging study. Thirty-three children participating in a summer treatment program received transdermal methylphenidate, 6.25, 12.5, or 25 cm² 12 hours daily for 8 days.⁶ All three patch sizes were associated with improved academic, social, and behavioral functioning based on a range of measures.

Dose response rate diminished with higher dosages, and significant further improvements were difficult to detect as dosages increased. The children also received intensive behavioral treatment during the study, which might have accounted for some therapeutic gains and diminished the researchers’ ability to detect subtle improvements with increased dosages.

Children also had fewer negative behaviors during the first hour when the patch was applied at 6 AM instead of 7 AM. This suggests that the patch might produce optimal effect when placed first thing in the morning.

Randomized crossover trial.⁷ Across 6 weeks, 27 children were given placebo or transdermal methylphenidate, 12.5, 25, or 37.5 cm²/d. The children also received behavior modification treatment on alternating weeks. Medication was randomly assigned and varied daily for 4 days per week over 6 weeks, and behavioral treatment was varied weekly for 4 weeks. Each subject took each dosage for 2 days without behavioral treatment and for 4 days with behavioral treatment.

Academic productivity, interactions with peers and adults, and compliance during class improved with all dosages compared with placebo. Although most children removed the patch by 3:30 PM after 9 hours of use, parents reported that positive behavioral effects lasted into the evening.

As in the dose-ranging study, dose response diminished with higher dosages. Optimal effects were achieved on some measures with 12.5 cm² of transdermal methylphenidate, which produces the same plasma drug level as 10 mg of oral methylphenidate.⁷

Multisite crossover study.⁵ Eighty children received transdermal methylphenidate—12.5, 18.75, 25, or 37.5 cm² based on response to medication—over 5 weeks for 9 hours daily. Dosages were titrated by changing patch sizes until each child reached his or her optimal dosage. Children then received their optimal dosage or placebo for 1 week, then received the opposite treatment for another week. Results were measured in a simulated classroom.

Overall, children showed statistically significant improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Teacher Rating Scale scores while receiving their optimal dosage. Improvement was seen 2 hours after patches were applied and continued for 12 hours. Children also were more able to solve math problems during optimal dosage periods than while using placebo.

Nearly 80% of children were rated as significantly improved while receiving transdermal methylphenidate based on Clinical Global Impressions of Improvement scores. Roughly 12% of children showed significant improvement with placebo. Parents reported that their children were markedly less hyperactive and impulsive and more attentive during optimal dosage periods.

Tolerability

No serious side effects were reported during clinical trials of transdermal methylphenidate in children ages 6 to 12.^5-7 Side effects commonly associated with oral methylphenidate—anorexia, decreased appetite, headache, insomnia, and abdominal pain—were most frequently reported with the patch.⁵

In one study,⁶ 61% of children who wore the patch for 12 hours/day reported appetite loss and 47% reported insomnia. Insomnia prevalence diminished substantially when daily wear was limited to 9 hours.^2,5 Loss of appetite was reported less often with lower-dose patches (12.5, 18.75 cm²) than with higher-dose patches (25, 37.5 cm²).

Although many children complained of erythema at the patch site,^5-7 most reported minimal irritation or discomfort.⁵ Redness usually dissipated about 8 hours after the patch was removed.⁶

Despite concerns that youths with impulsive behaviors might remove the patches prematurely, very few children did so during clinical trials.^5-7 Those who did had comorbid symptomatic conduct disturbances. Compliance with patch placement and maintenance was very high during dose optimization (98%) and analog classroom analysis (97%).^5-7

Dosing

Start transdermal methylphenidate at 12.5 cm² (10 mg) for children who have never taken methylphenidate or were previously stabilized on the drug. If the child does not respond after 1 week, switch to the 18.75 cm² (15-mg) patch; keep switching to the next largest patch each week until optimal response is achieved. In clinical trials,^5-7 18.75 or 25 cm² (10 mg) of transdermal methylphenidate produced optimal response for most children.

Advise the child and parents to place the patch on the right and left hip on alternate days to minimize irritation. Counsel children to inform parents if the patch causes itching, burning, or irritation; tell parents to call you if they notice or the child complains of irritation. Children who experience intolerable skin sensitivity with the patch can resume taking oral methylphenidate the day after the patch is removed.

As with oral methylphenidate, the transdermal formulation may be discontinued without a taper and another formulation or medication may be started the next day. Ask the child and parents about side effects at each visit. See the child every 2 to 4 weeks during the titration period and monthly after symptoms are stabilized.

Consider trying a “drug holiday” for at least 2 weeks during the summer to see how the child behaves without methylphenidate, then evaluate the need for medication and determine the optimal dosage close to when the school year begins.

Related resources

• Transdermal methylphenidate Web site. www.daytrana.com.
• Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41:26S-49S.

Drug brand names

• Methylphenidate (oral) • Concerta, Ritalin, Metadate
• Methylphenidate (transdermal) • Daytrana

Disclosures

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

When prescribing methylphenidate to children with attention-deficit/hyperactivity disorder (ADHD), psychiatrists have had two options:

• immediate-release oral methylphenidate, which works for 3 to 5 hours, necessitating multiple daily doses
• extended-release oral methylphenidate, which can prevent irritability and other rebound symptoms caused by multiple daily dosing.¹ Because its effects last 12 hours, however, once-daily dosing with this formulation is inflexible.

A new option—a transdermal methylphenidate patch FDA-approved for treating ADHD in children ages 6 to 12 (Table 1)—offers flexible methylphenidate coverage based on response to or need for the medication.

Table 1

Transdermal methylphenidate: Fast facts

Clinical implications

The transdermal patch allows dosing to be tailored—or changed day to day as needed—to maximize effectiveness and reduce side-effect risk. The manufacturer recommends that the patch be worn for 9 hours daily, but it can be removed sooner if children experience appetite loss, insomnia, or other adverse effects with 9 hours of exposure to methylphenidate.

