Anxiety disorders are remarkably common among pediatric patients^1,2 and are associated with significant morbidity³ and increased risk of suicidality in adolescents.^4,5 Effective diagnosis and treatment of pediatric anxiety disorders are critical for reducing psychosocial morbidity,^3,6 suicidality, and the risk of secondary mood disorders.7

This article summarizes open-label studies and randomized controlled trials (RCTs) of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors, atypical anxiolytics, and benzodiazepines in children and adolescents with generalized anxiety disorder (GAD), social phobia, separation anxiety disorder, and panic disorder. Although we focus on psychopharmacologic treatments, the best outcomes generally are observed with multimodal treatments that combine psychotherapy and pharmacotherapy.

Generalized anxiety disorder

Researchers have evaluated SSRIs, benzodiazepines, and buspirone in pediatric patients with GAD. In a double-blind, placebo-controlled trial of 22 patients age 5 to 17, sertraline, 50 mg/d, was associated with improvement in Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scores over 9 weeks.⁸ The Child-Adolescent Anxiety Multimodal Study compared cognitive-behavioral therapy (CBT) to sertraline or sertraline plus CBT in 488 patients age 7 to 17, 78% of whom had GAD.⁹ Sertraline monotherapy was superior to placebo and not statistically different from CBT, while combination treatment was superior to both monotherapy conditions in improving CGI score. In both trials, sertraline was well tolerated.

One study evaluated fluoxetine, 5 to 40 mg/d, or CBT in 14 youths with GAD; both treatments improved symptoms.¹⁰ In a study of 320 GAD patients age 6 to 17, venlafaxine extended-release (XR) initiated at 37.5 mg/d was associated with improved HAM-A scores.¹¹ In general, venlafaxine was well tolerated; adverse effects included increased blood pressure, asthenia, pain, anorexia, somnolence, weight loss, and possibly treatment-emergent suicidal ideation.

Two RCTs of buspirone, 15 to 60 mg/d, that evaluated 559 children and adolescents age 6 to 17 with GAD did not observe significant differences between buspirone and placebo.¹² By contrast, 2 open-label studies of youths with anxiety suggested improvement associated with buspirone.¹² Treatment-emergent adverse events included nausea, stomachache, and headache.

Clinical trials of benzodiazepines in anxious children and adolescents have yielded mixed results. A 4-week, open-label trial of alprazolam, 0.5 mg to 1.5 mg/d, in 12 adolescents with overanxious disorder—the DSM-III forerunner of GAD—found improvements in anxiety, depression, psychomotor excitation, and hyperactivity, but patients experienced sedation, activation, headache, and nausea.¹³ However, a double-blind RCT in 30 youths age 8 to 16 found no statistically significant difference between alprazolam and placebo.¹⁴ Alprazolam generally was well tolerated; fatigue and dry mouth were reported, but no withdrawal symptoms. Additionally, benzodiazepine use may be associated with tolerance and—in young children—disinhibition.

Social phobia

Researchers have evaluated paroxetine, citalopram, fluoxetine, and venlafaxine for treating social phobia in pediatric patients. In an RCT, 78% of paroxetine-treated patients with social phobia responded compared with 38% for placebo over 16 weeks. Adverse events—including withdrawal symptoms—were twice as likely in patients who received paroxetine. Additionally, 4 paroxetine patients exhibited suicidal ideation vs 0 patients who received placebo.¹⁵

In an RCT of 293 children and adolescents age 8 to 17 with social phobia, venlafaxine XR was initiated at 37.5 mg/d and titrated to 112.5 mg/d, 150 mg/d, or 225 mg/d, depending on body weight.¹⁶ The venlafaxine group experienced significantly improved anxiety symptoms and the medication generally was well tolerated, although 3 venlafaxine-treated patients developed suicidal ideation compared with 0 in the placebo group.

An RCT compared Social Effectiveness Therapy for Children (SET-C) and fluoxetine, 10 to 40 mg/d, for 139 patients age 7 to 17 with social phobia.¹⁷ SET-C is a CBT for children and adolescents that focuses on increasing interpersonal skills and becoming more comfortable in social situations; it involves psychoeducation, social skills training, and exposure exercises. At endpoint, 53% of patients in the SET-C group no longer met diagnostic criteria for social phobia. Fluoxetine was well tolerated; no severe adverse events were reported.

In an open-label study of sertraline (mean dose = 123 mg/d) for 14 young persons with social phobia, 36% of patients responded and 29% partially responded at 8 weeks.¹⁸ Adverse events generally were mild and included nausea, diarrhea, and headache. In a 12-week study, 12 pediatric patients with social phobia received citalopram, 10 to 40 mg/d, and eight 15-minute counseling sessions. At endpoint, clinicians rated 83% of patients as much improved or very much improved. The medication generally was well tolerated.¹⁹

Separation anxiety disorder

In a 4-week, double-blind crossover pilot study, researchers randomly assigned 15 children age 7 to 13 with separation anxiety disorder to clonazepam, up to 2 mg/d, or placebo.²⁰ There was no significant difference in CGI-I score between clonazepam and placebo. Side effects—including drowsiness, irritability and “oppositional behavior”—were more frequent in patients treated with clonazepam.

Panic disorder

Only 2 open-label studies of SSRIs have been conducted in pediatric patients with panic disorder. The first evaluated the effectiveness and tolerability of fluoxetine, sertraline, or paroxetine over 6 months in 12 patients; 67% no longer met criteria for panic disorder at endpoint.²¹ In this study, benzodiazepines—including clonazepam and lorazepam—were used in 67% of patients at the start of SSRI treatment. The authors suggested this strategy may be clinically useful for patients with panic disorder.

In the second study, Fairbanks et al²² examined the use of fluoxetine for 6 to 9 weeks in 16 outpatients with mixed anxiety disorders who did not respond to psychotherapy. Patients age ≤12 were given 5 to 40 mg/d and those age ≥13 received 5 to 80 mg/d. Fluoxetine was associated with clinically significant improvement in 3 of the 5 patients who had panic disorder. Although overall fluoxetine was well tolerated, drowsiness, dyssomnia, decreased appetite, nausea, and abdominal pain were the most common side effects. Fluoxetine was not associated with suicidal ideation.

Mixed anxiety disorders

Most trials of pediatric anxiety have evaluated patients with “mixed anxiety disorders” because GAD, social phobia, and separation anxiety disorder are highly comorbid and share diagnostic features (Figure 1).⁹ An RCT of fluvoxamine, up to 300 mg/d, in 128 pediatric patients with ≥1 anxiety disorders found significant differences in CGI-I and endpoint Pediatric Anxiety Rating Scale (PARS) scores.²³ Fluvoxamine was well tolerated but associated with increased motor activity and abdominal discomfort compared with placebo.

Two open-label trials of pediatric patients with mixed anxiety disorders suggested fluoxetine may be beneficial. Fairbanks et al²² documented clinical improvement in 10 of 10 patients with separation anxiety disorder, 8 of 10 with social phobia, 4 of 6 with specific phobia, 3 of 5 with panic disorder, and 1 of 7 with GAD. Birmaher et al²⁴ evaluated 21 pediatric patients with overanxious disorder, social phobia, or separation anxiety who had not responded to psychotherapy and were not depressed; all patients received flexibly-dosed fluoxetine for up to 10 months. Fluoxetine was well tolerated and 81% of patients improved.

