Current Psychiatry

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.

Patients may use diagnostic labels of psychiatric disorders when describing their mental distress to clinicians. Sometimes they use these words appropriately, but often they don’t understand the meaning of psychiatric terms they have read or heard (Table). For example, a study of U.S. newspapers found that 28% of articles incorrectly used “schizophrenic” to refer to a “split” or inconsistent personality.¹

Terminology confusion could lead to 2 clinical problems:

• The patient may be confident in his or her self-diagnosis, which can strain the therapeutic relationship.
  
• The clinician may passively accept that the patient’s use of terms is accurate, resulting in a distorted diagnosis.
  

Table

Psychiatric terms patients misuse to describe symptoms

Searching for meaning

When a patient uses a psychiatric term to describe symptoms, clarify what he or she means by asking; “Can you tell me more about your experience of (the term) without using that word to describe it?” Alternately, you could say, “Let’s not worry about applying a label right now, just describe what you are going through.”

Another approach is to offer phrases that are synonyms of the term’s standard use. For example, ask your patient, “By ‘schizophrenic’ do you mean ‘being in 2 minds’ or ‘having really unusual experiences?’” Using popular culture references also may be helpful. For example, “When I use the term ‘schizophrenia,’ I think of someone like Russell Crowe’s character in the movie A Beautiful Mind.” Similarly, for obsessive-compulsive disorder, reference Jack Nicholson’s character in As Good as it Gets.

Clarifying terminology also can help you gather a complete family history. A patient may say “Oh, that sounds like my mother” when you accurately describe a psychiatric symptom or disorder.

Patients may use diagnostic labels of psychiatric disorders when describing their mental distress to clinicians. Sometimes they use these words appropriately, but often they don’t understand the meaning of psychiatric terms they have read or heard (Table). For example, a study of U.S. newspapers found that 28% of articles incorrectly used “schizophrenic” to refer to a “split” or inconsistent personality.¹

Terminology confusion could lead to 2 clinical problems:

• The patient may be confident in his or her self-diagnosis, which can strain the therapeutic relationship.
  
• The clinician may passively accept that the patient’s use of terms is accurate, resulting in a distorted diagnosis.
  

Table

Psychiatric terms patients misuse to describe symptoms

Searching for meaning

When a patient uses a psychiatric term to describe symptoms, clarify what he or she means by asking; “Can you tell me more about your experience of (the term) without using that word to describe it?” Alternately, you could say, “Let’s not worry about applying a label right now, just describe what you are going through.”

Another approach is to offer phrases that are synonyms of the term’s standard use. For example, ask your patient, “By ‘schizophrenic’ do you mean ‘being in 2 minds’ or ‘having really unusual experiences?’” Using popular culture references also may be helpful. For example, “When I use the term ‘schizophrenia,’ I think of someone like Russell Crowe’s character in the movie A Beautiful Mind.” Similarly, for obsessive-compulsive disorder, reference Jack Nicholson’s character in As Good as it Gets.

Clarifying terminology also can help you gather a complete family history. A patient may say “Oh, that sounds like my mother” when you accurately describe a psychiatric symptom or disorder.

Patients may use diagnostic labels of psychiatric disorders when describing their mental distress to clinicians. Sometimes they use these words appropriately, but often they don’t understand the meaning of psychiatric terms they have read or heard (Table). For example, a study of U.S. newspapers found that 28% of articles incorrectly used “schizophrenic” to refer to a “split” or inconsistent personality.¹

Terminology confusion could lead to 2 clinical problems:

• The patient may be confident in his or her self-diagnosis, which can strain the therapeutic relationship.
  
• The clinician may passively accept that the patient’s use of terms is accurate, resulting in a distorted diagnosis.
  

Table

Psychiatric terms patients misuse to describe symptoms

Searching for meaning

When a patient uses a psychiatric term to describe symptoms, clarify what he or she means by asking; “Can you tell me more about your experience of (the term) without using that word to describe it?” Alternately, you could say, “Let’s not worry about applying a label right now, just describe what you are going through.”

Another approach is to offer phrases that are synonyms of the term’s standard use. For example, ask your patient, “By ‘schizophrenic’ do you mean ‘being in 2 minds’ or ‘having really unusual experiences?’” Using popular culture references also may be helpful. For example, “When I use the term ‘schizophrenia,’ I think of someone like Russell Crowe’s character in the movie A Beautiful Mind.” Similarly, for obsessive-compulsive disorder, reference Jack Nicholson’s character in As Good as it Gets.

Clarifying terminology also can help you gather a complete family history. A patient may say “Oh, that sounds like my mother” when you accurately describe a psychiatric symptom or disorder.

Transferring to another psychiatrist can distress mental health patients and disrupt treatment, whether you part ways with them because of an insurance change or relocation. A smooth transfer helps maintain patients’ clinical progress and reduces the risk of losing them to follow-up. We suggest a timeline for saying good-bye (Table) and some strategies to ease the transition.

Table

Timeline for transferring your patient’s care

Starting the conversation

Inform the patient of your approximate departure date as soon as possible. Most residents, for example, should have this conversation in January, allowing approximately 6 months to address issues your departure may bring up. Don’t be surprised if your patient does not recall this conversation, however, because he or she might unconsciously repress this information. You might have to discuss your departure several times before it becomes “real” for your patient.

Identify specific issues to address before transferring the patient’s care. For example, explore whether any medications need to be changed.

Tell your patient you would like to write the transfer summary together, and encourage him or her to think about what information to include. If another physician transferred the patient to you, inquire about that process. Did the earlier physician do or say something that was helpful?

Initiating transfer of care

Encourage your patient to talk about feelings related to the transfer by asking how he or she thinks the process will go. Don’t assume your patient is anxious or upset about the change, however. Some patients “bond” to the clinic rather than to a particular doctor.

Be alert for unconscious communication about your impending departure. For example, your patient might talk about others who have left in the past. Consider these statements as opportunities to discuss your departure against the backdrop of other losses and changes.

Patients might unconsciously act out in response to your upcoming departure. For example, a patient who has faithfully attended appointments might “accidentally” miss a visit or discontinue 1 or more medications.

Examine your feelings about the impending transfer of care. Guard against attributing your feelings about the process to your patient. If you find that these feelings lead to difficulty helping your patient find closure, consider consulting with a colleague or mentor.

1 month before the transfer

Your patient might initiate more intense work than in the past. Your impending departure might make it seem safer to share previously undiscussed information because there is little time to explore it.

Although you may be tempted to take advantage of your patient’s impulse, carefully assess this strategy. This is the time to work toward closure, rather than delving into new areas. Keep treatment structured; avoid increasing or decreasing the frequency of visits as you approach the last session.

Also avoid changing the patient’s medication regimen, if possible. If your patient is anxious about your departure, new medication side effects might exacerbate this anxiety.

If possible, personally introduce your patient to the new physician and discuss the transfer summary. Don’t say that the new doctor is “really good.” The qualities you like about this clinician might not appeal to the patient. Encourage the patient to “interview” the new physician.

Don’t discuss what you will be doing after you leave. If the patient asks, talk about your plans in general terms. Detailed or persistent questioning might have psychological meaning and could be discussed in psychotherapy.

The last session

Write 1 or 2 prescription refills. Many patients are concerned about a possible delay in starting treatment with the new physician, and adequate refills may allay fears about obtaining medication. Having refills also may act as a temporary “transitional object” until the patient feels comfortable with the new physician.

Tell your patient that many individuals don’t follow up with a new physician, but it is important to do so. Discussing this phenomenon may increase the probability that your patient will follow up because you can talk about his or her concerns about seeing a new physician or ending treatment with you.

Don’t agree to correspond with the patient after you transfer care. Further communication might interfere with the new therapeutic relationship. The patient might communicate clinical concerns to you, not to the new physician.

Don’t initiate a hug at the end of the session. If your patient initiates a hug or a handshake, you may accept it if you are comfortable with physical contact. End the session on a positive note, and express your best wishes for the patient’s continued growth and well-being.

Still having problems?

If the transition of your patient’s care is unusually difficult, do not hesitate to ask a supervisor or colleague for assistance.

Transferring to another psychiatrist can distress mental health patients and disrupt treatment, whether you part ways with them because of an insurance change or relocation. A smooth transfer helps maintain patients’ clinical progress and reduces the risk of losing them to follow-up. We suggest a timeline for saying good-bye (Table) and some strategies to ease the transition.

Table

Timeline for transferring your patient’s care

Starting the conversation

Inform the patient of your approximate departure date as soon as possible. Most residents, for example, should have this conversation in January, allowing approximately 6 months to address issues your departure may bring up. Don’t be surprised if your patient does not recall this conversation, however, because he or she might unconsciously repress this information. You might have to discuss your departure several times before it becomes “real” for your patient.

Identify specific issues to address before transferring the patient’s care. For example, explore whether any medications need to be changed.

Tell your patient you would like to write the transfer summary together, and encourage him or her to think about what information to include. If another physician transferred the patient to you, inquire about that process. Did the earlier physician do or say something that was helpful?

Initiating transfer of care

Encourage your patient to talk about feelings related to the transfer by asking how he or she thinks the process will go. Don’t assume your patient is anxious or upset about the change, however. Some patients “bond” to the clinic rather than to a particular doctor.

Be alert for unconscious communication about your impending departure. For example, your patient might talk about others who have left in the past. Consider these statements as opportunities to discuss your departure against the backdrop of other losses and changes.

Patients might unconsciously act out in response to your upcoming departure. For example, a patient who has faithfully attended appointments might “accidentally” miss a visit or discontinue 1 or more medications.

Examine your feelings about the impending transfer of care. Guard against attributing your feelings about the process to your patient. If you find that these feelings lead to difficulty helping your patient find closure, consider consulting with a colleague or mentor.

1 month before the transfer

Your patient might initiate more intense work than in the past. Your impending departure might make it seem safer to share previously undiscussed information because there is little time to explore it.

Although you may be tempted to take advantage of your patient’s impulse, carefully assess this strategy. This is the time to work toward closure, rather than delving into new areas. Keep treatment structured; avoid increasing or decreasing the frequency of visits as you approach the last session.

Also avoid changing the patient’s medication regimen, if possible. If your patient is anxious about your departure, new medication side effects might exacerbate this anxiety.

If possible, personally introduce your patient to the new physician and discuss the transfer summary. Don’t say that the new doctor is “really good.” The qualities you like about this clinician might not appeal to the patient. Encourage the patient to “interview” the new physician.

Don’t discuss what you will be doing after you leave. If the patient asks, talk about your plans in general terms. Detailed or persistent questioning might have psychological meaning and could be discussed in psychotherapy.

The last session

Write 1 or 2 prescription refills. Many patients are concerned about a possible delay in starting treatment with the new physician, and adequate refills may allay fears about obtaining medication. Having refills also may act as a temporary “transitional object” until the patient feels comfortable with the new physician.

Tell your patient that many individuals don’t follow up with a new physician, but it is important to do so. Discussing this phenomenon may increase the probability that your patient will follow up because you can talk about his or her concerns about seeing a new physician or ending treatment with you.

Don’t agree to correspond with the patient after you transfer care. Further communication might interfere with the new therapeutic relationship. The patient might communicate clinical concerns to you, not to the new physician.

Don’t initiate a hug at the end of the session. If your patient initiates a hug or a handshake, you may accept it if you are comfortable with physical contact. End the session on a positive note, and express your best wishes for the patient’s continued growth and well-being.

Still having problems?

If the transition of your patient’s care is unusually difficult, do not hesitate to ask a supervisor or colleague for assistance.

Transferring to another psychiatrist can distress mental health patients and disrupt treatment, whether you part ways with them because of an insurance change or relocation. A smooth transfer helps maintain patients’ clinical progress and reduces the risk of losing them to follow-up. We suggest a timeline for saying good-bye (Table) and some strategies to ease the transition.

Table

Timeline for transferring your patient’s care

Starting the conversation

Inform the patient of your approximate departure date as soon as possible. Most residents, for example, should have this conversation in January, allowing approximately 6 months to address issues your departure may bring up. Don’t be surprised if your patient does not recall this conversation, however, because he or she might unconsciously repress this information. You might have to discuss your departure several times before it becomes “real” for your patient.

Identify specific issues to address before transferring the patient’s care. For example, explore whether any medications need to be changed.

Tell your patient you would like to write the transfer summary together, and encourage him or her to think about what information to include. If another physician transferred the patient to you, inquire about that process. Did the earlier physician do or say something that was helpful?

Initiating transfer of care

Encourage your patient to talk about feelings related to the transfer by asking how he or she thinks the process will go. Don’t assume your patient is anxious or upset about the change, however. Some patients “bond” to the clinic rather than to a particular doctor.

Be alert for unconscious communication about your impending departure. For example, your patient might talk about others who have left in the past. Consider these statements as opportunities to discuss your departure against the backdrop of other losses and changes.

Patients might unconsciously act out in response to your upcoming departure. For example, a patient who has faithfully attended appointments might “accidentally” miss a visit or discontinue 1 or more medications.

Examine your feelings about the impending transfer of care. Guard against attributing your feelings about the process to your patient. If you find that these feelings lead to difficulty helping your patient find closure, consider consulting with a colleague or mentor.

1 month before the transfer

Your patient might initiate more intense work than in the past. Your impending departure might make it seem safer to share previously undiscussed information because there is little time to explore it.

Although you may be tempted to take advantage of your patient’s impulse, carefully assess this strategy. This is the time to work toward closure, rather than delving into new areas. Keep treatment structured; avoid increasing or decreasing the frequency of visits as you approach the last session.

Also avoid changing the patient’s medication regimen, if possible. If your patient is anxious about your departure, new medication side effects might exacerbate this anxiety.

If possible, personally introduce your patient to the new physician and discuss the transfer summary. Don’t say that the new doctor is “really good.” The qualities you like about this clinician might not appeal to the patient. Encourage the patient to “interview” the new physician.

Don’t discuss what you will be doing after you leave. If the patient asks, talk about your plans in general terms. Detailed or persistent questioning might have psychological meaning and could be discussed in psychotherapy.

The last session

Write 1 or 2 prescription refills. Many patients are concerned about a possible delay in starting treatment with the new physician, and adequate refills may allay fears about obtaining medication. Having refills also may act as a temporary “transitional object” until the patient feels comfortable with the new physician.