Minimizing daily exposure to methylphenidate can also reduce the risk of long-term effects. Findings from one large, randomized clinical trial² suggest that chronic exposure to high-dose stimulant medications might suppress growth in height and weight, although other data indicate that initial height reductions found in children receiving methylphenidate for ADHD were no longer significant in adulthood.³

The patch also could benefit youths who have trouble following dosing schedules and young children who are unable to swallow pills.

How it works

The patch contains methylphenidate dispersed in an acrylic multipolymeric adhesive that is further dispersed in a silicone adhesive.⁴ The methylphenidate within the acrylic adhesive flows into the skin, then into the bloodstream. The patch is worn on the hip—where it is covered by clothing and unlikely to be dislodged—and changed daily.

The patch comes in four sizes—12.5, 18.75, 25, and 37.5 cm²—which, respectively, deliver 10, 15, 20, and 30 mg of methylphenidate over 9 hours.⁴ Methylphenidate concentration is the same for all four sizes, so patch size and duration of use determine dose delivery.

In clinical trials, therapeutic effect was seen 2 hours after patch placement and continued through 12 hours.⁵ Methylphenidate is delivered continuously while the patch is in place and for as long as 2 hours after it is removed.

Pharmacokinetics

Methylphenidate, a known CNS stimulant, blocks norepinephrine and dopamine reuptake in the presynaptic neuron, thereby releasing more of these neuro-transmitters into the extraneuronal space.⁴ Methylphenidate’s precise therapeutic action in ADHD is not known.

Methylphenidate is a racemic mixture of d- and l-enantiomers, the first of which is believed to be more active. Whereas the liver removes the l-enantiomer from oral methylphenidate, the transdermal formulation bypasses the liver and preserves the l-enantiomer, thus increasing exposure to racemic methylphenidate. This means that optimal dosages of transdermal methylphenidate (10 to 30 mg/d) may be lower compared with the oral formulation^5-7 (Table 2).

Methylphenidate’s d-enantiomer has a mean 3- to 4-hour elimination half-life, approximately twice that of the l-enantiomer. This is why transdermal methylphenidate continues to exert therapeutic effect several hours after the patch is removed.⁵

Table 2

Transdermal methylphenidate dosage delivery in children ages 6 to 12

Efficacy

Results from randomized, double-blind, placebo-controlled trials support short-term use of transdermal methylphenidate in ADHD. The following studies recruited children ages 6 to 12 with the disorder.

Dose-ranging study. Thirty-three children participating in a summer treatment program received transdermal methylphenidate, 6.25, 12.5, or 25 cm² 12 hours daily for 8 days.⁶ All three patch sizes were associated with improved academic, social, and behavioral functioning based on a range of measures.

Dose response rate diminished with higher dosages, and significant further improvements were difficult to detect as dosages increased. The children also received intensive behavioral treatment during the study, which might have accounted for some therapeutic gains and diminished the researchers’ ability to detect subtle improvements with increased dosages.

Children also had fewer negative behaviors during the first hour when the patch was applied at 6 AM instead of 7 AM. This suggests that the patch might produce optimal effect when placed first thing in the morning.

Randomized crossover trial.⁷ Across 6 weeks, 27 children were given placebo or transdermal methylphenidate, 12.5, 25, or 37.5 cm²/d. The children also received behavior modification treatment on alternating weeks. Medication was randomly assigned and varied daily for 4 days per week over 6 weeks, and behavioral treatment was varied weekly for 4 weeks. Each subject took each dosage for 2 days without behavioral treatment and for 4 days with behavioral treatment.

Academic productivity, interactions with peers and adults, and compliance during class improved with all dosages compared with placebo. Although most children removed the patch by 3:30 PM after 9 hours of use, parents reported that positive behavioral effects lasted into the evening.

As in the dose-ranging study, dose response diminished with higher dosages. Optimal effects were achieved on some measures with 12.5 cm² of transdermal methylphenidate, which produces the same plasma drug level as 10 mg of oral methylphenidate.⁷

Multisite crossover study.⁵ Eighty children received transdermal methylphenidate—12.5, 18.75, 25, or 37.5 cm² based on response to medication—over 5 weeks for 9 hours daily. Dosages were titrated by changing patch sizes until each child reached his or her optimal dosage. Children then received their optimal dosage or placebo for 1 week, then received the opposite treatment for another week. Results were measured in a simulated classroom.

Overall, children showed statistically significant improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Teacher Rating Scale scores while receiving their optimal dosage. Improvement was seen 2 hours after patches were applied and continued for 12 hours. Children also were more able to solve math problems during optimal dosage periods than while using placebo.

Nearly 80% of children were rated as significantly improved while receiving transdermal methylphenidate based on Clinical Global Impressions of Improvement scores. Roughly 12% of children showed significant improvement with placebo. Parents reported that their children were markedly less hyperactive and impulsive and more attentive during optimal dosage periods.

Tolerability

No serious side effects were reported during clinical trials of transdermal methylphenidate in children ages 6 to 12.^5-7 Side effects commonly associated with oral methylphenidate—anorexia, decreased appetite, headache, insomnia, and abdominal pain—were most frequently reported with the patch.⁵

In one study,⁶ 61% of children who wore the patch for 12 hours/day reported appetite loss and 47% reported insomnia. Insomnia prevalence diminished substantially when daily wear was limited to 9 hours.^2,5 Loss of appetite was reported less often with lower-dose patches (12.5, 18.75 cm²) than with higher-dose patches (25, 37.5 cm²).

Although many children complained of erythema at the patch site,^5-7 most reported minimal irritation or discomfort.⁵ Redness usually dissipated about 8 hours after the patch was removed.⁶

Despite concerns that youths with impulsive behaviors might remove the patches prematurely, very few children did so during clinical trials.^5-7 Those who did had comorbid symptomatic conduct disturbances. Compliance with patch placement and maintenance was very high during dose optimization (98%) and analog classroom analysis (97%).^5-7

Dosing

Start transdermal methylphenidate at 12.5 cm² (10 mg) for children who have never taken methylphenidate or were previously stabilized on the drug. If the child does not respond after 1 week, switch to the 18.75 cm² (15-mg) patch; keep switching to the next largest patch each week until optimal response is achieved. In clinical trials,^5-7 18.75 or 25 cm² (10 mg) of transdermal methylphenidate produced optimal response for most children.