Finally, in a 12-week RCT of 74 patients age 7 to 17 with GAD, separation anxiety disorder, and/or social phobia, fluoxetine, 10 to 20 mg/d, was associated with improved scores on the Screen for Anxiety Related Emotional Disorders, PARS, CGI-I, CGI-S, and Children’s Global Assessment Scale.²⁵ A follow-up open-label trial suggested that maintenance treatment is associated with sustained improvement.²⁶

Figure 1: The pediatric anxiety disorders triad: Comorbidity is common

In the Child-Adolescent Multimodal Treatment Study, GAD was the most common disorder; however, GAD, SAD, and SoP were highly comorbid
GAD: generalized anxiety disorder; SAD: separation anxiety disorder; SoP: social phobia
Source: Reference 9

Anxiety disorders with ADHD

Anxiety disorders often are comorbid with attention-deficit/hyperactivity disorder (ADHD). An RCT of patients age 8 to 17 with ADHD and comorbid anxiety found that atomoxetine was associated with improved PARS scores and ADHD symptoms.²⁷ The target dose was 1.2 mg/kg/d. Atomoxetine was well-tolerated; decreased appetite was the only significant adverse event in the treatment group vs placebo.

Multimodal treatment

Although this article reviews evidence for psychopharmacologic treatments, psychotherapeutic treatment of young patients with anxiety disorders has seen significant advances.²⁸ Most psychotherapy studies have evaluated the efficacy of CBT,^29-31 although there is evidence for psychodynamic therapy and interpersonal therapy.³² The American Academy of Child & Adolescent Psychiatry recommends a multimodal treatment approach because combination treatment appears to be more effective than monotherapy.^8,28,33 Also, clinicians who treat pediatric patients who have an anxiety disorder should evaluate the family’s role on anxiety symptoms and may consider family therapy.

Treatment considerations

Evidence supports the efficacy of sertraline, citalopram, paroxetine, fluvoxamine, fluoxetine, and venlafaxine for treating children and adolescents with anxiety disorders (Figure 2).^{8,9,11,15,16,23,25} Some practitioners suggest using differing dosing strategies for pediatric anxiety disorders compared with those used to treat adults (Table).³⁴ When considering SSRIs for children and adolescents, keep in mind the “black-box” warning regarding suicidality in these patients. Carefully monitor patients for treatment-emergent suicidality and routinely reassess for the presence and severity of suicidal ideation and suicide risk.

Figure 2: Number needed to treat for SSRIs and SNRIs in pediatric anxiety disorders

GAD: generalized anxiety disorder; RUPP: Research Unit on Pediatric Psychopharmacology; SAD: separation anxiety disorder; SNRI: serotonin-norepinephrine reuptake inhibitor; SoP: social phobia; SSRI: selective serotonin reuptake inhibitorTable

Practical dosing of SSRIs and SNRIs in pediatric patients with anxiety^a

Related Resources

• Connolly SD, Bernstein GA; Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267-283.
• Anxiety and Depression Association of America. www.adaa.org.
• American Academy of Child & Adolescent Psychiatry. www.aacap.org.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Fluoxetine • Prozac
• Fluvoxamine • Luvox, Luvox CR
• Lorazepam • Ativan
• Paroxetine • Paxil, Paxil CR
• Sertraline • Zoloft
• Venlafaxine • Effexor, Effexor XR

Disclosures

Dr. Strawn has received research support from the American Academy of Child & Adolescent Psychiatry, Eli Lilly and Company, and Shire, and is an employee of the University of Cincinnati, Cincinnati, OH.

Dr. McReynolds was employed by Eli Lilly and Company from 1997 to 2005.

Anxiety disorders are remarkably common among pediatric patients^1,2 and are associated with significant morbidity³ and increased risk of suicidality in adolescents.^4,5 Effective diagnosis and treatment of pediatric anxiety disorders are critical for reducing psychosocial morbidity,^3,6 suicidality, and the risk of secondary mood disorders.7

This article summarizes open-label studies and randomized controlled trials (RCTs) of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors, atypical anxiolytics, and benzodiazepines in children and adolescents with generalized anxiety disorder (GAD), social phobia, separation anxiety disorder, and panic disorder. Although we focus on psychopharmacologic treatments, the best outcomes generally are observed with multimodal treatments that combine psychotherapy and pharmacotherapy.

Generalized anxiety disorder

Researchers have evaluated SSRIs, benzodiazepines, and buspirone in pediatric patients with GAD. In a double-blind, placebo-controlled trial of 22 patients age 5 to 17, sertraline, 50 mg/d, was associated with improvement in Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scores over 9 weeks.⁸ The Child-Adolescent Anxiety Multimodal Study compared cognitive-behavioral therapy (CBT) to sertraline or sertraline plus CBT in 488 patients age 7 to 17, 78% of whom had GAD.⁹ Sertraline monotherapy was superior to placebo and not statistically different from CBT, while combination treatment was superior to both monotherapy conditions in improving CGI score. In both trials, sertraline was well tolerated.

One study evaluated fluoxetine, 5 to 40 mg/d, or CBT in 14 youths with GAD; both treatments improved symptoms.¹⁰ In a study of 320 GAD patients age 6 to 17, venlafaxine extended-release (XR) initiated at 37.5 mg/d was associated with improved HAM-A scores.¹¹ In general, venlafaxine was well tolerated; adverse effects included increased blood pressure, asthenia, pain, anorexia, somnolence, weight loss, and possibly treatment-emergent suicidal ideation.

Two RCTs of buspirone, 15 to 60 mg/d, that evaluated 559 children and adolescents age 6 to 17 with GAD did not observe significant differences between buspirone and placebo.¹² By contrast, 2 open-label studies of youths with anxiety suggested improvement associated with buspirone.¹² Treatment-emergent adverse events included nausea, stomachache, and headache.

Clinical trials of benzodiazepines in anxious children and adolescents have yielded mixed results. A 4-week, open-label trial of alprazolam, 0.5 mg to 1.5 mg/d, in 12 adolescents with overanxious disorder—the DSM-III forerunner of GAD—found improvements in anxiety, depression, psychomotor excitation, and hyperactivity, but patients experienced sedation, activation, headache, and nausea.¹³ However, a double-blind RCT in 30 youths age 8 to 16 found no statistically significant difference between alprazolam and placebo.¹⁴ Alprazolam generally was well tolerated; fatigue and dry mouth were reported, but no withdrawal symptoms. Additionally, benzodiazepine use may be associated with tolerance and—in young children—disinhibition.

Social phobia

Researchers have evaluated paroxetine, citalopram, fluoxetine, and venlafaxine for treating social phobia in pediatric patients. In an RCT, 78% of paroxetine-treated patients with social phobia responded compared with 38% for placebo over 16 weeks. Adverse events—including withdrawal symptoms—were twice as likely in patients who received paroxetine. Additionally, 4 paroxetine patients exhibited suicidal ideation vs 0 patients who received placebo.¹⁵

In an RCT of 293 children and adolescents age 8 to 17 with social phobia, venlafaxine XR was initiated at 37.5 mg/d and titrated to 112.5 mg/d, 150 mg/d, or 225 mg/d, depending on body weight.¹⁶ The venlafaxine group experienced significantly improved anxiety symptoms and the medication generally was well tolerated, although 3 venlafaxine-treated patients developed suicidal ideation compared with 0 in the placebo group.