Tell your patient that many individuals don’t follow up with a new physician, but it is important to do so. Discussing this phenomenon may increase the probability that your patient will follow up because you can talk about his or her concerns about seeing a new physician or ending treatment with you.

Don’t agree to correspond with the patient after you transfer care. Further communication might interfere with the new therapeutic relationship. The patient might communicate clinical concerns to you, not to the new physician.

Don’t initiate a hug at the end of the session. If your patient initiates a hug or a handshake, you may accept it if you are comfortable with physical contact. End the session on a positive note, and express your best wishes for the patient’s continued growth and well-being.

Still having problems?

If the transition of your patient’s care is unusually difficult, do not hesitate to ask a supervisor or colleague for assistance.

My comments are somewhat biased because my medical practice is exclusively dedicated to treating attention-deficit/hyperactivity disorder (ADHD) and the associated comorbid disorders for the last 30 years. However, Dr. James W. Jefferson’s brilliant article (Rediscovering antidepressants: The spectrum beyond depression, Current Psychiatry, October 2007) has one major omission in my opinion. My suggestion is to add methylphenidate to antidepressant treatment. Methylphenidate is in fact a mild antidepressant and was introduced as such many years ago.

Over the years I have seen hundreds of adults who have seen many doctors and received many antidepressants for depression with no or minimal benefit. The majority of these patients—with very few exceptions—are undiagnosed adults with ADHD.

One sequela of untreated ADHD is depression. When a patient is placed on an effective dose of a stimulant such as methylphenidate and monitored to optimal levels together with an antidepressant, the results are nothing less than dramatic.

There are very few resistant depressions but, rather, many missed ADHD diagnoses. The response time is also very exciting. Sometimes results as measured by the Hamilton Depression Rating Scale and the modified Conners’ Adult ADHD Rating Scale will show within 10 to 20 days. These results often are confirmed by the patient and family members, making this treatment a clear-cut success story.

My oldest patient is 84 years old, and she has told me that for the first time in her life she is living a "whole" life instead of a "half" life. I must admit I was hesitant to treat such an old patient, but her result is very gratifying indeed.

Billy Levin, MbChB
Benoni, South Africa

My comments are somewhat biased because my medical practice is exclusively dedicated to treating attention-deficit/hyperactivity disorder (ADHD) and the associated comorbid disorders for the last 30 years. However, Dr. James W. Jefferson’s brilliant article (Rediscovering antidepressants: The spectrum beyond depression, Current Psychiatry, October 2007) has one major omission in my opinion. My suggestion is to add methylphenidate to antidepressant treatment. Methylphenidate is in fact a mild antidepressant and was introduced as such many years ago.

Over the years I have seen hundreds of adults who have seen many doctors and received many antidepressants for depression with no or minimal benefit. The majority of these patients—with very few exceptions—are undiagnosed adults with ADHD.

One sequela of untreated ADHD is depression. When a patient is placed on an effective dose of a stimulant such as methylphenidate and monitored to optimal levels together with an antidepressant, the results are nothing less than dramatic.

There are very few resistant depressions but, rather, many missed ADHD diagnoses. The response time is also very exciting. Sometimes results as measured by the Hamilton Depression Rating Scale and the modified Conners’ Adult ADHD Rating Scale will show within 10 to 20 days. These results often are confirmed by the patient and family members, making this treatment a clear-cut success story.

My oldest patient is 84 years old, and she has told me that for the first time in her life she is living a "whole" life instead of a "half" life. I must admit I was hesitant to treat such an old patient, but her result is very gratifying indeed.

Billy Levin, MbChB
Benoni, South Africa

My comments are somewhat biased because my medical practice is exclusively dedicated to treating attention-deficit/hyperactivity disorder (ADHD) and the associated comorbid disorders for the last 30 years. However, Dr. James W. Jefferson’s brilliant article (Rediscovering antidepressants: The spectrum beyond depression, Current Psychiatry, October 2007) has one major omission in my opinion. My suggestion is to add methylphenidate to antidepressant treatment. Methylphenidate is in fact a mild antidepressant and was introduced as such many years ago.

Over the years I have seen hundreds of adults who have seen many doctors and received many antidepressants for depression with no or minimal benefit. The majority of these patients—with very few exceptions—are undiagnosed adults with ADHD.

One sequela of untreated ADHD is depression. When a patient is placed on an effective dose of a stimulant such as methylphenidate and monitored to optimal levels together with an antidepressant, the results are nothing less than dramatic.

There are very few resistant depressions but, rather, many missed ADHD diagnoses. The response time is also very exciting. Sometimes results as measured by the Hamilton Depression Rating Scale and the modified Conners’ Adult ADHD Rating Scale will show within 10 to 20 days. These results often are confirmed by the patient and family members, making this treatment a clear-cut success story.

My oldest patient is 84 years old, and she has told me that for the first time in her life she is living a "whole" life instead of a "half" life. I must admit I was hesitant to treat such an old patient, but her result is very gratifying indeed.

Billy Levin, MbChB
Benoni, South Africa

I appreciate Current Psychiatry’s emphasis on sharpening one’s psychiatric diagnostic skills (“Neurocognitive impairment: Feigned, exaggerated, or real?” Current Psychiatry, August 2007). I have found a few additional questions may help validate symptoms of neurocognitive impairment during a psychiatric interview. These questions were developed as a result of my informal survey of individuals with head injuries, usually months after the injury.

Ask about a patient’s job. Significant changes in employment status—such as job loss or changes in job responsibilities or how others relate to the individual in the workplace— usually occur in the first 6 months after an injury.

Has the patient thought about or obtained a gun permit? In response to their perceived weaker status, many patients acquired weapons. I have no knowledge if these guns were misused.

In an informal survey, I also asked these injured individuals to name their favorite movie and actor. The Godfather: Part II and/or the film’s actors Robert De Niro, Al Pacino, and James Caan were chosen by 85% of patients from a certain generation. One possible reason for this choice was suggested by a 14-year veteran of the Canadian Forces, who felt that the motion picture allowed one to fantasize about striking out at others without harming oneself. Positive answers to 1 or more of these questions suggested symptom validity.

The psychologist’s documentation of an organic cause of the neurocognitive impairment compared favorably to an abnormal finding on a computerized brain mapping electroencephalogram (EEG). The recent computerization of multiple EEGs will allow physicians to identify abnormal patterns of electrical activity and suggest a diagnosis. A finding of 2 standard deviations from average may indicate neurocognitive impairment.

Leonard R. Friedman, MD
Revere, MA

I appreciate Current Psychiatry’s emphasis on sharpening one’s psychiatric diagnostic skills (“Neurocognitive impairment: Feigned, exaggerated, or real?” Current Psychiatry, August 2007). I have found a few additional questions may help validate symptoms of neurocognitive impairment during a psychiatric interview. These questions were developed as a result of my informal survey of individuals with head injuries, usually months after the injury.

Ask about a patient’s job. Significant changes in employment status—such as job loss or changes in job responsibilities or how others relate to the individual in the workplace— usually occur in the first 6 months after an injury.

Has the patient thought about or obtained a gun permit? In response to their perceived weaker status, many patients acquired weapons. I have no knowledge if these guns were misused.

In an informal survey, I also asked these injured individuals to name their favorite movie and actor. The Godfather: Part II and/or the film’s actors Robert De Niro, Al Pacino, and James Caan were chosen by 85% of patients from a certain generation. One possible reason for this choice was suggested by a 14-year veteran of the Canadian Forces, who felt that the motion picture allowed one to fantasize about striking out at others without harming oneself. Positive answers to 1 or more of these questions suggested symptom validity.

The psychologist’s documentation of an organic cause of the neurocognitive impairment compared favorably to an abnormal finding on a computerized brain mapping electroencephalogram (EEG). The recent computerization of multiple EEGs will allow physicians to identify abnormal patterns of electrical activity and suggest a diagnosis. A finding of 2 standard deviations from average may indicate neurocognitive impairment.

Leonard R. Friedman, MD
Revere, MA

I appreciate Current Psychiatry’s emphasis on sharpening one’s psychiatric diagnostic skills (“Neurocognitive impairment: Feigned, exaggerated, or real?” Current Psychiatry, August 2007). I have found a few additional questions may help validate symptoms of neurocognitive impairment during a psychiatric interview. These questions were developed as a result of my informal survey of individuals with head injuries, usually months after the injury.

Ask about a patient’s job. Significant changes in employment status—such as job loss or changes in job responsibilities or how others relate to the individual in the workplace— usually occur in the first 6 months after an injury.

Has the patient thought about or obtained a gun permit? In response to their perceived weaker status, many patients acquired weapons. I have no knowledge if these guns were misused.

In an informal survey, I also asked these injured individuals to name their favorite movie and actor. The Godfather: Part II and/or the film’s actors Robert De Niro, Al Pacino, and James Caan were chosen by 85% of patients from a certain generation. One possible reason for this choice was suggested by a 14-year veteran of the Canadian Forces, who felt that the motion picture allowed one to fantasize about striking out at others without harming oneself. Positive answers to 1 or more of these questions suggested symptom validity.

The psychologist’s documentation of an organic cause of the neurocognitive impairment compared favorably to an abnormal finding on a computerized brain mapping electroencephalogram (EEG). The recent computerization of multiple EEGs will allow physicians to identify abnormal patterns of electrical activity and suggest a diagnosis. A finding of 2 standard deviations from average may indicate neurocognitive impairment.

Leonard R. Friedman, MD
Revere, MA

The stepwise risk assessment in the article “Suicide intervention: How to recognize risk, focus on patient safety” is very precise and hits the bull’seye for risk assessment (Current Psychiatry, September 2007). It is important that we identify the predictors of suicide because risk is a dynamic concept and difficult to determine in all cases. Dr. David J. Muzina provided a good discussion of the risk factors associated with suicide and “protective factors.” This article will help me perform a better suicide risk assessments when on call and during routine clinical work.

Vineet Padmanabhan
Bangor, North Wales, United Kingdom

I found “Suicide intervention: How to recognize risk, focus on patient safety” to be interesting and informative. However, there is one group at high risk for suicide that was not mentioned. That is the group that suffers from gender identity dysphoria (GID) or “Harry Benjamin syndrome” (HBS) as it is now becoming known.

Major reasons for suicide in this group include feelings of helplessness, rejection by family, lack of support, and abuse from the public in general. Also, transsexuals might become depressed because of job discrimination and inability to raise required funds to pay for gender correction surgery.

I am familiar with the subject as I had GID/HBS but was fortunate enough to be able to pay for my surgery. I belong to an online suicide prevention group where we supply information, encouragement, and the telephone numbers of group members who may be contacted for immediate emotional support.

Pamela J.S. Dunn
Wesley Chapel, FL

The stepwise risk assessment in the article “Suicide intervention: How to recognize risk, focus on patient safety” is very precise and hits the bull’seye for risk assessment (Current Psychiatry, September 2007). It is important that we identify the predictors of suicide because risk is a dynamic concept and difficult to determine in all cases. Dr. David J. Muzina provided a good discussion of the risk factors associated with suicide and “protective factors.” This article will help me perform a better suicide risk assessments when on call and during routine clinical work.

Vineet Padmanabhan
Bangor, North Wales, United Kingdom

I found “Suicide intervention: How to recognize risk, focus on patient safety” to be interesting and informative. However, there is one group at high risk for suicide that was not mentioned. That is the group that suffers from gender identity dysphoria (GID) or “Harry Benjamin syndrome” (HBS) as it is now becoming known.

Major reasons for suicide in this group include feelings of helplessness, rejection by family, lack of support, and abuse from the public in general. Also, transsexuals might become depressed because of job discrimination and inability to raise required funds to pay for gender correction surgery.

I am familiar with the subject as I had GID/HBS but was fortunate enough to be able to pay for my surgery. I belong to an online suicide prevention group where we supply information, encouragement, and the telephone numbers of group members who may be contacted for immediate emotional support.

Pamela J.S. Dunn
Wesley Chapel, FL

The stepwise risk assessment in the article “Suicide intervention: How to recognize risk, focus on patient safety” is very precise and hits the bull’seye for risk assessment (Current Psychiatry, September 2007). It is important that we identify the predictors of suicide because risk is a dynamic concept and difficult to determine in all cases. Dr. David J. Muzina provided a good discussion of the risk factors associated with suicide and “protective factors.” This article will help me perform a better suicide risk assessments when on call and during routine clinical work.

Vineet Padmanabhan
Bangor, North Wales, United Kingdom

I found “Suicide intervention: How to recognize risk, focus on patient safety” to be interesting and informative. However, there is one group at high risk for suicide that was not mentioned. That is the group that suffers from gender identity dysphoria (GID) or “Harry Benjamin syndrome” (HBS) as it is now becoming known.

Major reasons for suicide in this group include feelings of helplessness, rejection by family, lack of support, and abuse from the public in general. Also, transsexuals might become depressed because of job discrimination and inability to raise required funds to pay for gender correction surgery.

I am familiar with the subject as I had GID/HBS but was fortunate enough to be able to pay for my surgery. I belong to an online suicide prevention group where we supply information, encouragement, and the telephone numbers of group members who may be contacted for immediate emotional support.

Pamela J.S. Dunn
Wesley Chapel, FL

In “Managing anxiety in patients with implanted cardiac defibrillators” (Current Psychiatry, September 2007), Drs. Douglas P. Gibson and Kristin K. Kuntz address the potential psychiatric sequela of shocks from implanted cardiac defibrillators (ICDs). Depression is a known risk factor for developing and dying from cardiac disease,¹ and recent evidence suggests that anxiety disorders also are associated with increased cardiac risk.² Autonomic dysfunction is 1 potential mechanism that could explain the increased cardiac mortality associated with depression and anxiety. Patients with depression have a higher risk of ICD shocks induced by ventricular arrhythmias than nondepressed patients.³ This suggests a vicious circle when anxiety and depression could increase arrhythmic risk through autonomic dysfunction, and arrhythmias leading to ICD shocks may cause or worsen depression and anxiety.

Drs. Gibson and Kuntz also describe how cognitive-behavioral therapy (CBT) can reduce anxiety and depressive symptoms associated with ICD shocks. A paper published last year described how CBT may help decrease ICD shocks.⁴ Therefore it is possible that psychotherapeutic interventions such as CBT may do more than help improve depression and anxiety symptoms, whether preceded or caused by ICD shocks. CBT also might help reduce ventricular arrhythmias. This is important because we do not have good empiric evidence that current treatments for depression—pharmacologic or psychotherapeutic—reduce cardiac risk.¹

A recent paper suggests that autonomic dysfunction may improve with sertraline treatment.⁵ However, the rationale for treating cardiac patients for depression and anxiety should be improvement of psychiatric symptoms and not an as-yet-unfounded belief that such treatments may also reduce the cardiac mortality and morbidity.