Advise the child and parents to place the patch on the right and left hip on alternate days to minimize irritation. Counsel children to inform parents if the patch causes itching, burning, or irritation; tell parents to call you if they notice or the child complains of irritation. Children who experience intolerable skin sensitivity with the patch can resume taking oral methylphenidate the day after the patch is removed.

As with oral methylphenidate, the transdermal formulation may be discontinued without a taper and another formulation or medication may be started the next day. Ask the child and parents about side effects at each visit. See the child every 2 to 4 weeks during the titration period and monthly after symptoms are stabilized.

Consider trying a “drug holiday” for at least 2 weeks during the summer to see how the child behaves without methylphenidate, then evaluate the need for medication and determine the optimal dosage close to when the school year begins.

Related resources

• Transdermal methylphenidate Web site. www.daytrana.com.
• Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41:26S-49S.

Drug brand names

• Methylphenidate (oral) • Concerta, Ritalin, Metadate
• Methylphenidate (transdermal) • Daytrana

Disclosures

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

When prescribing methylphenidate to children with attention-deficit/hyperactivity disorder (ADHD), psychiatrists have had two options:

• immediate-release oral methylphenidate, which works for 3 to 5 hours, necessitating multiple daily doses
• extended-release oral methylphenidate, which can prevent irritability and other rebound symptoms caused by multiple daily dosing.¹ Because its effects last 12 hours, however, once-daily dosing with this formulation is inflexible.

A new option—a transdermal methylphenidate patch FDA-approved for treating ADHD in children ages 6 to 12 (Table 1)—offers flexible methylphenidate coverage based on response to or need for the medication.

Table 1

Transdermal methylphenidate: Fast facts

Clinical implications

The transdermal patch allows dosing to be tailored—or changed day to day as needed—to maximize effectiveness and reduce side-effect risk. The manufacturer recommends that the patch be worn for 9 hours daily, but it can be removed sooner if children experience appetite loss, insomnia, or other adverse effects with 9 hours of exposure to methylphenidate.

Minimizing daily exposure to methylphenidate can also reduce the risk of long-term effects. Findings from one large, randomized clinical trial² suggest that chronic exposure to high-dose stimulant medications might suppress growth in height and weight, although other data indicate that initial height reductions found in children receiving methylphenidate for ADHD were no longer significant in adulthood.³

The patch also could benefit youths who have trouble following dosing schedules and young children who are unable to swallow pills.

How it works

The patch contains methylphenidate dispersed in an acrylic multipolymeric adhesive that is further dispersed in a silicone adhesive.⁴ The methylphenidate within the acrylic adhesive flows into the skin, then into the bloodstream. The patch is worn on the hip—where it is covered by clothing and unlikely to be dislodged—and changed daily.

The patch comes in four sizes—12.5, 18.75, 25, and 37.5 cm²—which, respectively, deliver 10, 15, 20, and 30 mg of methylphenidate over 9 hours.⁴ Methylphenidate concentration is the same for all four sizes, so patch size and duration of use determine dose delivery.

In clinical trials, therapeutic effect was seen 2 hours after patch placement and continued through 12 hours.⁵ Methylphenidate is delivered continuously while the patch is in place and for as long as 2 hours after it is removed.

Pharmacokinetics

Methylphenidate, a known CNS stimulant, blocks norepinephrine and dopamine reuptake in the presynaptic neuron, thereby releasing more of these neuro-transmitters into the extraneuronal space.⁴ Methylphenidate’s precise therapeutic action in ADHD is not known.

Methylphenidate is a racemic mixture of d- and l-enantiomers, the first of which is believed to be more active. Whereas the liver removes the l-enantiomer from oral methylphenidate, the transdermal formulation bypasses the liver and preserves the l-enantiomer, thus increasing exposure to racemic methylphenidate. This means that optimal dosages of transdermal methylphenidate (10 to 30 mg/d) may be lower compared with the oral formulation^5-7 (Table 2).

Methylphenidate’s d-enantiomer has a mean 3- to 4-hour elimination half-life, approximately twice that of the l-enantiomer. This is why transdermal methylphenidate continues to exert therapeutic effect several hours after the patch is removed.⁵

Table 2

Transdermal methylphenidate dosage delivery in children ages 6 to 12

Efficacy

Results from randomized, double-blind, placebo-controlled trials support short-term use of transdermal methylphenidate in ADHD. The following studies recruited children ages 6 to 12 with the disorder.

Dose-ranging study. Thirty-three children participating in a summer treatment program received transdermal methylphenidate, 6.25, 12.5, or 25 cm² 12 hours daily for 8 days.⁶ All three patch sizes were associated with improved academic, social, and behavioral functioning based on a range of measures.

Dose response rate diminished with higher dosages, and significant further improvements were difficult to detect as dosages increased. The children also received intensive behavioral treatment during the study, which might have accounted for some therapeutic gains and diminished the researchers’ ability to detect subtle improvements with increased dosages.

Children also had fewer negative behaviors during the first hour when the patch was applied at 6 AM instead of 7 AM. This suggests that the patch might produce optimal effect when placed first thing in the morning.

Randomized crossover trial.⁷ Across 6 weeks, 27 children were given placebo or transdermal methylphenidate, 12.5, 25, or 37.5 cm²/d. The children also received behavior modification treatment on alternating weeks. Medication was randomly assigned and varied daily for 4 days per week over 6 weeks, and behavioral treatment was varied weekly for 4 weeks. Each subject took each dosage for 2 days without behavioral treatment and for 4 days with behavioral treatment.

Academic productivity, interactions with peers and adults, and compliance during class improved with all dosages compared with placebo. Although most children removed the patch by 3:30 PM after 9 hours of use, parents reported that positive behavioral effects lasted into the evening.