An RCT compared Social Effectiveness Therapy for Children (SET-C) and fluoxetine, 10 to 40 mg/d, for 139 patients age 7 to 17 with social phobia.¹⁷ SET-C is a CBT for children and adolescents that focuses on increasing interpersonal skills and becoming more comfortable in social situations; it involves psychoeducation, social skills training, and exposure exercises. At endpoint, 53% of patients in the SET-C group no longer met diagnostic criteria for social phobia. Fluoxetine was well tolerated; no severe adverse events were reported.

In an open-label study of sertraline (mean dose = 123 mg/d) for 14 young persons with social phobia, 36% of patients responded and 29% partially responded at 8 weeks.¹⁸ Adverse events generally were mild and included nausea, diarrhea, and headache. In a 12-week study, 12 pediatric patients with social phobia received citalopram, 10 to 40 mg/d, and eight 15-minute counseling sessions. At endpoint, clinicians rated 83% of patients as much improved or very much improved. The medication generally was well tolerated.¹⁹

Separation anxiety disorder

In a 4-week, double-blind crossover pilot study, researchers randomly assigned 15 children age 7 to 13 with separation anxiety disorder to clonazepam, up to 2 mg/d, or placebo.²⁰ There was no significant difference in CGI-I score between clonazepam and placebo. Side effects—including drowsiness, irritability and “oppositional behavior”—were more frequent in patients treated with clonazepam.

Panic disorder

Only 2 open-label studies of SSRIs have been conducted in pediatric patients with panic disorder. The first evaluated the effectiveness and tolerability of fluoxetine, sertraline, or paroxetine over 6 months in 12 patients; 67% no longer met criteria for panic disorder at endpoint.²¹ In this study, benzodiazepines—including clonazepam and lorazepam—were used in 67% of patients at the start of SSRI treatment. The authors suggested this strategy may be clinically useful for patients with panic disorder.

In the second study, Fairbanks et al²² examined the use of fluoxetine for 6 to 9 weeks in 16 outpatients with mixed anxiety disorders who did not respond to psychotherapy. Patients age ≤12 were given 5 to 40 mg/d and those age ≥13 received 5 to 80 mg/d. Fluoxetine was associated with clinically significant improvement in 3 of the 5 patients who had panic disorder. Although overall fluoxetine was well tolerated, drowsiness, dyssomnia, decreased appetite, nausea, and abdominal pain were the most common side effects. Fluoxetine was not associated with suicidal ideation.

Mixed anxiety disorders

Most trials of pediatric anxiety have evaluated patients with “mixed anxiety disorders” because GAD, social phobia, and separation anxiety disorder are highly comorbid and share diagnostic features (Figure 1).⁹ An RCT of fluvoxamine, up to 300 mg/d, in 128 pediatric patients with ≥1 anxiety disorders found significant differences in CGI-I and endpoint Pediatric Anxiety Rating Scale (PARS) scores.²³ Fluvoxamine was well tolerated but associated with increased motor activity and abdominal discomfort compared with placebo.

Two open-label trials of pediatric patients with mixed anxiety disorders suggested fluoxetine may be beneficial. Fairbanks et al²² documented clinical improvement in 10 of 10 patients with separation anxiety disorder, 8 of 10 with social phobia, 4 of 6 with specific phobia, 3 of 5 with panic disorder, and 1 of 7 with GAD. Birmaher et al²⁴ evaluated 21 pediatric patients with overanxious disorder, social phobia, or separation anxiety who had not responded to psychotherapy and were not depressed; all patients received flexibly-dosed fluoxetine for up to 10 months. Fluoxetine was well tolerated and 81% of patients improved.

Finally, in a 12-week RCT of 74 patients age 7 to 17 with GAD, separation anxiety disorder, and/or social phobia, fluoxetine, 10 to 20 mg/d, was associated with improved scores on the Screen for Anxiety Related Emotional Disorders, PARS, CGI-I, CGI-S, and Children’s Global Assessment Scale.²⁵ A follow-up open-label trial suggested that maintenance treatment is associated with sustained improvement.²⁶

Figure 1: The pediatric anxiety disorders triad: Comorbidity is common

In the Child-Adolescent Multimodal Treatment Study, GAD was the most common disorder; however, GAD, SAD, and SoP were highly comorbid
GAD: generalized anxiety disorder; SAD: separation anxiety disorder; SoP: social phobia
Source: Reference 9

Anxiety disorders with ADHD

Anxiety disorders often are comorbid with attention-deficit/hyperactivity disorder (ADHD). An RCT of patients age 8 to 17 with ADHD and comorbid anxiety found that atomoxetine was associated with improved PARS scores and ADHD symptoms.²⁷ The target dose was 1.2 mg/kg/d. Atomoxetine was well-tolerated; decreased appetite was the only significant adverse event in the treatment group vs placebo.

Multimodal treatment

Although this article reviews evidence for psychopharmacologic treatments, psychotherapeutic treatment of young patients with anxiety disorders has seen significant advances.²⁸ Most psychotherapy studies have evaluated the efficacy of CBT,^29-31 although there is evidence for psychodynamic therapy and interpersonal therapy.³² The American Academy of Child & Adolescent Psychiatry recommends a multimodal treatment approach because combination treatment appears to be more effective than monotherapy.^8,28,33 Also, clinicians who treat pediatric patients who have an anxiety disorder should evaluate the family’s role on anxiety symptoms and may consider family therapy.

Treatment considerations

Evidence supports the efficacy of sertraline, citalopram, paroxetine, fluvoxamine, fluoxetine, and venlafaxine for treating children and adolescents with anxiety disorders (Figure 2).^{8,9,11,15,16,23,25} Some practitioners suggest using differing dosing strategies for pediatric anxiety disorders compared with those used to treat adults (Table).³⁴ When considering SSRIs for children and adolescents, keep in mind the “black-box” warning regarding suicidality in these patients. Carefully monitor patients for treatment-emergent suicidality and routinely reassess for the presence and severity of suicidal ideation and suicide risk.

Figure 2: Number needed to treat for SSRIs and SNRIs in pediatric anxiety disorders

GAD: generalized anxiety disorder; RUPP: Research Unit on Pediatric Psychopharmacology; SAD: separation anxiety disorder; SNRI: serotonin-norepinephrine reuptake inhibitor; SoP: social phobia; SSRI: selective serotonin reuptake inhibitorTable

Practical dosing of SSRIs and SNRIs in pediatric patients with anxiety^a

Related Resources

• Connolly SD, Bernstein GA; Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267-283.
• Anxiety and Depression Association of America. www.adaa.org.
• American Academy of Child & Adolescent Psychiatry. www.aacap.org.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Fluoxetine • Prozac
• Fluvoxamine • Luvox, Luvox CR
• Lorazepam • Ativan
• Paroxetine • Paxil, Paxil CR
• Sertraline • Zoloft
• Venlafaxine • Effexor, Effexor XR

Disclosures

Dr. Strawn has received research support from the American Academy of Child & Adolescent Psychiatry, Eli Lilly and Company, and Shire, and is an employee of the University of Cincinnati, Cincinnati, OH.

Dr. McReynolds was employed by Eli Lilly and Company from 1997 to 2005.