Jonas Hannestad, MD, PhD
Department of psychiatry
Yale University
New Haven, CT

In “Managing anxiety in patients with implanted cardiac defibrillators” (Current Psychiatry, September 2007), Drs. Douglas P. Gibson and Kristin K. Kuntz address the potential psychiatric sequela of shocks from implanted cardiac defibrillators (ICDs). Depression is a known risk factor for developing and dying from cardiac disease,¹ and recent evidence suggests that anxiety disorders also are associated with increased cardiac risk.² Autonomic dysfunction is 1 potential mechanism that could explain the increased cardiac mortality associated with depression and anxiety. Patients with depression have a higher risk of ICD shocks induced by ventricular arrhythmias than nondepressed patients.³ This suggests a vicious circle when anxiety and depression could increase arrhythmic risk through autonomic dysfunction, and arrhythmias leading to ICD shocks may cause or worsen depression and anxiety.

Drs. Gibson and Kuntz also describe how cognitive-behavioral therapy (CBT) can reduce anxiety and depressive symptoms associated with ICD shocks. A paper published last year described how CBT may help decrease ICD shocks.⁴ Therefore it is possible that psychotherapeutic interventions such as CBT may do more than help improve depression and anxiety symptoms, whether preceded or caused by ICD shocks. CBT also might help reduce ventricular arrhythmias. This is important because we do not have good empiric evidence that current treatments for depression—pharmacologic or psychotherapeutic—reduce cardiac risk.¹

A recent paper suggests that autonomic dysfunction may improve with sertraline treatment.⁵ However, the rationale for treating cardiac patients for depression and anxiety should be improvement of psychiatric symptoms and not an as-yet-unfounded belief that such treatments may also reduce the cardiac mortality and morbidity.

Jonas Hannestad, MD, PhD
Department of psychiatry
Yale University
New Haven, CT

In “Managing anxiety in patients with implanted cardiac defibrillators” (Current Psychiatry, September 2007), Drs. Douglas P. Gibson and Kristin K. Kuntz address the potential psychiatric sequela of shocks from implanted cardiac defibrillators (ICDs). Depression is a known risk factor for developing and dying from cardiac disease,¹ and recent evidence suggests that anxiety disorders also are associated with increased cardiac risk.² Autonomic dysfunction is 1 potential mechanism that could explain the increased cardiac mortality associated with depression and anxiety. Patients with depression have a higher risk of ICD shocks induced by ventricular arrhythmias than nondepressed patients.³ This suggests a vicious circle when anxiety and depression could increase arrhythmic risk through autonomic dysfunction, and arrhythmias leading to ICD shocks may cause or worsen depression and anxiety.

Drs. Gibson and Kuntz also describe how cognitive-behavioral therapy (CBT) can reduce anxiety and depressive symptoms associated with ICD shocks. A paper published last year described how CBT may help decrease ICD shocks.⁴ Therefore it is possible that psychotherapeutic interventions such as CBT may do more than help improve depression and anxiety symptoms, whether preceded or caused by ICD shocks. CBT also might help reduce ventricular arrhythmias. This is important because we do not have good empiric evidence that current treatments for depression—pharmacologic or psychotherapeutic—reduce cardiac risk.¹

A recent paper suggests that autonomic dysfunction may improve with sertraline treatment.⁵ However, the rationale for treating cardiac patients for depression and anxiety should be improvement of psychiatric symptoms and not an as-yet-unfounded belief that such treatments may also reduce the cardiac mortality and morbidity.

Jonas Hannestad, MD, PhD
Department of psychiatry
Yale University
New Haven, CT

Polypharmacy has been a 4-letter word for a long time in schizophrenia management. Prescribing more than 1 antipsychotic to a patient with refractory symptoms has evoked images of a potentially harmful, nonevidence-based cocktail with no proven advantage over monotherapy.

Compare schizophrenia with bipolar disorder, for which combination therapy—an antipsychotic plus a mood stabilizer plus an antidepressant/ antianxiety agent—is the standard of care. Similarly, augmentation therapy is viewed as necessary for difficult cases of unipolar depression.

In the United States, approximately 40% of schizophrenia patients receive 2 or more concomitant antipsychotics (atypical and conventional agents).¹ Clearly, many clinicians resort to antipsychotic polypharmacy in a desperate attempt to manage chronic, treatment-resistant illness, even though no published data support this practice.

This situation may be changing, however, because of evolving under-standings of schizophrenia’s neurobiology. Before long, clinicians may employ concomitant agents with different mechanisms in novel approaches to improve outcomes in patients with schizophrenia.

Novel polypharmacy. The dopamine pathways approach is inadequate for achieving true remission across all of chronic schizophrenia’s symptom domains. Positive and negative symptoms and cognitive impairment that persist despite antipsychotic therapy call for new treatment approaches. Here are some of my speculations—suggested by emerging data about schizophrenia’s pathophysiology—about “futuristic” adjuncts to antipsychotics:

Add a glutamate modulator (such as lamotrigine). This combination has shown benefit in patients who have not responded to clozapine.² Many lines of evidence show that the glutamate system is impaired in schizophrenia, and this approach is promising.

Add a GABA agonist (such as valproate or benzodiazepines). Recent findings of a GABA deficit in frontal lobe chandelier cells in schizophrenia gives this combination legitimacy.³

Add an anti-inflammatory agent (such as a COX-2 inhibitor). Several studies report increased inflammatory cytokines in patients with schizophrenia. Others have found an antipsychotic/anti-inflammatory combination more efficacious than an antipsychotic alone.⁴

Add a cognitive enhancing agent. Antipsychotics as monotherapy fail to reverse schizophrenia’s severe cognitive deficits (~2 standard deviations below healthy individuals’ cognition).The National Institute of Mental Health-sponsored MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia)⁵ is testing potential neuro-protective and myelin-repair agents to improve deficits in memory, attention, and executive function in schizophrenia. Potential mechanisms include alpha 7 nicotinic receptor agonists, D1 receptor agonists, or AMPA glutamatergic receptor agonists. These agents might become available in a few years.

Add a neuroprotective agent. As a neurodegenerative disorder, schizophrenia could benefit from induction of neurotrophic factors (such as nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], or vascular endothelial growth factor [VEGF]) and neurogenesis stimulation. Atypical antipsychotics —but not typical agents—have shown neurotrophic activity,⁶ but combining them with other neurotrophic agents such as lithium or selective serotonin reuptake inhibitors⁷ might expedite brain tissue regeneration and improve patients’ function.

Add a myelin repair agent. Many schizophrenia studies suggest impaired myelin (white-matter) structure, which may explain the “disconnection” among brain regions that results in thought disorder. A recent report indicates that citalopram restored white-matter integrity in patients with obsessive-compulsive disorder after a few weeks of use.⁸ If these results are replicated in schizophrenia, antipsychotic-myelin repair agent combinations may become a rational polypharmacy.

What lies ahead. Future schizophrenia treatment almost certainly will include drug combinations that:

• address clinical domains not managed with current antipsychotic monotherapy
• help override treatment resistance or refractoriness (hallucinations or delusions).

Combinations of 3 or more drugs often are used to treat serious medical disorders such as cancer, HIV, or malignant hypertension. Management of a severe, disabling psychiatric disorder such as schizophrenia should be no less aggressive.

Polypharmacy has been a 4-letter word for a long time in schizophrenia management. Prescribing more than 1 antipsychotic to a patient with refractory symptoms has evoked images of a potentially harmful, nonevidence-based cocktail with no proven advantage over monotherapy.

Compare schizophrenia with bipolar disorder, for which combination therapy—an antipsychotic plus a mood stabilizer plus an antidepressant/ antianxiety agent—is the standard of care. Similarly, augmentation therapy is viewed as necessary for difficult cases of unipolar depression.

In the United States, approximately 40% of schizophrenia patients receive 2 or more concomitant antipsychotics (atypical and conventional agents).¹ Clearly, many clinicians resort to antipsychotic polypharmacy in a desperate attempt to manage chronic, treatment-resistant illness, even though no published data support this practice.

This situation may be changing, however, because of evolving under-standings of schizophrenia’s neurobiology. Before long, clinicians may employ concomitant agents with different mechanisms in novel approaches to improve outcomes in patients with schizophrenia.

Novel polypharmacy. The dopamine pathways approach is inadequate for achieving true remission across all of chronic schizophrenia’s symptom domains. Positive and negative symptoms and cognitive impairment that persist despite antipsychotic therapy call for new treatment approaches. Here are some of my speculations—suggested by emerging data about schizophrenia’s pathophysiology—about “futuristic” adjuncts to antipsychotics:

Add a glutamate modulator (such as lamotrigine). This combination has shown benefit in patients who have not responded to clozapine.² Many lines of evidence show that the glutamate system is impaired in schizophrenia, and this approach is promising.

Add a GABA agonist (such as valproate or benzodiazepines). Recent findings of a GABA deficit in frontal lobe chandelier cells in schizophrenia gives this combination legitimacy.³

Add an anti-inflammatory agent (such as a COX-2 inhibitor). Several studies report increased inflammatory cytokines in patients with schizophrenia. Others have found an antipsychotic/anti-inflammatory combination more efficacious than an antipsychotic alone.⁴

Add a cognitive enhancing agent. Antipsychotics as monotherapy fail to reverse schizophrenia’s severe cognitive deficits (~2 standard deviations below healthy individuals’ cognition).The National Institute of Mental Health-sponsored MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia)⁵ is testing potential neuro-protective and myelin-repair agents to improve deficits in memory, attention, and executive function in schizophrenia. Potential mechanisms include alpha 7 nicotinic receptor agonists, D1 receptor agonists, or AMPA glutamatergic receptor agonists. These agents might become available in a few years.

Add a neuroprotective agent. As a neurodegenerative disorder, schizophrenia could benefit from induction of neurotrophic factors (such as nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], or vascular endothelial growth factor [VEGF]) and neurogenesis stimulation. Atypical antipsychotics —but not typical agents—have shown neurotrophic activity,⁶ but combining them with other neurotrophic agents such as lithium or selective serotonin reuptake inhibitors⁷ might expedite brain tissue regeneration and improve patients’ function.

Add a myelin repair agent. Many schizophrenia studies suggest impaired myelin (white-matter) structure, which may explain the “disconnection” among brain regions that results in thought disorder. A recent report indicates that citalopram restored white-matter integrity in patients with obsessive-compulsive disorder after a few weeks of use.⁸ If these results are replicated in schizophrenia, antipsychotic-myelin repair agent combinations may become a rational polypharmacy.

What lies ahead. Future schizophrenia treatment almost certainly will include drug combinations that:

• address clinical domains not managed with current antipsychotic monotherapy
• help override treatment resistance or refractoriness (hallucinations or delusions).

Combinations of 3 or more drugs often are used to treat serious medical disorders such as cancer, HIV, or malignant hypertension. Management of a severe, disabling psychiatric disorder such as schizophrenia should be no less aggressive.

Polypharmacy has been a 4-letter word for a long time in schizophrenia management. Prescribing more than 1 antipsychotic to a patient with refractory symptoms has evoked images of a potentially harmful, nonevidence-based cocktail with no proven advantage over monotherapy.

Compare schizophrenia with bipolar disorder, for which combination therapy—an antipsychotic plus a mood stabilizer plus an antidepressant/ antianxiety agent—is the standard of care. Similarly, augmentation therapy is viewed as necessary for difficult cases of unipolar depression.

In the United States, approximately 40% of schizophrenia patients receive 2 or more concomitant antipsychotics (atypical and conventional agents).¹ Clearly, many clinicians resort to antipsychotic polypharmacy in a desperate attempt to manage chronic, treatment-resistant illness, even though no published data support this practice.

This situation may be changing, however, because of evolving under-standings of schizophrenia’s neurobiology. Before long, clinicians may employ concomitant agents with different mechanisms in novel approaches to improve outcomes in patients with schizophrenia.

Novel polypharmacy. The dopamine pathways approach is inadequate for achieving true remission across all of chronic schizophrenia’s symptom domains. Positive and negative symptoms and cognitive impairment that persist despite antipsychotic therapy call for new treatment approaches. Here are some of my speculations—suggested by emerging data about schizophrenia’s pathophysiology—about “futuristic” adjuncts to antipsychotics:

Add a glutamate modulator (such as lamotrigine). This combination has shown benefit in patients who have not responded to clozapine.² Many lines of evidence show that the glutamate system is impaired in schizophrenia, and this approach is promising.

Add a GABA agonist (such as valproate or benzodiazepines). Recent findings of a GABA deficit in frontal lobe chandelier cells in schizophrenia gives this combination legitimacy.³

Add an anti-inflammatory agent (such as a COX-2 inhibitor). Several studies report increased inflammatory cytokines in patients with schizophrenia. Others have found an antipsychotic/anti-inflammatory combination more efficacious than an antipsychotic alone.⁴

Add a cognitive enhancing agent. Antipsychotics as monotherapy fail to reverse schizophrenia’s severe cognitive deficits (~2 standard deviations below healthy individuals’ cognition).The National Institute of Mental Health-sponsored MATRICS initiative (Measurement and Treatment Research to Improve Cognition in Schizophrenia)⁵ is testing potential neuro-protective and myelin-repair agents to improve deficits in memory, attention, and executive function in schizophrenia. Potential mechanisms include alpha 7 nicotinic receptor agonists, D1 receptor agonists, or AMPA glutamatergic receptor agonists. These agents might become available in a few years.

Add a neuroprotective agent. As a neurodegenerative disorder, schizophrenia could benefit from induction of neurotrophic factors (such as nerve growth factor [NGF], brain-derived neurotrophic factor [BDNF], or vascular endothelial growth factor [VEGF]) and neurogenesis stimulation. Atypical antipsychotics —but not typical agents—have shown neurotrophic activity,⁶ but combining them with other neurotrophic agents such as lithium or selective serotonin reuptake inhibitors⁷ might expedite brain tissue regeneration and improve patients’ function.