As in the dose-ranging study, dose response diminished with higher dosages. Optimal effects were achieved on some measures with 12.5 cm² of transdermal methylphenidate, which produces the same plasma drug level as 10 mg of oral methylphenidate.⁷

Multisite crossover study.⁵ Eighty children received transdermal methylphenidate—12.5, 18.75, 25, or 37.5 cm² based on response to medication—over 5 weeks for 9 hours daily. Dosages were titrated by changing patch sizes until each child reached his or her optimal dosage. Children then received their optimal dosage or placebo for 1 week, then received the opposite treatment for another week. Results were measured in a simulated classroom.

Overall, children showed statistically significant improvement in Swanson, Kotkin, Agler, M-Flynn, and Pelham (SKAMP) Teacher Rating Scale scores while receiving their optimal dosage. Improvement was seen 2 hours after patches were applied and continued for 12 hours. Children also were more able to solve math problems during optimal dosage periods than while using placebo.

Nearly 80% of children were rated as significantly improved while receiving transdermal methylphenidate based on Clinical Global Impressions of Improvement scores. Roughly 12% of children showed significant improvement with placebo. Parents reported that their children were markedly less hyperactive and impulsive and more attentive during optimal dosage periods.

Tolerability

No serious side effects were reported during clinical trials of transdermal methylphenidate in children ages 6 to 12.^5-7 Side effects commonly associated with oral methylphenidate—anorexia, decreased appetite, headache, insomnia, and abdominal pain—were most frequently reported with the patch.⁵

In one study,⁶ 61% of children who wore the patch for 12 hours/day reported appetite loss and 47% reported insomnia. Insomnia prevalence diminished substantially when daily wear was limited to 9 hours.^2,5 Loss of appetite was reported less often with lower-dose patches (12.5, 18.75 cm²) than with higher-dose patches (25, 37.5 cm²).

Although many children complained of erythema at the patch site,^5-7 most reported minimal irritation or discomfort.⁵ Redness usually dissipated about 8 hours after the patch was removed.⁶

Despite concerns that youths with impulsive behaviors might remove the patches prematurely, very few children did so during clinical trials.^5-7 Those who did had comorbid symptomatic conduct disturbances. Compliance with patch placement and maintenance was very high during dose optimization (98%) and analog classroom analysis (97%).^5-7

Dosing

Start transdermal methylphenidate at 12.5 cm² (10 mg) for children who have never taken methylphenidate or were previously stabilized on the drug. If the child does not respond after 1 week, switch to the 18.75 cm² (15-mg) patch; keep switching to the next largest patch each week until optimal response is achieved. In clinical trials,^5-7 18.75 or 25 cm² (10 mg) of transdermal methylphenidate produced optimal response for most children.

Advise the child and parents to place the patch on the right and left hip on alternate days to minimize irritation. Counsel children to inform parents if the patch causes itching, burning, or irritation; tell parents to call you if they notice or the child complains of irritation. Children who experience intolerable skin sensitivity with the patch can resume taking oral methylphenidate the day after the patch is removed.

As with oral methylphenidate, the transdermal formulation may be discontinued without a taper and another formulation or medication may be started the next day. Ask the child and parents about side effects at each visit. See the child every 2 to 4 weeks during the titration period and monthly after symptoms are stabilized.

Consider trying a “drug holiday” for at least 2 weeks during the summer to see how the child behaves without methylphenidate, then evaluate the need for medication and determine the optimal dosage close to when the school year begins.

Related resources

• Transdermal methylphenidate Web site. www.daytrana.com.
• Greenhill LL, Pliszka S, Dulcan MK, et al. Practice parameter for the use of stimulant medications in the treatment of children, adolescents, and adults. J Am Acad Child Adolesc Psychiatry 2002;41:26S-49S.

Drug brand names

• Methylphenidate (oral) • Concerta, Ritalin, Metadate
• Methylphenidate (transdermal) • Daytrana

Disclosures

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

Many psychiatrists do not prescribe monoamine oxidase inhibitors (MAOIs) for fear of causing a potentially fatal hypertensive reaction, even though restricting foods high in the amino acid tyramine usually prevents this effect.¹ Consequently, most depressed patients who might respond well to MAOIs do not receive them.^2,3

Transdermal selegiline, FDA-approved for treating major depressive disorder (MDD) (Table 1), offers the clinical efficacy of an MAOI but without adverse interactions with food at the 6-mg strength. Transdermal selegiline may inhibit too much gastrointestinal MAO-A at 9 mg/d and 12 mg/d to clear tyramine from foods, so tyramine-rich foods must be restricted at these dosages (Table 2).

Table 1

Transdermal selegiline: Fast facts

Table 2

Restrict these foods when prescribing transdermal selegiline at 9 or 12 mg/d

How it works

MAO enzyme subtypes A and B metabolize CNS monoamines, but primarily MAO-A metabolizes tyramine in the gut before the amino acid enters systemic circulation. At low concentrations, selegiline selectively inhibits MAO-B.⁴

Oral selegiline, approved as a adjunct to levodopa/carbidopa for patients with Parkinson’s disease,⁵ has been shown to be effective for treating depression at ≥30 mg/d.⁶ Because the drug does not selectively inhibit MAOB at ≥20 mg/d, dietary tyramine must be restricted when oral selegiline is used off-label at therapeutic dosages for depression. Otherwise, selegiline has been well-tolerated up to 60 mg/d.⁷

The 6-mg “patch” delivers more selegiline to the bloodstream than does low-dose oral selegiline but without inhibiting gut MAO-A. This provides the brain MAO-A and MAO-B inhibition necessary for an antidepressant effect while eliminating the need for dietary restrictions at this lowest dosage.

Clinical implications

Transdermal selegiline offers an MAOI antidepressant option that might help:

• patients whose depression has not responded satisfactorily to selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs)
• adults and children with chronic depression marked by atypical features, including reactive mood, rejection sensitivity, anergia, and reversed vegetative symptoms—such as oversleeping, overeating, and psychomotor retardation. Although transdermal selegiline’s efficacy against these features has not been studied, patients with this depressive subtype tend to respond preferentially to MAOIs.