Anxiety disorders are remarkably common among pediatric patients^1,2 and are associated with significant morbidity³ and increased risk of suicidality in adolescents.^4,5 Effective diagnosis and treatment of pediatric anxiety disorders are critical for reducing psychosocial morbidity,^3,6 suicidality, and the risk of secondary mood disorders.7

This article summarizes open-label studies and randomized controlled trials (RCTs) of selective serotonin reuptake inhibitors (SSRIs), selective serotonin-norepinephrine reuptake inhibitors, atypical anxiolytics, and benzodiazepines in children and adolescents with generalized anxiety disorder (GAD), social phobia, separation anxiety disorder, and panic disorder. Although we focus on psychopharmacologic treatments, the best outcomes generally are observed with multimodal treatments that combine psychotherapy and pharmacotherapy.

Generalized anxiety disorder

Researchers have evaluated SSRIs, benzodiazepines, and buspirone in pediatric patients with GAD. In a double-blind, placebo-controlled trial of 22 patients age 5 to 17, sertraline, 50 mg/d, was associated with improvement in Hamilton Anxiety Rating Scale (HAM-A), Clinical Global Impression-Severity (CGI-S), and Clinical Global Impression-Improvement (CGI-I) scores over 9 weeks.⁸ The Child-Adolescent Anxiety Multimodal Study compared cognitive-behavioral therapy (CBT) to sertraline or sertraline plus CBT in 488 patients age 7 to 17, 78% of whom had GAD.⁹ Sertraline monotherapy was superior to placebo and not statistically different from CBT, while combination treatment was superior to both monotherapy conditions in improving CGI score. In both trials, sertraline was well tolerated.

One study evaluated fluoxetine, 5 to 40 mg/d, or CBT in 14 youths with GAD; both treatments improved symptoms.¹⁰ In a study of 320 GAD patients age 6 to 17, venlafaxine extended-release (XR) initiated at 37.5 mg/d was associated with improved HAM-A scores.¹¹ In general, venlafaxine was well tolerated; adverse effects included increased blood pressure, asthenia, pain, anorexia, somnolence, weight loss, and possibly treatment-emergent suicidal ideation.

Two RCTs of buspirone, 15 to 60 mg/d, that evaluated 559 children and adolescents age 6 to 17 with GAD did not observe significant differences between buspirone and placebo.¹² By contrast, 2 open-label studies of youths with anxiety suggested improvement associated with buspirone.¹² Treatment-emergent adverse events included nausea, stomachache, and headache.

Clinical trials of benzodiazepines in anxious children and adolescents have yielded mixed results. A 4-week, open-label trial of alprazolam, 0.5 mg to 1.5 mg/d, in 12 adolescents with overanxious disorder—the DSM-III forerunner of GAD—found improvements in anxiety, depression, psychomotor excitation, and hyperactivity, but patients experienced sedation, activation, headache, and nausea.¹³ However, a double-blind RCT in 30 youths age 8 to 16 found no statistically significant difference between alprazolam and placebo.¹⁴ Alprazolam generally was well tolerated; fatigue and dry mouth were reported, but no withdrawal symptoms. Additionally, benzodiazepine use may be associated with tolerance and—in young children—disinhibition.

Social phobia

Researchers have evaluated paroxetine, citalopram, fluoxetine, and venlafaxine for treating social phobia in pediatric patients. In an RCT, 78% of paroxetine-treated patients with social phobia responded compared with 38% for placebo over 16 weeks. Adverse events—including withdrawal symptoms—were twice as likely in patients who received paroxetine. Additionally, 4 paroxetine patients exhibited suicidal ideation vs 0 patients who received placebo.¹⁵

In an RCT of 293 children and adolescents age 8 to 17 with social phobia, venlafaxine XR was initiated at 37.5 mg/d and titrated to 112.5 mg/d, 150 mg/d, or 225 mg/d, depending on body weight.¹⁶ The venlafaxine group experienced significantly improved anxiety symptoms and the medication generally was well tolerated, although 3 venlafaxine-treated patients developed suicidal ideation compared with 0 in the placebo group.

An RCT compared Social Effectiveness Therapy for Children (SET-C) and fluoxetine, 10 to 40 mg/d, for 139 patients age 7 to 17 with social phobia.¹⁷ SET-C is a CBT for children and adolescents that focuses on increasing interpersonal skills and becoming more comfortable in social situations; it involves psychoeducation, social skills training, and exposure exercises. At endpoint, 53% of patients in the SET-C group no longer met diagnostic criteria for social phobia. Fluoxetine was well tolerated; no severe adverse events were reported.

In an open-label study of sertraline (mean dose = 123 mg/d) for 14 young persons with social phobia, 36% of patients responded and 29% partially responded at 8 weeks.¹⁸ Adverse events generally were mild and included nausea, diarrhea, and headache. In a 12-week study, 12 pediatric patients with social phobia received citalopram, 10 to 40 mg/d, and eight 15-minute counseling sessions. At endpoint, clinicians rated 83% of patients as much improved or very much improved. The medication generally was well tolerated.¹⁹

Separation anxiety disorder

In a 4-week, double-blind crossover pilot study, researchers randomly assigned 15 children age 7 to 13 with separation anxiety disorder to clonazepam, up to 2 mg/d, or placebo.²⁰ There was no significant difference in CGI-I score between clonazepam and placebo. Side effects—including drowsiness, irritability and “oppositional behavior”—were more frequent in patients treated with clonazepam.

Panic disorder

Only 2 open-label studies of SSRIs have been conducted in pediatric patients with panic disorder. The first evaluated the effectiveness and tolerability of fluoxetine, sertraline, or paroxetine over 6 months in 12 patients; 67% no longer met criteria for panic disorder at endpoint.²¹ In this study, benzodiazepines—including clonazepam and lorazepam—were used in 67% of patients at the start of SSRI treatment. The authors suggested this strategy may be clinically useful for patients with panic disorder.

In the second study, Fairbanks et al²² examined the use of fluoxetine for 6 to 9 weeks in 16 outpatients with mixed anxiety disorders who did not respond to psychotherapy. Patients age ≤12 were given 5 to 40 mg/d and those age ≥13 received 5 to 80 mg/d. Fluoxetine was associated with clinically significant improvement in 3 of the 5 patients who had panic disorder. Although overall fluoxetine was well tolerated, drowsiness, dyssomnia, decreased appetite, nausea, and abdominal pain were the most common side effects. Fluoxetine was not associated with suicidal ideation.

Mixed anxiety disorders

Most trials of pediatric anxiety have evaluated patients with “mixed anxiety disorders” because GAD, social phobia, and separation anxiety disorder are highly comorbid and share diagnostic features (Figure 1).⁹ An RCT of fluvoxamine, up to 300 mg/d, in 128 pediatric patients with ≥1 anxiety disorders found significant differences in CGI-I and endpoint Pediatric Anxiety Rating Scale (PARS) scores.²³ Fluvoxamine was well tolerated but associated with increased motor activity and abdominal discomfort compared with placebo.