Add a myelin repair agent. Many schizophrenia studies suggest impaired myelin (white-matter) structure, which may explain the “disconnection” among brain regions that results in thought disorder. A recent report indicates that citalopram restored white-matter integrity in patients with obsessive-compulsive disorder after a few weeks of use.⁸ If these results are replicated in schizophrenia, antipsychotic-myelin repair agent combinations may become a rational polypharmacy.

What lies ahead. Future schizophrenia treatment almost certainly will include drug combinations that:

• address clinical domains not managed with current antipsychotic monotherapy
• help override treatment resistance or refractoriness (hallucinations or delusions).

Combinations of 3 or more drugs often are used to treat serious medical disorders such as cancer, HIV, or malignant hypertension. Management of a severe, disabling psychiatric disorder such as schizophrenia should be no less aggressive.

HISTORY: Depressed and sick

Mr. T, age 53, was diagnosed last year with hepatitis C and for 20 years has battled recurrent major depression with euthymia between episodes. His hepatologist asks us to evaluate his recent depressed mood and erratic behavior.

Less than 2 months ago, the hepatologist prescribed ribavirin, 1,000 mg bid, and peginterferon alfa-2B, 10 million IU/1.0 mL weekly, for hepatitis C. Soon afterward, Mr. T became irritable, especially toward his wife. He now refuses to leave his house most days because of overwhelming sadness and hopelessness. Once an avid motorcycle enthusiast, Mr. T has stopped riding and complains of fatigue, “fuzzy” thinking, and diminished concentration, but he denies suicidal thoughts or intent. He weighs 232 lb but has lost 15 lb in the last 6 weeks.

Five weeks ago, the hepatologist added bupropion XL, 150 mg/d, for Mr. T’s depressive symptoms, but the patient complained that the antidepressant “amped me up” and “made my mind race.” After 3 weeks, the hepatologist switched to escitalopram, 10 mg/d, but Mr. T’s agitation continued.

Several days after starting escitalopram, Mr. T experienced what he calls a “pink cloud” period—intensely pleasurable episodes that he says began in late childhood, usually last about 4 days, and occur 6 times annually. During these episodes, his thoughts race, his speech is mildly pressured, and he sleeps 5 hours or less nightly. While euphoric, he drives his motorcycle at 100 mph, starts several projects at once, and is distractible.

Once the “pink clouds” clear, Mr. T feels fatigued and “let down” as he does now. He says he has never reported these euphoric periods because he usually enjoys them.

Mr. T also has longstanding anxiety. Most days he is “on edge” and restless, feels muscle tension in his neck, and has trouble falling and staying sleep. After changing jobs last year, he began having panic attacks triggered by excessive worry. He denies anticipatory fear or avoidance, so we rule out panic disorder.

Additionally, Mr. T has been engaging in weekly binge-eating episodes during which he consumes nearly 50 large-sized cookies and 2 to 3 2-ounce bags of potato chips in 2 hours. He is wracked with guilt after bingeing and often feels embarrassed about being overweight (body mass index, 31 kg/m²). He does not purge but moderately restricts his diet between binges. He says he started bingeing at age 20, and at one point was bingeing 3 times a week.

Mr. T also complains that ribavirin and peginterferon are causing headaches, fatigue, and myalgias. He also takes hydrochlorothiazide, 25 mg/d, for hypertension, and is allergic to sulfonamides. He denies using alcohol and drugs but smokes 2 packs of cigarettes per day.

We diagnose bipolar II disorder based on Mr. T’s extreme mood shifts, history of major depressive episodes, recent hypomania, lack of manic or mixed episodes, and significant distress. His hypomania episodes last <1 week; episodes that last ≥1 week or require hospitalization would signal bipolar I disorder.

We rule out interferon-induced depression and hypomania¹ because Mr. T showed signs of mood dysfunction long before he contracted hepatitis C. We also diagnose generalized anxiety disorder and eating disorder, not otherwise specified.

The authors’ observations

Diagnosing and managing bipolar disorder is challenging, especially when hypomania is not readily apparent.²

After we discuss treatment options with Mr. T, he chooses lamotrigine because it causes relatively few side effects and is less likely than valproic acid and other mood-stabilizing anticonvulsants to cause hepatotoxicity or pancreatitis.³ Lamotrigine also might reduce Mr. T’s anxiety.⁴

We do not try lithium because Mr. T is taking a diuretic (hydrochlorothiazide), which can cause lithium toxicity when used concomitantly. Also, lithium requires close laboratory monitoring, interacts with many medications, and can cause drowsiness, dry mouth, blurry vision, and fatigue.⁵ These
factors contraindicate lithium for Mr. T, who is taking several medications and suffers side effects from ribavirin and interferon.

Olanzapine might control Mr. T’s mood swings, but the neuroleptic can cause weight gain and metabolic syndrome⁶ and might complicate his eating disorder.

TREATMENT: A ‘rash’ reaction

We add lamotrigine, 25 mg/d, for 2 weeks and then increase to 50 mg/d.

Two days after the lamotrigine increase, Mr. T reports a rash on the left side of his trunk and left hip, buttock, and elbow (Figure). He also complains of mild chills and night sweats, although these symptoms emerged several weeks ago. He denies blistering, fevers, dysuria, nausea, or vomiting. We see no signs of lymphadenopathy, and mucosae are unaffected. Since he started lamotrigine, he says, he has not tried unfamiliar brands of shampoos, laundry detergents, or shower gels that might irritate his skin.

Figure: Did lamotrigine cause Mr. T’s rash?

Folliculocentric pustules around patient’s left elbow and throughout his left side.We have Mr. T come in that day for an emergency physical examination. At presentation, the rash appears infectious with isolated pustules throughout. We refer him to a dermatologist for same-day evaluation.

The authors’ observations

A rash is an immunologic reaction to an offending agent. If lamotrigine were causing the rash, lowering the dosage would not mitigate it.

We continued lamotrigine because the dermatologist could examine the rash within 24 hours of Mr. T’s complaint. Also, the agent was decreasing the patient’s mood, irritability, and anger. If we believed lamotrigine was causing the rash and could not obtain an immediate dermatology consult, we would have stopped the medication.

FOLLOW-UP: ‘Hot’ findings

During the patient history interview, the dermatologist discovers that Mr. T recently installed a whirlpool bath, and that the eruption occurred 3 to 5 days after the patient first used it. Physical examination shows groups of discrete folliculocentric pustules with surrounding erythema mainly on his extensor surfaces and left buttock. These findings and Mr. T’s history suggest a skin infection.

The dermatologist diagnoses hot tub folliculitis, an infection caused by exposure to contaminated whirlpools, hot tubs, or water slides. Cultures obtained that day grow Pseudomonas aeruginosa, confirming the diagnosis. The dermatologist tells Mr. T to stop using his whirlpool bath and prescribes topical gentamicin and ciprofloxacin, 500 mg bid for 10 days. We continue lamotrigine based on the dermatologist’s recommendation.

Two weeks later, Mr. T’s eruption resolves, and we increase lamotrigine to 100 mg/d, which improves his mood and achieves steady-state effectiveness.⁷ We continue escitalopram, 10 mg/d, then increase to 20 mg/d to treat his generalized anxiety. Mr. T begins experiencing anorgasmia 1 week after the escitalopram increase, so we switch to buspirone, 15 mg bid. After another 4 weeks, his anger, irritability, panic attacks, anxiety, and depression have diminished.

After 3 months, Mr. T’s hepatologist stops ribavirin and peginterferon because they are not helping his hepatitis C infection. Days later, Mr. T’s chills, sweats, and fatigue remit.

The hepatologist considers an experimental hepatitis C
medication.

We see Mr. T once monthly for supportive psychotherapy and medication management. Despite divorce proceedings and persistent mild depression he is optimistic, enjoys work, and rides his motorcycle safely twice a week.

The authors’ observations

Although Mr. T’s presentation and patient history clearly suggested an independent skin infection, distinguishing between an infection and anticonvulsant-induced rash can be difficult.

Lamotrigine and other antiepileptics (Table 1)⁸ have been associated with morbilliform eruptions, anticonvulsant hypersensitivity syndrome, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), a severe form of SJS with a 20% to 30% mortality rate.^9,10

Table 1

Estimated risk of severe rash among first-time antiepileptic users*

Although most lamotrigine-induced cutaneous eruptions are mild or self-limited, some are severe and potentially fatal. In clinical trials, approximately 10% of patients receiving lamotrigine for epilepsy developed cutaneous reactions.¹¹ Among 3,348 patients with epilepsy who received lamotrigine, 11 (0.3%) required hospitalization for SJS or TEN.¹¹

Anticonvulsant hypersensitivity syndrome, estimated to occur once per 1,000 to 10,000 exposures to anticonvulsants,¹² can lead to fever, lymphadenopathy, hepatomegaly, and arthralgias. Although hypersensitivity to aromatic anticonvulsants such as phenytoin, carbamazepine, or phenobarbital is most common, hypersensitivity to lamotrigine also has been reported.^13,14

Roughly 90% of patients with anticonvulsant hypersensitivity syndrome develop leukocytosis with eosinophilia, and some develop leukocytosis with agranulocytosis.^15-17 Fulminant hepatitis can occur, which leads to most deaths associated with this syndrome.

4 steps to gauging rash

Taking a thorough history, examining the eruption, ordering liver function tests (LFTs) and a complete blood count (CBC), and referring the patient to a dermatologist are key to determining the seriousness of an eruption and planning treatment in patients taking anticonvulsants (Table 2). See the patient within 12 hours after he reports the rash, as SJS and TEN often progress rapidly.

Table 2

4 steps to determining rash severity and cause

STEP 1: Take a thorough history

Ask the patient:

What medications are you taking? Because more than 100 medications could cause SJS or TEN, a detailed drug history is critical to determining whether a medication has induced the eruption.

When did you start taking the potentially offending medication? True lamotrigine-induced eruptions usually occur 5 days to 8 weeks after the first dose.¹⁰ SJS and TEN generally take 1 to 2 weeks to develop.

What is your current dosage? Has it increased or decreased recently? Rapid lamotrigine dosage escalations or use of lamotrigine with valproic acid can cause severe rash.^9,10,18 Valproic acid increases serum lamotrigine by inhibiting its hepatic metabolism, thereby raising side-effect risk. In clinical trials, 30% of patients who received both anticonvulsants developed a rash.¹⁰

Have any family members had rashes after taking an anticonvulsant? Compared with the general population, siblings and first-degree relatives of patients with anticonvulsant-related eruptions are at higher risk for this complication.¹⁹ Decreased epoxide hydrolase activity might negate these patients’ ability to detoxify the arene oxide metabolite, which can cause adverse effects if it accumulates.

Do you have other medical problems? Hepatitis C, for example, can theoretically increase lamotrigine’s half-life, thereby elevating side-effect risk.¹¹

Watch for anticonvulsant-related adverse events in patients with hepatic insufficiency because hepatitis might hinder anticonvulsant metabolism.²⁰ Other medical comorbidities—such as HIV infection and systemic lupus erythematosus—also could increase the risk of antiepileptic-induced rash.¹⁰

Have you had fever, chills, or other symptoms? Patients with SJS and TEN usually present with systemic symptoms such as malaise, rash, lymphadenopathy, mucosal lesions, and/or symptoms such as photophobia, difficulty swallowing, rectal erosions, or dysuria. Patients with anticonvulsant hypersensitivity syndrome typically have fever and associated arthralgias, skin pain, lymphadenopathy, or a burning sensation on their skin. These symptoms generally are absent in localized cutaneous infections.

STEP 2: Examine the eruption

Cutaneous SJS and TEN findings usually include abrupt onset of erythematous macules—which progress to targetoid lesions containing central bullae—followed by extensive epidermal necrosis. Superficial lip and mouth necrosis occur early, leading to severe stomatitis.

TEN and SJS can appear similar clinically, but TEN
covers >30% of body surface area, whereas SJS covers <10%.
Rashes that cover 10% to 30% of body surface suggest SJS-TEN overlap syndrome.

Anticonvulsant hypersensitivity syndrome usually manifests as
a morbilliform eruption on the face, arms, and/or torso. The
lesions might become edematous and progress to exfoliation or vesiculobullae. Facial edema is a hallmark of anticonvulsant hypersensitivity,^15,16 and pustules and/or erythroderma might also appear. Other warning signs include symmetrical widespread eruption and organomegaly.

STEP 3: Order laboratory tests

Check liver function and order a CBC with differential to measure eosinophils. Eosinophilia and abnormal LFT results can signal anticonvulsant hypersensitivity.

Eosinophils. A normal eosinophil count ranges between 0% and 5% of peripheral blood leukocytes in adults, at a count of 350 to 650/cm. Although upper limits of normal vary, values >500/cm suggest hypereosinophilia.²¹

LFTs. Normal aspartate aminotransferase and alanine aminotransferase levels are 0 to 42 U/L and 0 to 48 U/L, respectively. Any LFT elevation could signal anticonvulsant hypersensitivity syndrome.

STEP 4: Closely monitor the patient

Discontinue the anticonvulsant if findings suggest a cutaneous drug reaction, and contact the patient’s primary care physician or dermatologist immediately. Early consultation with a dermatologist can help determine the eruption’s cause and reveal therapeutic options.

Dr. Pejic is chief resident in the adult psychiatry residency program, Louisiana State University Health Sciences Center and Ochsner Clinic Foundation, New Orleans.

Dr. Klinger is a third-year dermatology resident, Dr. Conrad is assistant professor of clinical psychiatry, and Dr. Nesbitt is chairman, department of dermatology, Louisiana State University Health Sciences Center.

Related Resources

• High WA. Stevens-Johnson syndrome and toxic epidermal necrolysis in adults. UpToDate Online (version 15.1); June 9, 2007. www.uptodate.com.
• Martin KA, Krahn LE, Rosati MJ, Balan V. Hepatitis C: How to manage mood during interferon treatment. Current Psychiatry 2006;5(11):69-80. http://www.currentpsychiatry.com/article_pages.asp?AID=4553.

Drug Brand Names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol, Equetro, others
• Ciprofloxacin • Cipro, Proquin
• Escitalopram • Lexapro
• Hydrochlorothiazide • various
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Olanzapine • Zyprexa
• Peginterferon alfa-2B • PEG-Intron
• Phenytoin • Dilantin
• Ribavirin • Copegus, Rebetol, others
• Valproic acid • Depakote

Disclosure

Dr. Conrad receives research/grant support from AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, and Wyeth.