Pharmacokinetics

Transdermal selegiline achieves therapeutic blood levels and reaches sustained concentration within 4 to 8 hours of administration. Compared with oral selegiline, transdermal delivery results in higher plasma selegiline concentrations (1,500 pg/mL with the 6-mg patch) with much lower exposure to metabolites.⁸ The concentration is maintained with successive doses.

Transdermal selegiline clears rapidly upon discontinuation but MAO inhibition persists for 2 weeks, so wait 2 weeks after the last dose before starting a new antidepressant or stopping food restrictions with the 9-mg and 12-mg patches.

Efficacy

In two randomized, double-blind clinical trials,^9,10 a total of 466 adults ages 18 to 65 who met DSM-IV-TR criteria for MDD received transdermal selegiline, 6 mg/d, or placebo for 6 to 8 weeks. Participants had 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores ≥20 at baseline.

In the 6-week study,⁹ transdermal selegiline produced a 46% greater reduction in HAM-D-17 scores, a 52% greater decrease in HAM-D-28 scores, and a 79% greater drop in Montgomery-Asburg Depression Rating Scale (MADRS) scores compared with placebo. In the 8-week trial,¹⁰ HAM-D-28 and MADRS scores among the treatment group were significantly improved at endpoint compared with placebo, but HAM-D-17 scores were not.

In a 1-year, double-blind study,¹¹ 322 subjects with MDD—who had been rated as responders in a 10-week, open-label transdermal selegiline trial—received the 6-mg patch or placebo. At 6 months and 1 year, relapse was much less frequent among the treatment group compared with placebo. Relapse was defined as:

• HAM-D-17 ≥14
• Clinical Global Impressions of Severity score ≥3 with a ≥2-point increase from baseline
• and meeting DSM-IV criteria for MDD on two consecutive visits ≥11 days apart.

Side effects

Transdermal selegiline, 6 mg/d, has been well-tolerated in clinical trials. Inflammation at the application site was the most commonly reported side effect, occurring in 32% to 36% of treatment group subjects compared with 15% to 17% of the placebo groups.^9,10,12 Inflammation was usually mild, but approximately 3% of patients dropped out of one study,¹² citing this effect as the reason. Fair-skinned women are at highest risk for this reaction.

In the 1-year relapse prevention study,¹¹ 12% of treatment group patients reported insomnia compared with 7% of the placebo group. Insomnia incidence was the same in the selegiline and placebo groups during the 6- to 8-week clinical trials.^9,10

Unlike conventional oral MAOIs,¹³ the 6-mg selegiline patch has not been found to impair sexual function, alter appetite, or change body weight or blood pressure compared with placebo.^10-12 The toxicity of the 9- and 12-mg patches has not been studied in humans, but 8 mg/d and 12 mg/d of transdermal selegiline across 3 months were shown not to cause drug toxicity in dogs.¹⁴

Pediatric use

Although transdermal selegiline has not been studied in children and adolescents, the 6-mg patch could benefit some youths with depression. Before starting the drug, discuss with the child’s parents/guardians the FDA’s black box warning describing a possible association between selegiline and increased suicidal behavior in youths. This applies to all antidepressants.

Geriatric use

The patch might also help some older patients with depression. In a double-blind trial of high-dose oral selegiline (60 mg/d) involving 16 older patients (mean age 65.6), both the treatment and placebo groups remained almost free of side effects across 3 weeks.⁷ Although the sample was small, the findings suggest that older patients can tolerate selegiline at high dosages. Side effects also were minimal among treatment-group patients age ≥65 in the yearlong relapse prevention study.¹¹

Treatment adherence rates with transdermal selegiline have been high in published studies, suggesting that the patch’s visibility might reduce the risk of forgetting to take the medication. Observing whether the patch has been changed might help older patients and family members/caregivers keep track of dosing.

Contraindications

As with the oral form, do not prescribe transdermal selegiline to patients taking SSRIs, SNRIs, tricyclic antidepressants, mirtazapine, or bupropion.

When switching antidepressants, allow enough time for the previous agent to “wash out” before starting transdermal selegiline. How much time to allow for wash-out depends on the previous agent’s half-life.

The patch is also contraindicated for patients taking:

• carbamazepine or oxcarbazepine
• meperidine
• analgesics such as tramadol, methadone, and propoxyphene
• St. John’s wort
• cough syrups containing dextromethorphan
• amphetamines, such as mixed amphetamine salts
• cyclobenzaprine
• or cold remedies or weight-loss products that contain vasoconstrictors, such as pseudoephedrine, phenylephrine, phenylpropanolamine, or ephedrine.

Do not give transdermal selegiline during pregnancy, as its effect on fetal development has not been studied.

Dosing

Start transdermal selegiline at 6 mg/d. Instruct the patient to wear the patch on the upper torso, where vascularity is richer compared with the buttocks and legs. Tell the patient to change the patch daily and to apply it to a different spot each day to prevent inflammation. Consider increasing the dosage after 2 or 3 months if response is unsatisfactory.

For treating first, second, and some third depressive episodes, continue transdermal selegiline for 6 months to 1 year of sustained recovery; consider longer-term maintenance treatment for highly recurrent depression. Transdermal selegiline has not been tapered in clinical trials, and subjects have not reported withdrawal symptoms after 1 year of continuous treatment.

Related resources

• Deniker P. The search for new antidepressants and related drugs. In: Tipton KF, Doster P, Benedetti M (eds). Monoamine oxidase and disease. London: Academic Press; 1984:2-8.