Two open-label trials of pediatric patients with mixed anxiety disorders suggested fluoxetine may be beneficial. Fairbanks et al²² documented clinical improvement in 10 of 10 patients with separation anxiety disorder, 8 of 10 with social phobia, 4 of 6 with specific phobia, 3 of 5 with panic disorder, and 1 of 7 with GAD. Birmaher et al²⁴ evaluated 21 pediatric patients with overanxious disorder, social phobia, or separation anxiety who had not responded to psychotherapy and were not depressed; all patients received flexibly-dosed fluoxetine for up to 10 months. Fluoxetine was well tolerated and 81% of patients improved.

Finally, in a 12-week RCT of 74 patients age 7 to 17 with GAD, separation anxiety disorder, and/or social phobia, fluoxetine, 10 to 20 mg/d, was associated with improved scores on the Screen for Anxiety Related Emotional Disorders, PARS, CGI-I, CGI-S, and Children’s Global Assessment Scale.²⁵ A follow-up open-label trial suggested that maintenance treatment is associated with sustained improvement.²⁶

Figure 1: The pediatric anxiety disorders triad: Comorbidity is common

In the Child-Adolescent Multimodal Treatment Study, GAD was the most common disorder; however, GAD, SAD, and SoP were highly comorbid
GAD: generalized anxiety disorder; SAD: separation anxiety disorder; SoP: social phobia
Source: Reference 9

Anxiety disorders with ADHD

Anxiety disorders often are comorbid with attention-deficit/hyperactivity disorder (ADHD). An RCT of patients age 8 to 17 with ADHD and comorbid anxiety found that atomoxetine was associated with improved PARS scores and ADHD symptoms.²⁷ The target dose was 1.2 mg/kg/d. Atomoxetine was well-tolerated; decreased appetite was the only significant adverse event in the treatment group vs placebo.

Multimodal treatment

Although this article reviews evidence for psychopharmacologic treatments, psychotherapeutic treatment of young patients with anxiety disorders has seen significant advances.²⁸ Most psychotherapy studies have evaluated the efficacy of CBT,^29-31 although there is evidence for psychodynamic therapy and interpersonal therapy.³² The American Academy of Child & Adolescent Psychiatry recommends a multimodal treatment approach because combination treatment appears to be more effective than monotherapy.^8,28,33 Also, clinicians who treat pediatric patients who have an anxiety disorder should evaluate the family’s role on anxiety symptoms and may consider family therapy.

Treatment considerations

Evidence supports the efficacy of sertraline, citalopram, paroxetine, fluvoxamine, fluoxetine, and venlafaxine for treating children and adolescents with anxiety disorders (Figure 2).^{8,9,11,15,16,23,25} Some practitioners suggest using differing dosing strategies for pediatric anxiety disorders compared with those used to treat adults (Table).³⁴ When considering SSRIs for children and adolescents, keep in mind the “black-box” warning regarding suicidality in these patients. Carefully monitor patients for treatment-emergent suicidality and routinely reassess for the presence and severity of suicidal ideation and suicide risk.

Figure 2: Number needed to treat for SSRIs and SNRIs in pediatric anxiety disorders

GAD: generalized anxiety disorder; RUPP: Research Unit on Pediatric Psychopharmacology; SAD: separation anxiety disorder; SNRI: serotonin-norepinephrine reuptake inhibitor; SoP: social phobia; SSRI: selective serotonin reuptake inhibitorTable

Practical dosing of SSRIs and SNRIs in pediatric patients with anxiety^a

Related Resources

• Connolly SD, Bernstein GA; Work Group on Quality Issues. Practice parameter for the assessment and treatment of children and adolescents with anxiety disorders. J Am Acad Child Adolesc Psychiatry. 2007;46(2):267-283.
• Anxiety and Depression Association of America. www.adaa.org.
• American Academy of Child & Adolescent Psychiatry. www.aacap.org.

Drug Brand Names

• Alprazolam • Xanax
• Atomoxetine • Strattera
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Fluoxetine • Prozac
• Fluvoxamine • Luvox, Luvox CR
• Lorazepam • Ativan
• Paroxetine • Paxil, Paxil CR
• Sertraline • Zoloft
• Venlafaxine • Effexor, Effexor XR

Disclosures

Dr. Strawn has received research support from the American Academy of Child & Adolescent Psychiatry, Eli Lilly and Company, and Shire, and is an employee of the University of Cincinnati, Cincinnati, OH.

Dr. McReynolds was employed by Eli Lilly and Company from 1997 to 2005.

Sleep terrors (STs)—also known as night terrors—are characterized by sudden arousal accompanied by a piercing scream or cry in the first few hours after falling asleep. These parasomnias arise out of slow-wave sleep (stages 3 and 4 of nonrapid eye movement [non-REM] sleep) and affect approximately 5% of adults.1 The condition is twice as common in men than women, and usually affects children but may not develop until adulthood.1

During STs, a patient may act scared, afraid, agitated, anxious, or panicky without being fully aware of his or her surroundings. The episode may last 30 seconds to 5 minutes; most patients don’t remember the event the next morning. STs may leave individuals feeling exhausted and perplexed the next day. Verbalization during the episode is incoherent and a patient’s perception of the environment seems altered. Tachycardia, tachypnea, sweating, flushed skin, or mydriasis are prominent. When ST patients walk, they may do so violently and can cause harm to themselves or others.

The differential diagnosis of STs includes posttraumatic stress disorder; nocturnal seizures characterized by excessive motor activity and organic CNS lesions; REM sleep behavior disorder; sleep choking syndrome; and nocturnal panic attacks. Patients with STs report high rates of stressful events—eg, divorce or bereavement—in the previous year. They are more likely to have a history of mood and anxiety disorders and high levels of depression, anxiety, and obsessive-compulsive and phobic traits. One study found patients with STs were 4.3 times more likely to have had a car accident in the past year.²

Evaluating and treating STs

Rule out comorbid conditions such as obstructive sleep apnea and periodic limb movement disorder. Encourage your patient to improve his or her sleep hygiene by maintaining a regular sleep/wake cycle, exercising, and limiting caffeine and alcohol and exposure to bright light before bedtime.

Self-help techniques. To avoid injury, encourage your patient to remove dangerous objects from their sleeping area. Suggest locking the doors to the room or home, and putting medications in a secure place. Patients also may consider keeping their mattress close to the floor to limit the risk of injury.

Pharmacotherapy and psychotherapy. Along with counseling and support, your patient may benefit from cognitive-behavioral therapy, relaxation therapy, or hypnosis.³ Anticipatory arousal therapy may help by interrupting the altered underlying electrophysiology of partial arousal.

If your patient is concerned about physical injury during STs, consider prescribing clonazepam, temazepam, or diazepam.⁴ Trazodone and selective serotonin reuptake inhibitors such as paroxetine⁵ also have been used to treat STs.

Disclosure

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

Sleep terrors (STs)—also known as night terrors—are characterized by sudden arousal accompanied by a piercing scream or cry in the first few hours after falling asleep. These parasomnias arise out of slow-wave sleep (stages 3 and 4 of nonrapid eye movement [non-REM] sleep) and affect approximately 5% of adults.1 The condition is twice as common in men than women, and usually affects children but may not develop until adulthood.1

During STs, a patient may act scared, afraid, agitated, anxious, or panicky without being fully aware of his or her surroundings. The episode may last 30 seconds to 5 minutes; most patients don’t remember the event the next morning. STs may leave individuals feeling exhausted and perplexed the next day. Verbalization during the episode is incoherent and a patient’s perception of the environment seems altered. Tachycardia, tachypnea, sweating, flushed skin, or mydriasis are prominent. When ST patients walk, they may do so violently and can cause harm to themselves or others.