Drs. Pejic, Nesbitt, and Klinger report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Depressed and sick

Mr. T, age 53, was diagnosed last year with hepatitis C and for 20 years has battled recurrent major depression with euthymia between episodes. His hepatologist asks us to evaluate his recent depressed mood and erratic behavior.

Less than 2 months ago, the hepatologist prescribed ribavirin, 1,000 mg bid, and peginterferon alfa-2B, 10 million IU/1.0 mL weekly, for hepatitis C. Soon afterward, Mr. T became irritable, especially toward his wife. He now refuses to leave his house most days because of overwhelming sadness and hopelessness. Once an avid motorcycle enthusiast, Mr. T has stopped riding and complains of fatigue, “fuzzy” thinking, and diminished concentration, but he denies suicidal thoughts or intent. He weighs 232 lb but has lost 15 lb in the last 6 weeks.

Five weeks ago, the hepatologist added bupropion XL, 150 mg/d, for Mr. T’s depressive symptoms, but the patient complained that the antidepressant “amped me up” and “made my mind race.” After 3 weeks, the hepatologist switched to escitalopram, 10 mg/d, but Mr. T’s agitation continued.

Several days after starting escitalopram, Mr. T experienced what he calls a “pink cloud” period—intensely pleasurable episodes that he says began in late childhood, usually last about 4 days, and occur 6 times annually. During these episodes, his thoughts race, his speech is mildly pressured, and he sleeps 5 hours or less nightly. While euphoric, he drives his motorcycle at 100 mph, starts several projects at once, and is distractible.

Once the “pink clouds” clear, Mr. T feels fatigued and “let down” as he does now. He says he has never reported these euphoric periods because he usually enjoys them.

Mr. T also has longstanding anxiety. Most days he is “on edge” and restless, feels muscle tension in his neck, and has trouble falling and staying sleep. After changing jobs last year, he began having panic attacks triggered by excessive worry. He denies anticipatory fear or avoidance, so we rule out panic disorder.

Additionally, Mr. T has been engaging in weekly binge-eating episodes during which he consumes nearly 50 large-sized cookies and 2 to 3 2-ounce bags of potato chips in 2 hours. He is wracked with guilt after bingeing and often feels embarrassed about being overweight (body mass index, 31 kg/m²). He does not purge but moderately restricts his diet between binges. He says he started bingeing at age 20, and at one point was bingeing 3 times a week.

Mr. T also complains that ribavirin and peginterferon are causing headaches, fatigue, and myalgias. He also takes hydrochlorothiazide, 25 mg/d, for hypertension, and is allergic to sulfonamides. He denies using alcohol and drugs but smokes 2 packs of cigarettes per day.

We diagnose bipolar II disorder based on Mr. T’s extreme mood shifts, history of major depressive episodes, recent hypomania, lack of manic or mixed episodes, and significant distress. His hypomania episodes last <1 week; episodes that last ≥1 week or require hospitalization would signal bipolar I disorder.

We rule out interferon-induced depression and hypomania¹ because Mr. T showed signs of mood dysfunction long before he contracted hepatitis C. We also diagnose generalized anxiety disorder and eating disorder, not otherwise specified.

The authors’ observations

Diagnosing and managing bipolar disorder is challenging, especially when hypomania is not readily apparent.²

After we discuss treatment options with Mr. T, he chooses lamotrigine because it causes relatively few side effects and is less likely than valproic acid and other mood-stabilizing anticonvulsants to cause hepatotoxicity or pancreatitis.³ Lamotrigine also might reduce Mr. T’s anxiety.⁴

We do not try lithium because Mr. T is taking a diuretic (hydrochlorothiazide), which can cause lithium toxicity when used concomitantly. Also, lithium requires close laboratory monitoring, interacts with many medications, and can cause drowsiness, dry mouth, blurry vision, and fatigue.⁵ These
factors contraindicate lithium for Mr. T, who is taking several medications and suffers side effects from ribavirin and interferon.

Olanzapine might control Mr. T’s mood swings, but the neuroleptic can cause weight gain and metabolic syndrome⁶ and might complicate his eating disorder.

TREATMENT: A ‘rash’ reaction

We add lamotrigine, 25 mg/d, for 2 weeks and then increase to 50 mg/d.

Two days after the lamotrigine increase, Mr. T reports a rash on the left side of his trunk and left hip, buttock, and elbow (Figure). He also complains of mild chills and night sweats, although these symptoms emerged several weeks ago. He denies blistering, fevers, dysuria, nausea, or vomiting. We see no signs of lymphadenopathy, and mucosae are unaffected. Since he started lamotrigine, he says, he has not tried unfamiliar brands of shampoos, laundry detergents, or shower gels that might irritate his skin.

Figure: Did lamotrigine cause Mr. T’s rash?

Folliculocentric pustules around patient’s left elbow and throughout his left side.We have Mr. T come in that day for an emergency physical examination. At presentation, the rash appears infectious with isolated pustules throughout. We refer him to a dermatologist for same-day evaluation.

The authors’ observations

A rash is an immunologic reaction to an offending agent. If lamotrigine were causing the rash, lowering the dosage would not mitigate it.

We continued lamotrigine because the dermatologist could examine the rash within 24 hours of Mr. T’s complaint. Also, the agent was decreasing the patient’s mood, irritability, and anger. If we believed lamotrigine was causing the rash and could not obtain an immediate dermatology consult, we would have stopped the medication.

FOLLOW-UP: ‘Hot’ findings

During the patient history interview, the dermatologist discovers that Mr. T recently installed a whirlpool bath, and that the eruption occurred 3 to 5 days after the patient first used it. Physical examination shows groups of discrete folliculocentric pustules with surrounding erythema mainly on his extensor surfaces and left buttock. These findings and Mr. T’s history suggest a skin infection.

The dermatologist diagnoses hot tub folliculitis, an infection caused by exposure to contaminated whirlpools, hot tubs, or water slides. Cultures obtained that day grow Pseudomonas aeruginosa, confirming the diagnosis. The dermatologist tells Mr. T to stop using his whirlpool bath and prescribes topical gentamicin and ciprofloxacin, 500 mg bid for 10 days. We continue lamotrigine based on the dermatologist’s recommendation.

Two weeks later, Mr. T’s eruption resolves, and we increase lamotrigine to 100 mg/d, which improves his mood and achieves steady-state effectiveness.⁷ We continue escitalopram, 10 mg/d, then increase to 20 mg/d to treat his generalized anxiety. Mr. T begins experiencing anorgasmia 1 week after the escitalopram increase, so we switch to buspirone, 15 mg bid. After another 4 weeks, his anger, irritability, panic attacks, anxiety, and depression have diminished.

After 3 months, Mr. T’s hepatologist stops ribavirin and peginterferon because they are not helping his hepatitis C infection. Days later, Mr. T’s chills, sweats, and fatigue remit.

The hepatologist considers an experimental hepatitis C
medication.

We see Mr. T once monthly for supportive psychotherapy and medication management. Despite divorce proceedings and persistent mild depression he is optimistic, enjoys work, and rides his motorcycle safely twice a week.

The authors’ observations

Although Mr. T’s presentation and patient history clearly suggested an independent skin infection, distinguishing between an infection and anticonvulsant-induced rash can be difficult.

Lamotrigine and other antiepileptics (Table 1)⁸ have been associated with morbilliform eruptions, anticonvulsant hypersensitivity syndrome, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), a severe form of SJS with a 20% to 30% mortality rate.^9,10

Table 1

Estimated risk of severe rash among first-time antiepileptic users*

Although most lamotrigine-induced cutaneous eruptions are mild or self-limited, some are severe and potentially fatal. In clinical trials, approximately 10% of patients receiving lamotrigine for epilepsy developed cutaneous reactions.¹¹ Among 3,348 patients with epilepsy who received lamotrigine, 11 (0.3%) required hospitalization for SJS or TEN.¹¹

Anticonvulsant hypersensitivity syndrome, estimated to occur once per 1,000 to 10,000 exposures to anticonvulsants,¹² can lead to fever, lymphadenopathy, hepatomegaly, and arthralgias. Although hypersensitivity to aromatic anticonvulsants such as phenytoin, carbamazepine, or phenobarbital is most common, hypersensitivity to lamotrigine also has been reported.^13,14

Roughly 90% of patients with anticonvulsant hypersensitivity syndrome develop leukocytosis with eosinophilia, and some develop leukocytosis with agranulocytosis.^15-17 Fulminant hepatitis can occur, which leads to most deaths associated with this syndrome.

4 steps to gauging rash

Taking a thorough history, examining the eruption, ordering liver function tests (LFTs) and a complete blood count (CBC), and referring the patient to a dermatologist are key to determining the seriousness of an eruption and planning treatment in patients taking anticonvulsants (Table 2). See the patient within 12 hours after he reports the rash, as SJS and TEN often progress rapidly.

Table 2

4 steps to determining rash severity and cause

STEP 1: Take a thorough history

Ask the patient:

What medications are you taking? Because more than 100 medications could cause SJS or TEN, a detailed drug history is critical to determining whether a medication has induced the eruption.

When did you start taking the potentially offending medication? True lamotrigine-induced eruptions usually occur 5 days to 8 weeks after the first dose.¹⁰ SJS and TEN generally take 1 to 2 weeks to develop.

What is your current dosage? Has it increased or decreased recently? Rapid lamotrigine dosage escalations or use of lamotrigine with valproic acid can cause severe rash.^9,10,18 Valproic acid increases serum lamotrigine by inhibiting its hepatic metabolism, thereby raising side-effect risk. In clinical trials, 30% of patients who received both anticonvulsants developed a rash.¹⁰

Have any family members had rashes after taking an anticonvulsant? Compared with the general population, siblings and first-degree relatives of patients with anticonvulsant-related eruptions are at higher risk for this complication.¹⁹ Decreased epoxide hydrolase activity might negate these patients’ ability to detoxify the arene oxide metabolite, which can cause adverse effects if it accumulates.

Do you have other medical problems? Hepatitis C, for example, can theoretically increase lamotrigine’s half-life, thereby elevating side-effect risk.¹¹

Watch for anticonvulsant-related adverse events in patients with hepatic insufficiency because hepatitis might hinder anticonvulsant metabolism.²⁰ Other medical comorbidities—such as HIV infection and systemic lupus erythematosus—also could increase the risk of antiepileptic-induced rash.¹⁰

Have you had fever, chills, or other symptoms? Patients with SJS and TEN usually present with systemic symptoms such as malaise, rash, lymphadenopathy, mucosal lesions, and/or symptoms such as photophobia, difficulty swallowing, rectal erosions, or dysuria. Patients with anticonvulsant hypersensitivity syndrome typically have fever and associated arthralgias, skin pain, lymphadenopathy, or a burning sensation on their skin. These symptoms generally are absent in localized cutaneous infections.

STEP 2: Examine the eruption

Cutaneous SJS and TEN findings usually include abrupt onset of erythematous macules—which progress to targetoid lesions containing central bullae—followed by extensive epidermal necrosis. Superficial lip and mouth necrosis occur early, leading to severe stomatitis.

TEN and SJS can appear similar clinically, but TEN
covers >30% of body surface area, whereas SJS covers <10%.
Rashes that cover 10% to 30% of body surface suggest SJS-TEN overlap syndrome.

Anticonvulsant hypersensitivity syndrome usually manifests as
a morbilliform eruption on the face, arms, and/or torso. The
lesions might become edematous and progress to exfoliation or vesiculobullae. Facial edema is a hallmark of anticonvulsant hypersensitivity,^15,16 and pustules and/or erythroderma might also appear. Other warning signs include symmetrical widespread eruption and organomegaly.

STEP 3: Order laboratory tests

Check liver function and order a CBC with differential to measure eosinophils. Eosinophilia and abnormal LFT results can signal anticonvulsant hypersensitivity.

Eosinophils. A normal eosinophil count ranges between 0% and 5% of peripheral blood leukocytes in adults, at a count of 350 to 650/cm. Although upper limits of normal vary, values >500/cm suggest hypereosinophilia.²¹

LFTs. Normal aspartate aminotransferase and alanine aminotransferase levels are 0 to 42 U/L and 0 to 48 U/L, respectively. Any LFT elevation could signal anticonvulsant hypersensitivity syndrome.

STEP 4: Closely monitor the patient

Discontinue the anticonvulsant if findings suggest a cutaneous drug reaction, and contact the patient’s primary care physician or dermatologist immediately. Early consultation with a dermatologist can help determine the eruption’s cause and reveal therapeutic options.

Dr. Pejic is chief resident in the adult psychiatry residency program, Louisiana State University Health Sciences Center and Ochsner Clinic Foundation, New Orleans.

Dr. Klinger is a third-year dermatology resident, Dr. Conrad is assistant professor of clinical psychiatry, and Dr. Nesbitt is chairman, department of dermatology, Louisiana State University Health Sciences Center.

Related Resources

• High WA. Stevens-Johnson syndrome and toxic epidermal necrolysis in adults. UpToDate Online (version 15.1); June 9, 2007. www.uptodate.com.
• Martin KA, Krahn LE, Rosati MJ, Balan V. Hepatitis C: How to manage mood during interferon treatment. Current Psychiatry 2006;5(11):69-80. http://www.currentpsychiatry.com/article_pages.asp?AID=4553.

Drug Brand Names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol, Equetro, others
• Ciprofloxacin • Cipro, Proquin
• Escitalopram • Lexapro
• Hydrochlorothiazide • various
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Olanzapine • Zyprexa
• Peginterferon alfa-2B • PEG-Intron
• Phenytoin • Dilantin
• Ribavirin • Copegus, Rebetol, others
• Valproic acid • Depakote

Disclosure

Dr. Conrad receives research/grant support from AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, and Wyeth.

Drs. Pejic, Nesbitt, and Klinger report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

HISTORY: Depressed and sick

Mr. T, age 53, was diagnosed last year with hepatitis C and for 20 years has battled recurrent major depression with euthymia between episodes. His hepatologist asks us to evaluate his recent depressed mood and erratic behavior.