Drug brand names

• Amphetamine salts, mixed • Adderall
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro, others
• Cyclobenzaprine • Flexeril
• Meperidine • Demerol
• Mirtazapine • Remeron
• Oxcarbazepine • Trileptal
• Propoxyphene hydrochloride • Darvon
• Propoxyphene napsylate • Darvocet
• Selegiline (oral) • Eldepryl
• Selegiline (transdermal) • EMSAM
• Tramadol • Ultracet

Disclosure

Dr. Bodkin receives grant support from the National Institute of Mental Health, Eli Lilly & Co, Jazz Pharmaceuticals, Merck & Co., Organon, Sanofi-Aventis, and Somerset Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co. and Somerset Pharmaceuticals; and is a speaker for Bristol-Myers Squibb Co. He has been principal investigator in several multicenter clinical trials of selegiline.

Many psychiatrists do not prescribe monoamine oxidase inhibitors (MAOIs) for fear of causing a potentially fatal hypertensive reaction, even though restricting foods high in the amino acid tyramine usually prevents this effect.¹ Consequently, most depressed patients who might respond well to MAOIs do not receive them.^2,3

Transdermal selegiline, FDA-approved for treating major depressive disorder (MDD) (Table 1), offers the clinical efficacy of an MAOI but without adverse interactions with food at the 6-mg strength. Transdermal selegiline may inhibit too much gastrointestinal MAO-A at 9 mg/d and 12 mg/d to clear tyramine from foods, so tyramine-rich foods must be restricted at these dosages (Table 2).

Table 1

Transdermal selegiline: Fast facts

Table 2

Restrict these foods when prescribing transdermal selegiline at 9 or 12 mg/d

How it works

MAO enzyme subtypes A and B metabolize CNS monoamines, but primarily MAO-A metabolizes tyramine in the gut before the amino acid enters systemic circulation. At low concentrations, selegiline selectively inhibits MAO-B.⁴

Oral selegiline, approved as a adjunct to levodopa/carbidopa for patients with Parkinson’s disease,⁵ has been shown to be effective for treating depression at ≥30 mg/d.⁶ Because the drug does not selectively inhibit MAOB at ≥20 mg/d, dietary tyramine must be restricted when oral selegiline is used off-label at therapeutic dosages for depression. Otherwise, selegiline has been well-tolerated up to 60 mg/d.⁷

The 6-mg “patch” delivers more selegiline to the bloodstream than does low-dose oral selegiline but without inhibiting gut MAO-A. This provides the brain MAO-A and MAO-B inhibition necessary for an antidepressant effect while eliminating the need for dietary restrictions at this lowest dosage.

Clinical implications

Transdermal selegiline offers an MAOI antidepressant option that might help:

• patients whose depression has not responded satisfactorily to selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs)
• adults and children with chronic depression marked by atypical features, including reactive mood, rejection sensitivity, anergia, and reversed vegetative symptoms—such as oversleeping, overeating, and psychomotor retardation. Although transdermal selegiline’s efficacy against these features has not been studied, patients with this depressive subtype tend to respond preferentially to MAOIs.

Pharmacokinetics

Transdermal selegiline achieves therapeutic blood levels and reaches sustained concentration within 4 to 8 hours of administration. Compared with oral selegiline, transdermal delivery results in higher plasma selegiline concentrations (1,500 pg/mL with the 6-mg patch) with much lower exposure to metabolites.⁸ The concentration is maintained with successive doses.

Transdermal selegiline clears rapidly upon discontinuation but MAO inhibition persists for 2 weeks, so wait 2 weeks after the last dose before starting a new antidepressant or stopping food restrictions with the 9-mg and 12-mg patches.

Efficacy

In two randomized, double-blind clinical trials,^9,10 a total of 466 adults ages 18 to 65 who met DSM-IV-TR criteria for MDD received transdermal selegiline, 6 mg/d, or placebo for 6 to 8 weeks. Participants had 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores ≥20 at baseline.

In the 6-week study,⁹ transdermal selegiline produced a 46% greater reduction in HAM-D-17 scores, a 52% greater decrease in HAM-D-28 scores, and a 79% greater drop in Montgomery-Asburg Depression Rating Scale (MADRS) scores compared with placebo. In the 8-week trial,¹⁰ HAM-D-28 and MADRS scores among the treatment group were significantly improved at endpoint compared with placebo, but HAM-D-17 scores were not.

In a 1-year, double-blind study,¹¹ 322 subjects with MDD—who had been rated as responders in a 10-week, open-label transdermal selegiline trial—received the 6-mg patch or placebo. At 6 months and 1 year, relapse was much less frequent among the treatment group compared with placebo. Relapse was defined as:

• HAM-D-17 ≥14
• Clinical Global Impressions of Severity score ≥3 with a ≥2-point increase from baseline
• and meeting DSM-IV criteria for MDD on two consecutive visits ≥11 days apart.

Side effects

Transdermal selegiline, 6 mg/d, has been well-tolerated in clinical trials. Inflammation at the application site was the most commonly reported side effect, occurring in 32% to 36% of treatment group subjects compared with 15% to 17% of the placebo groups.^9,10,12 Inflammation was usually mild, but approximately 3% of patients dropped out of one study,¹² citing this effect as the reason. Fair-skinned women are at highest risk for this reaction.

In the 1-year relapse prevention study,¹¹ 12% of treatment group patients reported insomnia compared with 7% of the placebo group. Insomnia incidence was the same in the selegiline and placebo groups during the 6- to 8-week clinical trials.^9,10

Unlike conventional oral MAOIs,¹³ the 6-mg selegiline patch has not been found to impair sexual function, alter appetite, or change body weight or blood pressure compared with placebo.^10-12 The toxicity of the 9- and 12-mg patches has not been studied in humans, but 8 mg/d and 12 mg/d of transdermal selegiline across 3 months were shown not to cause drug toxicity in dogs.¹⁴

Pediatric use

Although transdermal selegiline has not been studied in children and adolescents, the 6-mg patch could benefit some youths with depression. Before starting the drug, discuss with the child’s parents/guardians the FDA’s black box warning describing a possible association between selegiline and increased suicidal behavior in youths. This applies to all antidepressants.