The differential diagnosis of STs includes posttraumatic stress disorder; nocturnal seizures characterized by excessive motor activity and organic CNS lesions; REM sleep behavior disorder; sleep choking syndrome; and nocturnal panic attacks. Patients with STs report high rates of stressful events—eg, divorce or bereavement—in the previous year. They are more likely to have a history of mood and anxiety disorders and high levels of depression, anxiety, and obsessive-compulsive and phobic traits. One study found patients with STs were 4.3 times more likely to have had a car accident in the past year.²

Evaluating and treating STs

Rule out comorbid conditions such as obstructive sleep apnea and periodic limb movement disorder. Encourage your patient to improve his or her sleep hygiene by maintaining a regular sleep/wake cycle, exercising, and limiting caffeine and alcohol and exposure to bright light before bedtime.

Self-help techniques. To avoid injury, encourage your patient to remove dangerous objects from their sleeping area. Suggest locking the doors to the room or home, and putting medications in a secure place. Patients also may consider keeping their mattress close to the floor to limit the risk of injury.

Pharmacotherapy and psychotherapy. Along with counseling and support, your patient may benefit from cognitive-behavioral therapy, relaxation therapy, or hypnosis.³ Anticipatory arousal therapy may help by interrupting the altered underlying electrophysiology of partial arousal.

If your patient is concerned about physical injury during STs, consider prescribing clonazepam, temazepam, or diazepam.⁴ Trazodone and selective serotonin reuptake inhibitors such as paroxetine⁵ also have been used to treat STs.

Disclosure

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

Sleep terrors (STs)—also known as night terrors—are characterized by sudden arousal accompanied by a piercing scream or cry in the first few hours after falling asleep. These parasomnias arise out of slow-wave sleep (stages 3 and 4 of nonrapid eye movement [non-REM] sleep) and affect approximately 5% of adults.1 The condition is twice as common in men than women, and usually affects children but may not develop until adulthood.1

During STs, a patient may act scared, afraid, agitated, anxious, or panicky without being fully aware of his or her surroundings. The episode may last 30 seconds to 5 minutes; most patients don’t remember the event the next morning. STs may leave individuals feeling exhausted and perplexed the next day. Verbalization during the episode is incoherent and a patient’s perception of the environment seems altered. Tachycardia, tachypnea, sweating, flushed skin, or mydriasis are prominent. When ST patients walk, they may do so violently and can cause harm to themselves or others.

The differential diagnosis of STs includes posttraumatic stress disorder; nocturnal seizures characterized by excessive motor activity and organic CNS lesions; REM sleep behavior disorder; sleep choking syndrome; and nocturnal panic attacks. Patients with STs report high rates of stressful events—eg, divorce or bereavement—in the previous year. They are more likely to have a history of mood and anxiety disorders and high levels of depression, anxiety, and obsessive-compulsive and phobic traits. One study found patients with STs were 4.3 times more likely to have had a car accident in the past year.²

Evaluating and treating STs

Rule out comorbid conditions such as obstructive sleep apnea and periodic limb movement disorder. Encourage your patient to improve his or her sleep hygiene by maintaining a regular sleep/wake cycle, exercising, and limiting caffeine and alcohol and exposure to bright light before bedtime.

Self-help techniques. To avoid injury, encourage your patient to remove dangerous objects from their sleeping area. Suggest locking the doors to the room or home, and putting medications in a secure place. Patients also may consider keeping their mattress close to the floor to limit the risk of injury.

Pharmacotherapy and psychotherapy. Along with counseling and support, your patient may benefit from cognitive-behavioral therapy, relaxation therapy, or hypnosis.³ Anticipatory arousal therapy may help by interrupting the altered underlying electrophysiology of partial arousal.

If your patient is concerned about physical injury during STs, consider prescribing clonazepam, temazepam, or diazepam.⁴ Trazodone and selective serotonin reuptake inhibitors such as paroxetine⁵ also have been used to treat STs.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Epidemiologic data suggest that people who consume diets rich in omega-3 fatty acids (FAs)—long-chain polyunsaturated FAs such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA)—have a decreased risk of major depressive disorder (MDD), postpartum depression, and bipolar disorder (BD).^1-5 Omega-3 FA concentration may impact serotonin and dopamine transmission via effects on cell membrane fluidity.⁶ Therefore, decreased intake may increase the risk of several psychiatric disorders. As the average Western diet has changed over the last 2 centuries, omega-3 FA consumption has decreased.⁷ Omega-3 FAs cannot be synthesized by the body and must come from exogenous sources, such as fish and nuts. For a discussion of different types of dietary fats, see Box 1.⁸

Should we advise our patients to increase their omega-3 FA consumption? The American Psychiatric Association (APA) and the American Heart Association (AHA) recommend omega-3 FA consumption for the general population and in some cases, supplementation for specific disorders (Box 2).^9-12 New data has been published since Current Psychiatry last reviewed the evidence for using omega-3 FAs for psychiatric conditions in 2004.⁸ This article looks at the latest evidence on the use of omega-3 FAs to treat mood disorders, schizophrenia, dementia, and other psychiatric conditions.

Box 1

Box 2

Limitations of the data

Reviewing the literature on omega-3 FAs to treat psychiatric disorders is hampered by several difficulties:¹³

• studies may evaluate the use of EPA alone, EPA combined with DHA, or DHA alone
• the doses of EPA and DHA and ratio of EPA to DHA of the supplements used in clinical trials varies greatly
• patients’ dietary consumption of omega-3 FAs is difficult to control
• DSM diagnostic criteria, as well as severity of illness, differ within studies.

In addition, studies may use omega-3 FAs as monotherapy or as adjuncts. All of these factors lead to difficulty interpreting the literature, as well as trouble in extracting data for meta-analysis.

Omega-3 FAs for mood disorders

MDD and other depressive diagnoses. Several meta-analyses examining the use of omega-3 FAs for treating depressive disorders have had equivocal findings. Variability in results might be partially explained by differences in the severity of baseline depression among diverse study populations, diagnostic variation, differing omega-3 supplementation protocols, or other issues.¹³ In addition, publication bias also may affect results.

In a 2011 literature review and meta-analysis of omega-3 FAs as monotherapy or an adjunct to antidepressants to treat MDD, Bloch and Hannestad⁶ concluded that omega-3 FAs offer a small but nonsignificant benefit in treating MDD. This review suggested that omega-3 FAs may be more effective in patients with more severe depression. The effects of varying levels of EPA vs DHA were not examined.

In a systematic review and meta-analysis, Appleton et al¹⁴ concluded that omega-3 FA supplements have little beneficial effect on depressed mood in individuals who do not have a depressive illness diagnosis (eg, MDD). However, this study did not consider the differential effects of EPA vs DHA on treatment response. Patients diagnosed with a depressive illness received greater benefits from omega-3 FA supplementation, although the patients in this study were heterogeneous. Similar to Bloch and Hannestad, Appleton et al¹⁴ found that omega-3 FA supplementation may be most beneficial for depressed patients with more severe symptoms, but is unlikely to help those with mild-to-moderate symptoms or individuals without symptoms who aim to prevent depression.