Less than 2 months ago, the hepatologist prescribed ribavirin, 1,000 mg bid, and peginterferon alfa-2B, 10 million IU/1.0 mL weekly, for hepatitis C. Soon afterward, Mr. T became irritable, especially toward his wife. He now refuses to leave his house most days because of overwhelming sadness and hopelessness. Once an avid motorcycle enthusiast, Mr. T has stopped riding and complains of fatigue, “fuzzy” thinking, and diminished concentration, but he denies suicidal thoughts or intent. He weighs 232 lb but has lost 15 lb in the last 6 weeks.

Five weeks ago, the hepatologist added bupropion XL, 150 mg/d, for Mr. T’s depressive symptoms, but the patient complained that the antidepressant “amped me up” and “made my mind race.” After 3 weeks, the hepatologist switched to escitalopram, 10 mg/d, but Mr. T’s agitation continued.

Several days after starting escitalopram, Mr. T experienced what he calls a “pink cloud” period—intensely pleasurable episodes that he says began in late childhood, usually last about 4 days, and occur 6 times annually. During these episodes, his thoughts race, his speech is mildly pressured, and he sleeps 5 hours or less nightly. While euphoric, he drives his motorcycle at 100 mph, starts several projects at once, and is distractible.

Once the “pink clouds” clear, Mr. T feels fatigued and “let down” as he does now. He says he has never reported these euphoric periods because he usually enjoys them.

Mr. T also has longstanding anxiety. Most days he is “on edge” and restless, feels muscle tension in his neck, and has trouble falling and staying sleep. After changing jobs last year, he began having panic attacks triggered by excessive worry. He denies anticipatory fear or avoidance, so we rule out panic disorder.

Additionally, Mr. T has been engaging in weekly binge-eating episodes during which he consumes nearly 50 large-sized cookies and 2 to 3 2-ounce bags of potato chips in 2 hours. He is wracked with guilt after bingeing and often feels embarrassed about being overweight (body mass index, 31 kg/m²). He does not purge but moderately restricts his diet between binges. He says he started bingeing at age 20, and at one point was bingeing 3 times a week.

Mr. T also complains that ribavirin and peginterferon are causing headaches, fatigue, and myalgias. He also takes hydrochlorothiazide, 25 mg/d, for hypertension, and is allergic to sulfonamides. He denies using alcohol and drugs but smokes 2 packs of cigarettes per day.

We diagnose bipolar II disorder based on Mr. T’s extreme mood shifts, history of major depressive episodes, recent hypomania, lack of manic or mixed episodes, and significant distress. His hypomania episodes last <1 week; episodes that last ≥1 week or require hospitalization would signal bipolar I disorder.

We rule out interferon-induced depression and hypomania¹ because Mr. T showed signs of mood dysfunction long before he contracted hepatitis C. We also diagnose generalized anxiety disorder and eating disorder, not otherwise specified.

The authors’ observations

Diagnosing and managing bipolar disorder is challenging, especially when hypomania is not readily apparent.²

After we discuss treatment options with Mr. T, he chooses lamotrigine because it causes relatively few side effects and is less likely than valproic acid and other mood-stabilizing anticonvulsants to cause hepatotoxicity or pancreatitis.³ Lamotrigine also might reduce Mr. T’s anxiety.⁴

We do not try lithium because Mr. T is taking a diuretic (hydrochlorothiazide), which can cause lithium toxicity when used concomitantly. Also, lithium requires close laboratory monitoring, interacts with many medications, and can cause drowsiness, dry mouth, blurry vision, and fatigue.⁵ These
factors contraindicate lithium for Mr. T, who is taking several medications and suffers side effects from ribavirin and interferon.

Olanzapine might control Mr. T’s mood swings, but the neuroleptic can cause weight gain and metabolic syndrome⁶ and might complicate his eating disorder.

TREATMENT: A ‘rash’ reaction

We add lamotrigine, 25 mg/d, for 2 weeks and then increase to 50 mg/d.

Two days after the lamotrigine increase, Mr. T reports a rash on the left side of his trunk and left hip, buttock, and elbow (Figure). He also complains of mild chills and night sweats, although these symptoms emerged several weeks ago. He denies blistering, fevers, dysuria, nausea, or vomiting. We see no signs of lymphadenopathy, and mucosae are unaffected. Since he started lamotrigine, he says, he has not tried unfamiliar brands of shampoos, laundry detergents, or shower gels that might irritate his skin.

Figure: Did lamotrigine cause Mr. T’s rash?

Folliculocentric pustules around patient’s left elbow and throughout his left side.We have Mr. T come in that day for an emergency physical examination. At presentation, the rash appears infectious with isolated pustules throughout. We refer him to a dermatologist for same-day evaluation.

The authors’ observations

A rash is an immunologic reaction to an offending agent. If lamotrigine were causing the rash, lowering the dosage would not mitigate it.

We continued lamotrigine because the dermatologist could examine the rash within 24 hours of Mr. T’s complaint. Also, the agent was decreasing the patient’s mood, irritability, and anger. If we believed lamotrigine was causing the rash and could not obtain an immediate dermatology consult, we would have stopped the medication.

FOLLOW-UP: ‘Hot’ findings

During the patient history interview, the dermatologist discovers that Mr. T recently installed a whirlpool bath, and that the eruption occurred 3 to 5 days after the patient first used it. Physical examination shows groups of discrete folliculocentric pustules with surrounding erythema mainly on his extensor surfaces and left buttock. These findings and Mr. T’s history suggest a skin infection.

The dermatologist diagnoses hot tub folliculitis, an infection caused by exposure to contaminated whirlpools, hot tubs, or water slides. Cultures obtained that day grow Pseudomonas aeruginosa, confirming the diagnosis. The dermatologist tells Mr. T to stop using his whirlpool bath and prescribes topical gentamicin and ciprofloxacin, 500 mg bid for 10 days. We continue lamotrigine based on the dermatologist’s recommendation.

Two weeks later, Mr. T’s eruption resolves, and we increase lamotrigine to 100 mg/d, which improves his mood and achieves steady-state effectiveness.⁷ We continue escitalopram, 10 mg/d, then increase to 20 mg/d to treat his generalized anxiety. Mr. T begins experiencing anorgasmia 1 week after the escitalopram increase, so we switch to buspirone, 15 mg bid. After another 4 weeks, his anger, irritability, panic attacks, anxiety, and depression have diminished.

After 3 months, Mr. T’s hepatologist stops ribavirin and peginterferon because they are not helping his hepatitis C infection. Days later, Mr. T’s chills, sweats, and fatigue remit.

The hepatologist considers an experimental hepatitis C
medication.

We see Mr. T once monthly for supportive psychotherapy and medication management. Despite divorce proceedings and persistent mild depression he is optimistic, enjoys work, and rides his motorcycle safely twice a week.

The authors’ observations

Although Mr. T’s presentation and patient history clearly suggested an independent skin infection, distinguishing between an infection and anticonvulsant-induced rash can be difficult.

Lamotrigine and other antiepileptics (Table 1)⁸ have been associated with morbilliform eruptions, anticonvulsant hypersensitivity syndrome, erythema multiforme, Stevens-Johnson syndrome (SJS), and toxic epidermal necrolysis (TEN), a severe form of SJS with a 20% to 30% mortality rate.^9,10

Table 1

Estimated risk of severe rash among first-time antiepileptic users*

Although most lamotrigine-induced cutaneous eruptions are mild or self-limited, some are severe and potentially fatal. In clinical trials, approximately 10% of patients receiving lamotrigine for epilepsy developed cutaneous reactions.¹¹ Among 3,348 patients with epilepsy who received lamotrigine, 11 (0.3%) required hospitalization for SJS or TEN.¹¹

Anticonvulsant hypersensitivity syndrome, estimated to occur once per 1,000 to 10,000 exposures to anticonvulsants,¹² can lead to fever, lymphadenopathy, hepatomegaly, and arthralgias. Although hypersensitivity to aromatic anticonvulsants such as phenytoin, carbamazepine, or phenobarbital is most common, hypersensitivity to lamotrigine also has been reported.^13,14

Roughly 90% of patients with anticonvulsant hypersensitivity syndrome develop leukocytosis with eosinophilia, and some develop leukocytosis with agranulocytosis.^15-17 Fulminant hepatitis can occur, which leads to most deaths associated with this syndrome.

4 steps to gauging rash

Taking a thorough history, examining the eruption, ordering liver function tests (LFTs) and a complete blood count (CBC), and referring the patient to a dermatologist are key to determining the seriousness of an eruption and planning treatment in patients taking anticonvulsants (Table 2). See the patient within 12 hours after he reports the rash, as SJS and TEN often progress rapidly.

Table 2

4 steps to determining rash severity and cause

STEP 1: Take a thorough history

Ask the patient:

What medications are you taking? Because more than 100 medications could cause SJS or TEN, a detailed drug history is critical to determining whether a medication has induced the eruption.

When did you start taking the potentially offending medication? True lamotrigine-induced eruptions usually occur 5 days to 8 weeks after the first dose.¹⁰ SJS and TEN generally take 1 to 2 weeks to develop.

What is your current dosage? Has it increased or decreased recently? Rapid lamotrigine dosage escalations or use of lamotrigine with valproic acid can cause severe rash.^9,10,18 Valproic acid increases serum lamotrigine by inhibiting its hepatic metabolism, thereby raising side-effect risk. In clinical trials, 30% of patients who received both anticonvulsants developed a rash.¹⁰

Have any family members had rashes after taking an anticonvulsant? Compared with the general population, siblings and first-degree relatives of patients with anticonvulsant-related eruptions are at higher risk for this complication.¹⁹ Decreased epoxide hydrolase activity might negate these patients’ ability to detoxify the arene oxide metabolite, which can cause adverse effects if it accumulates.

Do you have other medical problems? Hepatitis C, for example, can theoretically increase lamotrigine’s half-life, thereby elevating side-effect risk.¹¹

Watch for anticonvulsant-related adverse events in patients with hepatic insufficiency because hepatitis might hinder anticonvulsant metabolism.²⁰ Other medical comorbidities—such as HIV infection and systemic lupus erythematosus—also could increase the risk of antiepileptic-induced rash.¹⁰

Have you had fever, chills, or other symptoms? Patients with SJS and TEN usually present with systemic symptoms such as malaise, rash, lymphadenopathy, mucosal lesions, and/or symptoms such as photophobia, difficulty swallowing, rectal erosions, or dysuria. Patients with anticonvulsant hypersensitivity syndrome typically have fever and associated arthralgias, skin pain, lymphadenopathy, or a burning sensation on their skin. These symptoms generally are absent in localized cutaneous infections.

STEP 2: Examine the eruption

Cutaneous SJS and TEN findings usually include abrupt onset of erythematous macules—which progress to targetoid lesions containing central bullae—followed by extensive epidermal necrosis. Superficial lip and mouth necrosis occur early, leading to severe stomatitis.

TEN and SJS can appear similar clinically, but TEN
covers >30% of body surface area, whereas SJS covers <10%.
Rashes that cover 10% to 30% of body surface suggest SJS-TEN overlap syndrome.

Anticonvulsant hypersensitivity syndrome usually manifests as
a morbilliform eruption on the face, arms, and/or torso. The
lesions might become edematous and progress to exfoliation or vesiculobullae. Facial edema is a hallmark of anticonvulsant hypersensitivity,^15,16 and pustules and/or erythroderma might also appear. Other warning signs include symmetrical widespread eruption and organomegaly.

STEP 3: Order laboratory tests

Check liver function and order a CBC with differential to measure eosinophils. Eosinophilia and abnormal LFT results can signal anticonvulsant hypersensitivity.

Eosinophils. A normal eosinophil count ranges between 0% and 5% of peripheral blood leukocytes in adults, at a count of 350 to 650/cm. Although upper limits of normal vary, values >500/cm suggest hypereosinophilia.²¹

LFTs. Normal aspartate aminotransferase and alanine aminotransferase levels are 0 to 42 U/L and 0 to 48 U/L, respectively. Any LFT elevation could signal anticonvulsant hypersensitivity syndrome.

STEP 4: Closely monitor the patient

Discontinue the anticonvulsant if findings suggest a cutaneous drug reaction, and contact the patient’s primary care physician or dermatologist immediately. Early consultation with a dermatologist can help determine the eruption’s cause and reveal therapeutic options.

Dr. Pejic is chief resident in the adult psychiatry residency program, Louisiana State University Health Sciences Center and Ochsner Clinic Foundation, New Orleans.

Dr. Klinger is a third-year dermatology resident, Dr. Conrad is assistant professor of clinical psychiatry, and Dr. Nesbitt is chairman, department of dermatology, Louisiana State University Health Sciences Center.

Related Resources

• High WA. Stevens-Johnson syndrome and toxic epidermal necrolysis in adults. UpToDate Online (version 15.1); June 9, 2007. www.uptodate.com.
• Martin KA, Krahn LE, Rosati MJ, Balan V. Hepatitis C: How to manage mood during interferon treatment. Current Psychiatry 2006;5(11):69-80. http://www.currentpsychiatry.com/article_pages.asp?AID=4553.

Drug Brand Names

• Bupropion • Wellbutrin
• Buspirone • BuSpar
• Carbamazepine • Tegretol, Equetro, others
• Ciprofloxacin • Cipro, Proquin
• Escitalopram • Lexapro
• Hydrochlorothiazide • various
• Lamotrigine • Lamictal
• Lithium • Eskalith, others
• Olanzapine • Zyprexa
• Peginterferon alfa-2B • PEG-Intron
• Phenytoin • Dilantin
• Ribavirin • Copegus, Rebetol, others
• Valproic acid • Depakote

Disclosure

Dr. Conrad receives research/grant support from AstraZeneca, Bristol-Myers Squibb, Forest Pharmaceuticals, GlaxoSmithKline, and Wyeth.

Drs. Pejic, Nesbitt, and Klinger report no financial relationship with any company whose products are mentioned in this article or with manufacturers of competing products.

Ms. B, a middle-aged mother of 3, is being monitored for bipolar disorder. She has a history of stimulant abuse but has been in remission for 5 years. She complains of excessive daytime sleepiness. Most days she wakes at 7 AM, but sleeps on several occasions during the day. She also complains of fatigue and lack of motivation.

She is being treated with lithium, venlafaxine, and zolpidem and reports good adherence. Basic laboratory work and serum lithium levels are within acceptable ranges. Her symptoms do not improve when venlafaxine is titrated from 225 mg/d to 300 mg/d. She also reports previously failed trials with bupropion and fluoxetine.