Geriatric use

The patch might also help some older patients with depression. In a double-blind trial of high-dose oral selegiline (60 mg/d) involving 16 older patients (mean age 65.6), both the treatment and placebo groups remained almost free of side effects across 3 weeks.⁷ Although the sample was small, the findings suggest that older patients can tolerate selegiline at high dosages. Side effects also were minimal among treatment-group patients age ≥65 in the yearlong relapse prevention study.¹¹

Treatment adherence rates with transdermal selegiline have been high in published studies, suggesting that the patch’s visibility might reduce the risk of forgetting to take the medication. Observing whether the patch has been changed might help older patients and family members/caregivers keep track of dosing.

Contraindications

As with the oral form, do not prescribe transdermal selegiline to patients taking SSRIs, SNRIs, tricyclic antidepressants, mirtazapine, or bupropion.

When switching antidepressants, allow enough time for the previous agent to “wash out” before starting transdermal selegiline. How much time to allow for wash-out depends on the previous agent’s half-life.

The patch is also contraindicated for patients taking:

• carbamazepine or oxcarbazepine
• meperidine
• analgesics such as tramadol, methadone, and propoxyphene
• St. John’s wort
• cough syrups containing dextromethorphan
• amphetamines, such as mixed amphetamine salts
• cyclobenzaprine
• or cold remedies or weight-loss products that contain vasoconstrictors, such as pseudoephedrine, phenylephrine, phenylpropanolamine, or ephedrine.

Do not give transdermal selegiline during pregnancy, as its effect on fetal development has not been studied.

Dosing

Start transdermal selegiline at 6 mg/d. Instruct the patient to wear the patch on the upper torso, where vascularity is richer compared with the buttocks and legs. Tell the patient to change the patch daily and to apply it to a different spot each day to prevent inflammation. Consider increasing the dosage after 2 or 3 months if response is unsatisfactory.

For treating first, second, and some third depressive episodes, continue transdermal selegiline for 6 months to 1 year of sustained recovery; consider longer-term maintenance treatment for highly recurrent depression. Transdermal selegiline has not been tapered in clinical trials, and subjects have not reported withdrawal symptoms after 1 year of continuous treatment.

Related resources

• Deniker P. The search for new antidepressants and related drugs. In: Tipton KF, Doster P, Benedetti M (eds). Monoamine oxidase and disease. London: Academic Press; 1984:2-8.

Drug brand names

• Amphetamine salts, mixed • Adderall
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro, others
• Cyclobenzaprine • Flexeril
• Meperidine • Demerol
• Mirtazapine • Remeron
• Oxcarbazepine • Trileptal
• Propoxyphene hydrochloride • Darvon
• Propoxyphene napsylate • Darvocet
• Selegiline (oral) • Eldepryl
• Selegiline (transdermal) • EMSAM
• Tramadol • Ultracet

Disclosure

Dr. Bodkin receives grant support from the National Institute of Mental Health, Eli Lilly & Co, Jazz Pharmaceuticals, Merck & Co., Organon, Sanofi-Aventis, and Somerset Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co. and Somerset Pharmaceuticals; and is a speaker for Bristol-Myers Squibb Co. He has been principal investigator in several multicenter clinical trials of selegiline.

Many psychiatrists do not prescribe monoamine oxidase inhibitors (MAOIs) for fear of causing a potentially fatal hypertensive reaction, even though restricting foods high in the amino acid tyramine usually prevents this effect.¹ Consequently, most depressed patients who might respond well to MAOIs do not receive them.^2,3

Transdermal selegiline, FDA-approved for treating major depressive disorder (MDD) (Table 1), offers the clinical efficacy of an MAOI but without adverse interactions with food at the 6-mg strength. Transdermal selegiline may inhibit too much gastrointestinal MAO-A at 9 mg/d and 12 mg/d to clear tyramine from foods, so tyramine-rich foods must be restricted at these dosages (Table 2).

Table 1

Transdermal selegiline: Fast facts

Table 2

Restrict these foods when prescribing transdermal selegiline at 9 or 12 mg/d

How it works

MAO enzyme subtypes A and B metabolize CNS monoamines, but primarily MAO-A metabolizes tyramine in the gut before the amino acid enters systemic circulation. At low concentrations, selegiline selectively inhibits MAO-B.⁴

Oral selegiline, approved as a adjunct to levodopa/carbidopa for patients with Parkinson’s disease,⁵ has been shown to be effective for treating depression at ≥30 mg/d.⁶ Because the drug does not selectively inhibit MAOB at ≥20 mg/d, dietary tyramine must be restricted when oral selegiline is used off-label at therapeutic dosages for depression. Otherwise, selegiline has been well-tolerated up to 60 mg/d.⁷

The 6-mg “patch” delivers more selegiline to the bloodstream than does low-dose oral selegiline but without inhibiting gut MAO-A. This provides the brain MAO-A and MAO-B inhibition necessary for an antidepressant effect while eliminating the need for dietary restrictions at this lowest dosage.

Clinical implications

Transdermal selegiline offers an MAOI antidepressant option that might help:

• patients whose depression has not responded satisfactorily to selective serotonin reuptake inhibitors (SSRIs) or serotonin and norepinephrine reuptake inhibitors (SNRIs)
• adults and children with chronic depression marked by atypical features, including reactive mood, rejection sensitivity, anergia, and reversed vegetative symptoms—such as oversleeping, overeating, and psychomotor retardation. Although transdermal selegiline’s efficacy against these features has not been studied, patients with this depressive subtype tend to respond preferentially to MAOIs.

Pharmacokinetics

Transdermal selegiline achieves therapeutic blood levels and reaches sustained concentration within 4 to 8 hours of administration. Compared with oral selegiline, transdermal delivery results in higher plasma selegiline concentrations (1,500 pg/mL with the 6-mg patch) with much lower exposure to metabolites.⁸ The concentration is maintained with successive doses.

Transdermal selegiline clears rapidly upon discontinuation but MAO inhibition persists for 2 weeks, so wait 2 weeks after the last dose before starting a new antidepressant or stopping food restrictions with the 9-mg and 12-mg patches.