A meta-analysis by Martins¹⁵ looked at EPA vs DHA to treat depressive illness and found that only supplements that were mostly or completely EPA effectively treated depressive symptoms. Martins also found that severity of illness is key for positive treatment outcomes; there was a significant relationship between higher baseline depression levels and efficacy.¹⁵ Martins noted that omega-3 FA therapy was more effective as a treatment than a preventive strategy, and that adding omega-3 FAs to antidepressants was more efficacious than omega-3 FAs alone.¹⁵

A meta-analysis of clinical trials of omega-3 FAs for depressive illness suggested EPA should be ≥60% of total EPA + DHA.¹⁶

BD. A recent meta-analysis of 6 randomized controlled trials (RCTs) found that adding omega-3 supplements to mood stabilizers in patients with BD was associated with a statistically significant reduction of depressive symptoms, but was not effective for treating mania.¹⁷ The authors suggested patients with BD—especially those with comorbid cardiovascular or metabolic conditions— increase their dietary consumption of foods containing omega-3 FAs (Table)¹⁸ and, if necessary, take a supplement of 1 to 1.5 g/d of mixed EPA and DHA, with a higher ratio of EPA.¹⁹ See Box 3 for a box on how to read omega-3 supplement labels.

In a small RCT of 51 children and adolescents (age 6 to 17) with symptomatic bipolar I or bipolar II disorder, supplementation with flax oil (alpha-linolenic acid, a polyunsaturated omega-3 FA that is a precursor to EPA and DHA) did not affect symptoms as measured by several rating scales.²⁰

Perinatal and postpartum depression. Omega-3 FAs are considered a safe treatment for depressive disorders during pregnancy because they provide neurodevelopmental benefits for neonates and have few contraindications during pregnancy.²¹ RCTs of omega-3 FA monotherapy for perinatal depression have been small (≤51 patients) and produced mixed findings.²¹ A pilot study (N = 16) of patients with postpartum depression found a significant decrease in depressive symptoms with EPA treatment.²² More research is needed before omega-3 FA supplementation can be recommended during pregnancy.

Table

Foods with healthy fats: From best to worst

Box 3

Selecting an omega-3 supplement: What to tell patients

Because nutritional supplements vary, advise patients to look at the supplement facts on the back of a bottle of omega-3 fatty acids. The American Psychiatric Association recommends patients take a total eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) of 1 g/d; EPA should be ≥60% of total EPA + DHA.

This image is an example of a label that would meet the appropriate criteria. Total EPA + DHA = 1,490 mg and EPA is 60% of this combined total.

Source: Sublette ME, Ellis SP, Geant AL, et al. Meta-analysis of the effects of eicosapentaenoic acid (EPA) in clinical trials in depression. J Clin Psychiatry. 2011;72(12):1577-1584

Schizophrenia

In a Cochrane review of 8 studies of patients with schizophrenia, adjunctive treatment with omega-3 FAs led to >25% reduction in the Positive and Negative Syndrome Scale, but this improvement was not statistically significant.²³ Omega-3 FAs did not decrease tardive dyskinesia symptoms as measured by the Abnormal Involuntary Movement Scale. The authors stated that results were inconclusive, and use of omega-3 FAs in patients with schizophrenia remains experimental. In a separate meta-analysis that included 335 patients with schizophrenia, EPA augmentation had no beneficial effect on psychotic symptoms.²⁴

In a double-blind RCT of 81 adolescents and young adults (age 13 to 25) at ultra-high risk of psychotic illness, 5% of patients who received 1.2 g/d of omega-3 FAs developed a psychotic disorder compared with 28% of patients receiving placebo.²⁵ The authors concluded that supplementation with omega-3 FAs may be a safe and effective strategy for young patients with subthreshold psychotic symptoms.

Dementia

Studies evaluating the relationship between omega-3 FAs and dementia risk have revealed mixed findings.^26,27 In a pilot study of 10 geriatric patients with moderately severe dementia related to thrombotic cerebrovascular disorder, DHA supplementation led to improved Hamilton Depression Rating Scale and Mini-Mental State Examination (MMSE) scores compared with controls.²⁸ In another study, administering EPA to 64 patients with Alzheimer’s disease significantly improved MMSE scores, with maximum improvement at 3 months, but this benefit dissipated after 6 months of treatment.²⁹ In a study of 22 patients with various types of dementia, Suzuki et al³⁰ found that DHA supplementation improved scores on a Japanese dementia scale. These studies show promise, but more evidence is necessary before recommendations can be made.

Other psychiatric disorders

Omega-3 FAs as monotherapy or an adjunct to psychostimulants does not seem to improve symptoms in children who meet DSM-IV-TR criteria for attention-deficit/hyperactivity disorder (ADHD).^31-33 Studies of omega-3 FAs as treatment for anxiety and personality disorders are limited. To date, omega-3 FAs as adjunctive treatment in obsessive-compulsive disorder (OCD) and monotherapy in borderline personality disorder have not shown efficacy.^34,35

Using omega-3 FAs in practice

Based on new data and several recent meta-analyses, clinical recommendations have emerged. Sarris et al¹⁷ suggested patients with BD increase dietary intake of omega-3 FAs or take a supplement with 1 to 1.5 g/d of mixed EPA and DHA (with a higher ratio of EPA). In MDD, the type of omega-3 FA supplementation seems to be important; EPA seems to be the primary component for efficacy.^15,19 Additionally, the more severe the depression, the more likely symptoms will respond to omega-3 FAs.^6,14,15 Omega-3 FAs are not effective at preventing depression^14,15 and evidence is equivocal for treating perinatal depression.²¹ Omega-3 FA supplementation has not shown efficacy for patients with schizophrenia,^23,24 although it may prevent transition to psychosis in adolescents and young adults at ultra-high risk for a psychotic disorder.²⁵ Data examining omega-3 FA supplementation in postpartum depression²² and dementia^28,29 are limited but show promise. Omega-3 FAs appear to lack efficacy in ADHD,^31-33 OCD,³⁴ and borderline personality disorder.³⁵

Related Resources

• National Center for Complementary and Alternative Medicine. Omega-3 fatty acids. http://nccam.nih.gov/health/omega3.
• National Institutes of Health. Office of Dietary Supplements. Working group report: Omega-3 fatty acids and cardiovascular disease. http://ods.od.nih.gov/Health_Information/omega_3_fatty_acids.aspx.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatric symptoms are a common and debilitating manifestation of Huntington’s disease (HD), a progressive, inherited neurodegenerative disorder also characterized by chorea (involuntary, nonrepetitive movements) and cognitive decline. The prevalence of HD is 4 to 8 patients per 100,000 persons in most populations of European descent, with lower prevalence among non-Europeans.¹ HD is caused by an abnormal expansion of a trinucleotide (CAG) repeat sequence on chromosome 4, and is inherited in an autosomal dominant fashion, meaning a HD patient’s child has a 50% chance of inheriting the mutation. The expansion is located in the gene that encodes the “huntingtin” protein, the normal function of which is not well understood.

There’s no cure for HD, and treatments primarily are directed at symptom control. Psychiatric symptoms include depression, apathy, anxiety, and psychosis (Table).^2-4 Treating patients with HD can be challenging because most psychiatrists will see only a handful of patients with this multifaceted illness during their careers. See Box 1 for a case study of a patient with HD.