We decide to try a psychostimulant as an augmenting agent. Because of her past stimulant abuse, we add modafinil, 100 mg/d and increase to 200 mg/d. Ms. B reports improvement in her daytime sleepiness and fatigue and—except for a mild headache—tolerates the medication well.

Modafinil is being investigated for potential roles in managing inattention, excess sleepiness, fatigue, and cognitive dysfunction associated with:

• mood disorders (major depression and bipolar depression)
  
• attention-deficit/hyperactivity disorder (ADHD)
  
• schizophrenia
  
• cocaine dependence.
  

This article discusses how the drug promotes wakefulness, how it might improve cognitive function, and what the evidence reveals about off-label indications.

How it works

Although modafinil’s precise mechanism of action is unknown, it is believed to promote wakefulness more selectively than conventional stimulants such as amphetamine and methylphenidate. Modafinil does not bind to norepinephrine, serotonin, dopamine, or benzodiazepine receptors.^1,2 It might target specific hypothalamic regions such as the tuberomammillary nucleus and orexin neurons, which are peptide neurotransmitters that promote wakefulness.^3,4

Clinical trials found that modafinil has beneficial effects on:

• working memory, recognition memory, and sustained attention in healthy humans
  
• prefrontal-dependent cognitive functions in schizophrenia, major depression, and adult ADHD.⁵
  

Evidence for approved indications

Modafinil is indicated to improve wakefulness in patients who have excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work sleep disorder. It was approved for reducing excessive sleepiness in narcoleptic patients after two 9-week placebo-controlled clinical trials. The drug significantly reduced sleepiness and improved overall disease status as measured by the Clinical Global Impression of Change (CGI-C) scale.^6,7

In patients with shift work sleep disorder, a 12-week placebo-controlled clinical trial found that modafinil significantly improved sleep latency and CGI-C scores.¹⁰

Dosage and side effects. For patients with narcolepsy or obstructive sleep apnea, the recommended dose is 200 mg given in the morning.¹¹ For patients prescribed modafinil for work-time wakefulness, the dose is 200 mg 1 hour before their work shift. Lower doses are recommended for patients who are elderly or have hepatic impairment. Those with severe hepatic impairment typically are prescribed 100 mg/d.¹¹ Modafinil is rapidly absorbed and is metabolized primarily by the liver (Table 1). A summary of potential drug-drug interactions appears in Table 2.¹¹

In pivotal trials, adverse events that occurred more frequently with modafinil than with placebo and in >5% of the study population included headache, nausea, nervousness, rhinitis, diarrhea, back pain, insomnia, dizziness, and dyspepsia. Headache was most commonly reported; in most patients, it resolved soon after they started taking modafinil. Post-marketing reports have included cases of psychosis, mania, and suspected serious skin reactions, including Stevens-Johnson syndrome.¹¹ Modafinil lacks euphorigenic properties and has minimal potential for abuse.¹²

Table 1

Modafinil’s pharmacokinetics

Selected drug-drug interactions with modafinil

Evidence for off-label uses

Major depressive disorder (MDD). The fatigue and excessive sleepiness often seen with MDD often persist after other depressive symptoms have remitted with antidepressant treatment.¹³ Patients with these symptoms might benefit from modafinil’s stimulating properties. Conventional stimulants such as methylphenidate have been used to improve neurovegetative symptoms of depression, but modafinil offers several advantages:

• decreased adverse CNS effects
  
• fewer drug-drug interactions
  
• minimal risk for dependence or abuse.
  

A 6-week open-label study of 25 depressed patients with residual fatigue and sleepiness showed that adjunctive modafinil, 100 to 200 mg/d, significantly improved these symptoms, as well as Hamilton Rating Scale for Depression (HAM-D) score, as early as week 2. Seventy-six percent of patients responded to treatment, defined as a >50% reduction in HAM-D scores.¹⁶

Several open-label studies and case re-ports have evaluated adjunctive modafinil use in patients with:

• depression characterized by ongoing lethargy or apathy¹⁷
  
• depression with atypical features¹⁸
  
• seasonal affective disorder¹⁹
  
• partial response to antidepressants.^20,21
  

Bipolar depression. A 6-week, double-blind, placebo-controlled trial randomly assigned 85 patients with bipolar depression to adjunctive modafinil, 100 to 200 mg/d, or placebo for 6 weeks (Table 3).²² The number of patients receiving an antidepressant or mood stabilizer was not significantly different between the modafinil and placebo groups.

The primary outcome measure was change in the Inventory for Depressive Symptoms (IDS) score from baseline to endpoint. Forty-four percent of patients receiving modafinil achieved a ≥50% reduction in IDS score, compared with 23% of the placebo group; this difference was statistically significant (P=0.03).

In this study, modafinil was well tolerated and did not induce mania or hypomania. Cases of modafinil-induced mania have been reported elsewhere.^23,24

The mechanisms of modafinil’s antidepressant effects are unclear. The drug does not cause release of norepinephrine or dopamine. One study proposed that modafinil acts by releasing histamine and activating noradrenaline receptors.²⁵ Activation of these receptors increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons, increasing histamine levels. Another trial suggested that modafinil may improve mood by mechanisms similar to the antidepressant effects induced by sleep deprivation.²⁶

Summary. Modafinil may have a role in managing residual fatigue and excessive sleepiness associated with MDD and bipolar depression. Evidence for a mood-elevating effect is minimal; additional studies are needed. Adjunctive modafinil and conventional stimulants have not been compared head-to-head in patients with mood disorders. Modafinil’s tolerability profile and lack of euphorigenic and reinforcing properties make it a potentially attractive alternative, however.

ADHD. Approximately 30% of ADHD patients do not respond to or are unable to tolerate conventional stimulant medications such as methylphenidate and dextroamphetamine.²⁷ Several studies have evaluated modafinil as a potential treatment for ADHD based on the drug’s action on arousal and attention systems. Although modafinil’s precise mechanism of action in ADHD is unknown, proposed mechanisms include:

• hypothalamic and cerebral cortex neuronal activation
  
• action on histamine that results in internal vigilance.²⁸
  

Can modafinil help patients with mood disorders?

CASE 2: Another Tx for ADHD

Matt, age 8, is referred to our outpatient child psychiatric clinic after his parents noted declining school performance associated with increased aggression and irritability. Our assessment strongly supports a diagnosis of ADHD without comorbid conditions. We start Matt on methylphenidate, 5 mg twice daily, which quickly improves his ADHD symptoms. However, the medication causes GI side effects and profound sleep and weight changes.

In children and adolescents. Wigal et al²⁹ reviewed pooled data from 3 randomized, double-blind, placebo-controlled studies of modafinil in pediatric ADHD (Table 4). Modafinil was well tolerated and improved ADHD symptoms and behaviors regardless of patients’ stimulant use history.

In a recent open-label study, 220 children and young adolescents with ADHD who had completed 4 weeks of a double-blind, placebo-controlled trial were evaluated for an additional 8 weeks. Modafinil improved ADHD symptoms and overall clinical condition as determined by the parent- or clinician-completed ADHD Rating Scale-IV Home Version, the parent-completed Conners’ ADHD/DSM-IV Scale Parent Version, and the clinician-rated CGI scale.³⁰ Insomnia, headache, and decreased appetite were the most commonly reported adverse events.

In adults. The results of 2 double-blind, placebo-controlled trials of modafinil in adults with ADHD have been positive:

• In 1 study, modafinil (mean 206.8 mg/d) was more effective than placebo and comparable to dextroamphetamine in improving ADHD symptoms.³¹
  
• In another, modafinil (a single 200-mg dose) increased cognitive performance during treatment.³²
  

Schizophrenia. Double-blind, randomized placebo-controlled studies have evaluated modafinil for improving cognitive function and reducing negative symptoms in patients with schizophrenia. Results have been inconsistent.

One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).³³ Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.^34,35

Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania¹¹ may limit the drug’s usefulness in schizophrenia patients.

Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.³⁶ This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.³⁷

Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.

Table 4

Modafinil and ADHD: What the evidence says

Modafinil for schizophrenia or cocaine dependence:
More research is needed

• Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
  

• Atomoxetine • Strattera
  
• Bupropion • Wellbutrin
  
• Carbamazepine • Carbatrol, Tegretol, others
  
• Citalopram • Celexa
  
• Dextroamphetamine • Dexedrine, DextroStat
  
• Diazepam • Valium
  
• Erythromycin • Ery-Tab, Eryc, others
  
• Fluoxetine • Prozac
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin, others
  
• Modafinil • Provigil
  
• Phenytoin • Dilantin
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Zolpidem • Ambien
  

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

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

Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.

Ms. B, a middle-aged mother of 3, is being monitored for bipolar disorder. She has a history of stimulant abuse but has been in remission for 5 years. She complains of excessive daytime sleepiness. Most days she wakes at 7 AM, but sleeps on several occasions during the day. She also complains of fatigue and lack of motivation.

She is being treated with lithium, venlafaxine, and zolpidem and reports good adherence. Basic laboratory work and serum lithium levels are within acceptable ranges. Her symptoms do not improve when venlafaxine is titrated from 225 mg/d to 300 mg/d. She also reports previously failed trials with bupropion and fluoxetine.

We decide to try a psychostimulant as an augmenting agent. Because of her past stimulant abuse, we add modafinil, 100 mg/d and increase to 200 mg/d. Ms. B reports improvement in her daytime sleepiness and fatigue and—except for a mild headache—tolerates the medication well.

Modafinil is being investigated for potential roles in managing inattention, excess sleepiness, fatigue, and cognitive dysfunction associated with:

• mood disorders (major depression and bipolar depression)
  
• attention-deficit/hyperactivity disorder (ADHD)
  
• schizophrenia
  
• cocaine dependence.
  

This article discusses how the drug promotes wakefulness, how it might improve cognitive function, and what the evidence reveals about off-label indications.

How it works

Although modafinil’s precise mechanism of action is unknown, it is believed to promote wakefulness more selectively than conventional stimulants such as amphetamine and methylphenidate. Modafinil does not bind to norepinephrine, serotonin, dopamine, or benzodiazepine receptors.^1,2 It might target specific hypothalamic regions such as the tuberomammillary nucleus and orexin neurons, which are peptide neurotransmitters that promote wakefulness.^3,4

Clinical trials found that modafinil has beneficial effects on:

• working memory, recognition memory, and sustained attention in healthy humans
  
• prefrontal-dependent cognitive functions in schizophrenia, major depression, and adult ADHD.⁵
  

Evidence for approved indications

Modafinil is indicated to improve wakefulness in patients who have excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work sleep disorder. It was approved for reducing excessive sleepiness in narcoleptic patients after two 9-week placebo-controlled clinical trials. The drug significantly reduced sleepiness and improved overall disease status as measured by the Clinical Global Impression of Change (CGI-C) scale.^6,7

In patients with shift work sleep disorder, a 12-week placebo-controlled clinical trial found that modafinil significantly improved sleep latency and CGI-C scores.¹⁰

Dosage and side effects. For patients with narcolepsy or obstructive sleep apnea, the recommended dose is 200 mg given in the morning.¹¹ For patients prescribed modafinil for work-time wakefulness, the dose is 200 mg 1 hour before their work shift. Lower doses are recommended for patients who are elderly or have hepatic impairment. Those with severe hepatic impairment typically are prescribed 100 mg/d.¹¹ Modafinil is rapidly absorbed and is metabolized primarily by the liver (Table 1). A summary of potential drug-drug interactions appears in Table 2.¹¹

In pivotal trials, adverse events that occurred more frequently with modafinil than with placebo and in >5% of the study population included headache, nausea, nervousness, rhinitis, diarrhea, back pain, insomnia, dizziness, and dyspepsia. Headache was most commonly reported; in most patients, it resolved soon after they started taking modafinil. Post-marketing reports have included cases of psychosis, mania, and suspected serious skin reactions, including Stevens-Johnson syndrome.¹¹ Modafinil lacks euphorigenic properties and has minimal potential for abuse.¹²

Table 1

Modafinil’s pharmacokinetics

Selected drug-drug interactions with modafinil

Evidence for off-label uses

Major depressive disorder (MDD). The fatigue and excessive sleepiness often seen with MDD often persist after other depressive symptoms have remitted with antidepressant treatment.¹³ Patients with these symptoms might benefit from modafinil’s stimulating properties. Conventional stimulants such as methylphenidate have been used to improve neurovegetative symptoms of depression, but modafinil offers several advantages:

• decreased adverse CNS effects
  
• fewer drug-drug interactions
  
• minimal risk for dependence or abuse.
  

A 6-week open-label study of 25 depressed patients with residual fatigue and sleepiness showed that adjunctive modafinil, 100 to 200 mg/d, significantly improved these symptoms, as well as Hamilton Rating Scale for Depression (HAM-D) score, as early as week 2. Seventy-six percent of patients responded to treatment, defined as a >50% reduction in HAM-D scores.¹⁶

Several open-label studies and case re-ports have evaluated adjunctive modafinil use in patients with:

• depression characterized by ongoing lethargy or apathy¹⁷
  
• depression with atypical features¹⁸
  
• seasonal affective disorder¹⁹
  
• partial response to antidepressants.^20,21
  

Bipolar depression. A 6-week, double-blind, placebo-controlled trial randomly assigned 85 patients with bipolar depression to adjunctive modafinil, 100 to 200 mg/d, or placebo for 6 weeks (Table 3).²² The number of patients receiving an antidepressant or mood stabilizer was not significantly different between the modafinil and placebo groups.

The primary outcome measure was change in the Inventory for Depressive Symptoms (IDS) score from baseline to endpoint. Forty-four percent of patients receiving modafinil achieved a ≥50% reduction in IDS score, compared with 23% of the placebo group; this difference was statistically significant (P=0.03).

In this study, modafinil was well tolerated and did not induce mania or hypomania. Cases of modafinil-induced mania have been reported elsewhere.^23,24

The mechanisms of modafinil’s antidepressant effects are unclear. The drug does not cause release of norepinephrine or dopamine. One study proposed that modafinil acts by releasing histamine and activating noradrenaline receptors.²⁵ Activation of these receptors increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons, increasing histamine levels. Another trial suggested that modafinil may improve mood by mechanisms similar to the antidepressant effects induced by sleep deprivation.²⁶

Summary. Modafinil may have a role in managing residual fatigue and excessive sleepiness associated with MDD and bipolar depression. Evidence for a mood-elevating effect is minimal; additional studies are needed. Adjunctive modafinil and conventional stimulants have not been compared head-to-head in patients with mood disorders. Modafinil’s tolerability profile and lack of euphorigenic and reinforcing properties make it a potentially attractive alternative, however.