Efficacy

In two randomized, double-blind clinical trials,^9,10 a total of 466 adults ages 18 to 65 who met DSM-IV-TR criteria for MDD received transdermal selegiline, 6 mg/d, or placebo for 6 to 8 weeks. Participants had 17-item Hamilton Rating Scale for Depression (HAM-D-17) scores ≥20 at baseline.

In the 6-week study,⁹ transdermal selegiline produced a 46% greater reduction in HAM-D-17 scores, a 52% greater decrease in HAM-D-28 scores, and a 79% greater drop in Montgomery-Asburg Depression Rating Scale (MADRS) scores compared with placebo. In the 8-week trial,¹⁰ HAM-D-28 and MADRS scores among the treatment group were significantly improved at endpoint compared with placebo, but HAM-D-17 scores were not.

In a 1-year, double-blind study,¹¹ 322 subjects with MDD—who had been rated as responders in a 10-week, open-label transdermal selegiline trial—received the 6-mg patch or placebo. At 6 months and 1 year, relapse was much less frequent among the treatment group compared with placebo. Relapse was defined as:

• HAM-D-17 ≥14
• Clinical Global Impressions of Severity score ≥3 with a ≥2-point increase from baseline
• and meeting DSM-IV criteria for MDD on two consecutive visits ≥11 days apart.

Side effects

Transdermal selegiline, 6 mg/d, has been well-tolerated in clinical trials. Inflammation at the application site was the most commonly reported side effect, occurring in 32% to 36% of treatment group subjects compared with 15% to 17% of the placebo groups.^9,10,12 Inflammation was usually mild, but approximately 3% of patients dropped out of one study,¹² citing this effect as the reason. Fair-skinned women are at highest risk for this reaction.

In the 1-year relapse prevention study,¹¹ 12% of treatment group patients reported insomnia compared with 7% of the placebo group. Insomnia incidence was the same in the selegiline and placebo groups during the 6- to 8-week clinical trials.^9,10

Unlike conventional oral MAOIs,¹³ the 6-mg selegiline patch has not been found to impair sexual function, alter appetite, or change body weight or blood pressure compared with placebo.^10-12 The toxicity of the 9- and 12-mg patches has not been studied in humans, but 8 mg/d and 12 mg/d of transdermal selegiline across 3 months were shown not to cause drug toxicity in dogs.¹⁴

Pediatric use

Although transdermal selegiline has not been studied in children and adolescents, the 6-mg patch could benefit some youths with depression. Before starting the drug, discuss with the child’s parents/guardians the FDA’s black box warning describing a possible association between selegiline and increased suicidal behavior in youths. This applies to all antidepressants.

Geriatric use

The patch might also help some older patients with depression. In a double-blind trial of high-dose oral selegiline (60 mg/d) involving 16 older patients (mean age 65.6), both the treatment and placebo groups remained almost free of side effects across 3 weeks.⁷ Although the sample was small, the findings suggest that older patients can tolerate selegiline at high dosages. Side effects also were minimal among treatment-group patients age ≥65 in the yearlong relapse prevention study.¹¹

Treatment adherence rates with transdermal selegiline have been high in published studies, suggesting that the patch’s visibility might reduce the risk of forgetting to take the medication. Observing whether the patch has been changed might help older patients and family members/caregivers keep track of dosing.

Contraindications

As with the oral form, do not prescribe transdermal selegiline to patients taking SSRIs, SNRIs, tricyclic antidepressants, mirtazapine, or bupropion.

When switching antidepressants, allow enough time for the previous agent to “wash out” before starting transdermal selegiline. How much time to allow for wash-out depends on the previous agent’s half-life.

The patch is also contraindicated for patients taking:

• carbamazepine or oxcarbazepine
• meperidine
• analgesics such as tramadol, methadone, and propoxyphene
• St. John’s wort
• cough syrups containing dextromethorphan
• amphetamines, such as mixed amphetamine salts
• cyclobenzaprine
• or cold remedies or weight-loss products that contain vasoconstrictors, such as pseudoephedrine, phenylephrine, phenylpropanolamine, or ephedrine.

Do not give transdermal selegiline during pregnancy, as its effect on fetal development has not been studied.

Dosing

Start transdermal selegiline at 6 mg/d. Instruct the patient to wear the patch on the upper torso, where vascularity is richer compared with the buttocks and legs. Tell the patient to change the patch daily and to apply it to a different spot each day to prevent inflammation. Consider increasing the dosage after 2 or 3 months if response is unsatisfactory.

For treating first, second, and some third depressive episodes, continue transdermal selegiline for 6 months to 1 year of sustained recovery; consider longer-term maintenance treatment for highly recurrent depression. Transdermal selegiline has not been tapered in clinical trials, and subjects have not reported withdrawal symptoms after 1 year of continuous treatment.

Related resources

• Deniker P. The search for new antidepressants and related drugs. In: Tipton KF, Doster P, Benedetti M (eds). Monoamine oxidase and disease. London: Academic Press; 1984:2-8.

Drug brand names

• Amphetamine salts, mixed • Adderall
• Bupropion • Wellbutrin
• Carbamazepine • Tegretol, Equetro, others
• Cyclobenzaprine • Flexeril
• Meperidine • Demerol
• Mirtazapine • Remeron
• Oxcarbazepine • Trileptal
• Propoxyphene hydrochloride • Darvon
• Propoxyphene napsylate • Darvocet
• Selegiline (oral) • Eldepryl
• Selegiline (transdermal) • EMSAM
• Tramadol • Ultracet

Disclosure

Dr. Bodkin receives grant support from the National Institute of Mental Health, Eli Lilly & Co, Jazz Pharmaceuticals, Merck & Co., Organon, Sanofi-Aventis, and Somerset Pharmaceuticals; is a consultant to Bristol-Myers Squibb Co. and Somerset Pharmaceuticals; and is a speaker for Bristol-Myers Squibb Co. He has been principal investigator in several multicenter clinical trials of selegiline.