ADHD. Approximately 30% of ADHD patients do not respond to or are unable to tolerate conventional stimulant medications such as methylphenidate and dextroamphetamine.²⁷ Several studies have evaluated modafinil as a potential treatment for ADHD based on the drug’s action on arousal and attention systems. Although modafinil’s precise mechanism of action in ADHD is unknown, proposed mechanisms include:

• hypothalamic and cerebral cortex neuronal activation
  
• action on histamine that results in internal vigilance.²⁸
  

Can modafinil help patients with mood disorders?

CASE 2: Another Tx for ADHD

Matt, age 8, is referred to our outpatient child psychiatric clinic after his parents noted declining school performance associated with increased aggression and irritability. Our assessment strongly supports a diagnosis of ADHD without comorbid conditions. We start Matt on methylphenidate, 5 mg twice daily, which quickly improves his ADHD symptoms. However, the medication causes GI side effects and profound sleep and weight changes.

In children and adolescents. Wigal et al²⁹ reviewed pooled data from 3 randomized, double-blind, placebo-controlled studies of modafinil in pediatric ADHD (Table 4). Modafinil was well tolerated and improved ADHD symptoms and behaviors regardless of patients’ stimulant use history.

In a recent open-label study, 220 children and young adolescents with ADHD who had completed 4 weeks of a double-blind, placebo-controlled trial were evaluated for an additional 8 weeks. Modafinil improved ADHD symptoms and overall clinical condition as determined by the parent- or clinician-completed ADHD Rating Scale-IV Home Version, the parent-completed Conners’ ADHD/DSM-IV Scale Parent Version, and the clinician-rated CGI scale.³⁰ Insomnia, headache, and decreased appetite were the most commonly reported adverse events.

In adults. The results of 2 double-blind, placebo-controlled trials of modafinil in adults with ADHD have been positive:

• In 1 study, modafinil (mean 206.8 mg/d) was more effective than placebo and comparable to dextroamphetamine in improving ADHD symptoms.³¹
  
• In another, modafinil (a single 200-mg dose) increased cognitive performance during treatment.³²
  

Schizophrenia. Double-blind, randomized placebo-controlled studies have evaluated modafinil for improving cognitive function and reducing negative symptoms in patients with schizophrenia. Results have been inconsistent.

One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).³³ Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.^34,35

Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania¹¹ may limit the drug’s usefulness in schizophrenia patients.

Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.³⁶ This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.³⁷

Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.

Table 4

Modafinil and ADHD: What the evidence says

Modafinil for schizophrenia or cocaine dependence:
More research is needed

• Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
  

• Atomoxetine • Strattera
  
• Bupropion • Wellbutrin
  
• Carbamazepine • Carbatrol, Tegretol, others
  
• Citalopram • Celexa
  
• Dextroamphetamine • Dexedrine, DextroStat
  
• Diazepam • Valium
  
• Erythromycin • Ery-Tab, Eryc, others
  
• Fluoxetine • Prozac
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin, others
  
• Modafinil • Provigil
  
• Phenytoin • Dilantin
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Zolpidem • Ambien
  

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

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

Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.

Ms. B, a middle-aged mother of 3, is being monitored for bipolar disorder. She has a history of stimulant abuse but has been in remission for 5 years. She complains of excessive daytime sleepiness. Most days she wakes at 7 AM, but sleeps on several occasions during the day. She also complains of fatigue and lack of motivation.

She is being treated with lithium, venlafaxine, and zolpidem and reports good adherence. Basic laboratory work and serum lithium levels are within acceptable ranges. Her symptoms do not improve when venlafaxine is titrated from 225 mg/d to 300 mg/d. She also reports previously failed trials with bupropion and fluoxetine.

We decide to try a psychostimulant as an augmenting agent. Because of her past stimulant abuse, we add modafinil, 100 mg/d and increase to 200 mg/d. Ms. B reports improvement in her daytime sleepiness and fatigue and—except for a mild headache—tolerates the medication well.

Modafinil is being investigated for potential roles in managing inattention, excess sleepiness, fatigue, and cognitive dysfunction associated with:

• mood disorders (major depression and bipolar depression)
  
• attention-deficit/hyperactivity disorder (ADHD)
  
• schizophrenia
  
• cocaine dependence.
  

This article discusses how the drug promotes wakefulness, how it might improve cognitive function, and what the evidence reveals about off-label indications.

How it works

Although modafinil’s precise mechanism of action is unknown, it is believed to promote wakefulness more selectively than conventional stimulants such as amphetamine and methylphenidate. Modafinil does not bind to norepinephrine, serotonin, dopamine, or benzodiazepine receptors.^1,2 It might target specific hypothalamic regions such as the tuberomammillary nucleus and orexin neurons, which are peptide neurotransmitters that promote wakefulness.^3,4

Clinical trials found that modafinil has beneficial effects on:

• working memory, recognition memory, and sustained attention in healthy humans
  
• prefrontal-dependent cognitive functions in schizophrenia, major depression, and adult ADHD.⁵
  

Evidence for approved indications

Modafinil is indicated to improve wakefulness in patients who have excessive sleepiness associated with narcolepsy, obstructive sleep apnea, or shift work sleep disorder. It was approved for reducing excessive sleepiness in narcoleptic patients after two 9-week placebo-controlled clinical trials. The drug significantly reduced sleepiness and improved overall disease status as measured by the Clinical Global Impression of Change (CGI-C) scale.^6,7

In patients with shift work sleep disorder, a 12-week placebo-controlled clinical trial found that modafinil significantly improved sleep latency and CGI-C scores.¹⁰

Dosage and side effects. For patients with narcolepsy or obstructive sleep apnea, the recommended dose is 200 mg given in the morning.¹¹ For patients prescribed modafinil for work-time wakefulness, the dose is 200 mg 1 hour before their work shift. Lower doses are recommended for patients who are elderly or have hepatic impairment. Those with severe hepatic impairment typically are prescribed 100 mg/d.¹¹ Modafinil is rapidly absorbed and is metabolized primarily by the liver (Table 1). A summary of potential drug-drug interactions appears in Table 2.¹¹

In pivotal trials, adverse events that occurred more frequently with modafinil than with placebo and in >5% of the study population included headache, nausea, nervousness, rhinitis, diarrhea, back pain, insomnia, dizziness, and dyspepsia. Headache was most commonly reported; in most patients, it resolved soon after they started taking modafinil. Post-marketing reports have included cases of psychosis, mania, and suspected serious skin reactions, including Stevens-Johnson syndrome.¹¹ Modafinil lacks euphorigenic properties and has minimal potential for abuse.¹²

Table 1

Modafinil’s pharmacokinetics

Selected drug-drug interactions with modafinil

Evidence for off-label uses

Major depressive disorder (MDD). The fatigue and excessive sleepiness often seen with MDD often persist after other depressive symptoms have remitted with antidepressant treatment.¹³ Patients with these symptoms might benefit from modafinil’s stimulating properties. Conventional stimulants such as methylphenidate have been used to improve neurovegetative symptoms of depression, but modafinil offers several advantages:

• decreased adverse CNS effects
  
• fewer drug-drug interactions
  
• minimal risk for dependence or abuse.
  

A 6-week open-label study of 25 depressed patients with residual fatigue and sleepiness showed that adjunctive modafinil, 100 to 200 mg/d, significantly improved these symptoms, as well as Hamilton Rating Scale for Depression (HAM-D) score, as early as week 2. Seventy-six percent of patients responded to treatment, defined as a >50% reduction in HAM-D scores.¹⁶

Several open-label studies and case re-ports have evaluated adjunctive modafinil use in patients with:

• depression characterized by ongoing lethargy or apathy¹⁷
  
• depression with atypical features¹⁸
  
• seasonal affective disorder¹⁹
  
• partial response to antidepressants.^20,21
  

Bipolar depression. A 6-week, double-blind, placebo-controlled trial randomly assigned 85 patients with bipolar depression to adjunctive modafinil, 100 to 200 mg/d, or placebo for 6 weeks (Table 3).²² The number of patients receiving an antidepressant or mood stabilizer was not significantly different between the modafinil and placebo groups.

The primary outcome measure was change in the Inventory for Depressive Symptoms (IDS) score from baseline to endpoint. Forty-four percent of patients receiving modafinil achieved a ≥50% reduction in IDS score, compared with 23% of the placebo group; this difference was statistically significant (P=0.03).

In this study, modafinil was well tolerated and did not induce mania or hypomania. Cases of modafinil-induced mania have been reported elsewhere.^23,24

The mechanisms of modafinil’s antidepressant effects are unclear. The drug does not cause release of norepinephrine or dopamine. One study proposed that modafinil acts by releasing histamine and activating noradrenaline receptors.²⁵ Activation of these receptors increases dopamine and norepinephrine in these areas, and excites histaminergic tuberomammillary neurons, increasing histamine levels. Another trial suggested that modafinil may improve mood by mechanisms similar to the antidepressant effects induced by sleep deprivation.²⁶

Summary. Modafinil may have a role in managing residual fatigue and excessive sleepiness associated with MDD and bipolar depression. Evidence for a mood-elevating effect is minimal; additional studies are needed. Adjunctive modafinil and conventional stimulants have not been compared head-to-head in patients with mood disorders. Modafinil’s tolerability profile and lack of euphorigenic and reinforcing properties make it a potentially attractive alternative, however.

ADHD. Approximately 30% of ADHD patients do not respond to or are unable to tolerate conventional stimulant medications such as methylphenidate and dextroamphetamine.²⁷ Several studies have evaluated modafinil as a potential treatment for ADHD based on the drug’s action on arousal and attention systems. Although modafinil’s precise mechanism of action in ADHD is unknown, proposed mechanisms include:

• hypothalamic and cerebral cortex neuronal activation
  
• action on histamine that results in internal vigilance.²⁸
  

Can modafinil help patients with mood disorders?

CASE 2: Another Tx for ADHD

Matt, age 8, is referred to our outpatient child psychiatric clinic after his parents noted declining school performance associated with increased aggression and irritability. Our assessment strongly supports a diagnosis of ADHD without comorbid conditions. We start Matt on methylphenidate, 5 mg twice daily, which quickly improves his ADHD symptoms. However, the medication causes GI side effects and profound sleep and weight changes.

In children and adolescents. Wigal et al²⁹ reviewed pooled data from 3 randomized, double-blind, placebo-controlled studies of modafinil in pediatric ADHD (Table 4). Modafinil was well tolerated and improved ADHD symptoms and behaviors regardless of patients’ stimulant use history.

In a recent open-label study, 220 children and young adolescents with ADHD who had completed 4 weeks of a double-blind, placebo-controlled trial were evaluated for an additional 8 weeks. Modafinil improved ADHD symptoms and overall clinical condition as determined by the parent- or clinician-completed ADHD Rating Scale-IV Home Version, the parent-completed Conners’ ADHD/DSM-IV Scale Parent Version, and the clinician-rated CGI scale.³⁰ Insomnia, headache, and decreased appetite were the most commonly reported adverse events.

In adults. The results of 2 double-blind, placebo-controlled trials of modafinil in adults with ADHD have been positive:

• In 1 study, modafinil (mean 206.8 mg/d) was more effective than placebo and comparable to dextroamphetamine in improving ADHD symptoms.³¹
  
• In another, modafinil (a single 200-mg dose) increased cognitive performance during treatment.³²
  

Schizophrenia. Double-blind, randomized placebo-controlled studies have evaluated modafinil for improving cognitive function and reducing negative symptoms in patients with schizophrenia. Results have been inconsistent.

One double-blind, randomized, placebo-controlled crossover study of 20 patients with chronic schizophrenia found that modafinil, 200 mg/d, significantly improved short-term verbal memory span and attentional set shifting—the ability to discriminate and selectively attend to various stimulus dimensions (Table 5).³³ Two other controlled studies showed no differences between the effects of modafinil and placebo on schizophrenia’s fatigue, cognition, or positive or negative symptoms.^34,35

Summary. Although open-label studies have shown modafinil has beneficial effects on cognitive symptoms, controlled data are scarce. Reports of modafinil-induced psychosis or mania¹¹ may limit the drug’s usefulness in schizophrenia patients.

Cocaine dependence. No medications are FDA-approved for treating cocaine dependence. A placebo-controlled, double-blind trial found that modafinil blunts cocaine euphoria under controlled conditions.³⁶ This effect is hypothesized to be secondary to modafinil’s glutamate-enhancing and gamma-aminobutyric acid inhibitory effects.³⁷

Summary. A single study supports using modafinil to improve outcomes in cocaine-dependent patients receiving standardized psychosocial treatment. More research is needed.

Table 4

Modafinil and ADHD: What the evidence says

Modafinil for schizophrenia or cocaine dependence:
More research is needed

• Ballon JS, Feifel D. A systematic review of modafinil: potential clinical uses and mechanisms of action. J Clin Psychiatry 2006;67(4):554-66.
  

• Atomoxetine • Strattera
  
• Bupropion • Wellbutrin
  
• Carbamazepine • Carbatrol, Tegretol, others
  
• Citalopram • Celexa
  
• Dextroamphetamine • Dexedrine, DextroStat
  
• Diazepam • Valium
  
• Erythromycin • Ery-Tab, Eryc, others
  
• Fluoxetine • Prozac
  
• Lithium • Eskalith, Lithobid
  
• Methylphenidate • Ritalin, others
  
• Modafinil • Provigil
  
• Phenytoin • Dilantin
  
• Sertraline • Zoloft
  
• Venlafaxine • Effexor
  
• Zolpidem • Ambien
  

Dr. Ramaswamy receives research support from Bristol-Myers Squibb, Shire, and Forest Pharmaceuticals and is a consultant to Dainippon Sumitomo Pharma.

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

Dr. Wilson receives research support from, is a consultant to, or is a speaker for the National Institute of Mental Health, the Substance Abuse and Mental Health Services Administration, the Veterans Administration, the State of Nebraska, the State of Ohio, Health Futures Foundation, Inc., Abbott Laboratories, Astra-Zeneca, Bristol-Myers Squibb, Elan, Eli Lilly and Company, GlaxoSmithKline, Janssen, Ortho-McNeil, Pfizer, and Wyeth.