Table

Psychiatric symptoms of HD

Box 1

Psychiatric sequelae

In general, psychiatric symptoms of HD become increasingly prevalent over time (Box 2).^3,5 In a 2001 study of 52 HD patients by Paulsen et al,² 51 patients had ≥1 psychiatric symptom, such as dysphoria (69.2%), agitation (67.3%), irritability (65.4%), apathy (55.8%), and anxiety (51.9%); delusions (11.5%) and hallucinations (1.9%) were less prevalent.² Similarly, Thompson et al³ followed 111 HD patients for ≥3 years and all experienced psychiatric symptoms.

Box 2

Depressed mood and functional ability—not cognitive or motor symptoms⁶—are the 2 most critical factors linked to health-related quality of life in HD. Hamilton et al⁷ found that apathy or executive dysfunction in HD patients is strongly related to decline in ability to complete activities of daily living, and may be severely debilitating.

Apathy. Often mistaken for a symptom of depression, apathy’s presentation may resemble anhedonia or fatigue; however, research suggests that depression and apathy are distinct conditions. Naarding et al

Depression affects most HD patients, and often is most severe early in the disease course. Hubers et al⁸ found that 20% of 100 HD patients had suicidal ideation. The strongest predictor was depressed mood.

Sleep disturbances and daytime somnolence are common among HD patients, and patients with comorbid depression report more disturbed sleep. Managing disturbed sleep and daytime somnolence in HD, with emphasis on comorbid depression, may improve the quality of life of patients and their caregivers.⁹

Anxiety was present in >50% of HD patients in a study by Paulsen et al² and 37% evaluated by Craufurd et al.¹⁰ Craufurd et al¹⁰ also reported that 61% of patients were “physically tense and unable to relax.”

Among HD patients, 5% report obsessions and 10% report compulsive behaviors; these symptoms appear to become increasingly common as HD progresses.^4,10

Impulsivity and disinhibition. Craufurd et al¹⁰ found that 71% of HD patients experienced poor judgment and self-monitoring, 40% had poor temper control and verbal outbursts, 22% exhibited threatening behavior or violence, and 6% had disinhibited or inappropriate sexual behavior.¹⁰

Recent studies have shown higher rates of disinhibition in “presymptomatic” gene-positive subjects vs gene-negative controls, suggesting that these symptoms may arise early in HD.¹¹ Further, researchers demonstrated that patients lack symptom awareness and rate themselves as less impaired than their caregivers do.¹¹

In our clinical experience, impulsivity frequently is encountered and creates significant conflict between patients and their caregivers. We speculate that when coupled with depressive symptoms of HD, impulsivity and disinhibition may play an important role in the high rates of suicidality seen in these patients.

Psychosis. Delusions and hallucinations are less common in HD than other psychiatric symptoms. Craufurd et al¹⁰ reported 3% of HD patients had delusions, 3% had auditory hallucinations, 2% had tactile hallucinations, and no patients had visual hallucinations.

A few case reports and a small study by Tsuang et al¹² suggested that psychotic features in HD may be similar to those seen in paranoid schizophrenia. Tsuang et al¹² also noted that more severe HD-related psychosis tends to cluster in families, which suggests that susceptibility to HD psychosis may be heritable.

Treating psychiatric symptoms

High-quality randomized controlled trials of pharmacotherapies for psychiatric symptoms in HD patients are lacking. Decisions regarding which agents to use often are based on case reports or clinical experience. The suggestions below are based on available evidence and our clinical experience.

Depression. Depressive symptoms in HD seem to respond to conventional pharmacologic treatments for major depressive disorder (MDD). A small trial of venlafaxine extended-release (XR) in 26 HD patients with MDD showed statistically significant improvements in depressive symptoms; however, this trial was not blinded and did not have a placebo group.¹³ In addition, 1 in 5 patients developed significant side effects—nausea, irritability, or worsening chorea.¹³

Evidence for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants (TCAs) is lacking. Antidepressant choice should be based on patient response, side effect profile, and the need for secondary therapeutic effects.¹⁴

We often prescribe sertraline, citalopram, or escitalopram for our HD patients because of the relative absence of drug-drug interactions and favorable safety profile in medically and surgically ill patients. However, it’s important to tailor the treatment approach to your patient’s needs—eg, patients prone to forgetting their medicine may benefit from a drug with a longer half-life, such as fluoxetine. We avoid TCAs because of their anticholinergic effects, which may worsen dementia symptoms. Because HD patients have high rates of suicidality, agents that are highly toxic when taken in overdose should be used with caution.

One small study of HD patients with MDD or bipolar disorder showed clinical improvement in depressive symptoms after electroconvulsive therapy (ECT).¹⁵ Patients who suffered from comorbid delusions had the best improvements in mood.¹⁵ ECT likely is a good choice for HD patients who have failed several antidepressants, are suicidal, or who have depression with psychotic features.¹⁶

Apathy. A 2011 review concluded that no evidence-based recommendations regarding pharmacologic treatment for apathy in HD can be made because of lack of research.⁷ The Huntington’s Disease Society of America’s (HDSA) A Physician’s Guide to Managing Huntington’s Disease includes recommendations for treating apathy based on clinical experience.¹⁶ It suggests a nonsedating SSRI, followed by a trial of methylphenidate, pemoline, or dextroamphetamine if SSRIs were unsuccessful.

Anxiety. A small, open-label study of 11 patients found that olanzapine, 5 mg/d, significantly improved depression, anxiety, irritability, and obsessive behavior in HD patients.¹⁷

The HDSA guide suggests treating anxiety and obsessive-compulsive symptoms as you would in patients without HD. For anxiety, SSRIs and possibly a short-term trial of a low-dose benzodiazepine (ie, lorazepam, clonazepam) are suggested.¹⁶ Benzodiazepines may increase the risk of falls and delirium in this population. Anecdotally, buspirone is helpful in some patients, with a starting dose of 5 mg 2 to 3 times per day and increased to 20 to 30 mg/d in divided doses.¹⁶ For obsessive-compulsive symptoms, SSRIs are recommended; atypical antipsychotics are reserved for severe or refractory symptoms.¹⁶

Disinhibition and impulsivity. There’s no research on treating disinhibition and impulsivity in HD. In our clinical experience, atypical antipsychotics are the most helpful. Factors regarding choosing an agent and dosing levels are similar to those for psychotic symptoms.

Psychotic symptoms. Most studies of typical and atypical antipsychotics for HD psychosis have shown beneficial effects.^14,16-21 Neurologists frequently use these agents for managing chorea. Both neurologic and psychiatric features of the patient’s presentation must be considered when selecting a drug because treatment directed at 1 component of the disease may inadvertently exacerbate another. Specifically, higher potency antipsychotics (eg, haloperidol) are effective for chorea but can dramatically worsen bradykinesia; lower potency agents (eg, quetiapine) are less helpful for chorea but do not significantly worsen rigidity symptoms.

Olanzapine has been shown to improve chorea, anxiety, irritability, depression, sleep dysfunction, and weight loss in addition to psychotic symptoms.^14,17 We find that olanzapine treats a constellation of symptoms common among HD patients, and we prescribe it frequently. Because olanzapine is considered a mid-potency agent, we find it’s best suited for concurrent control of psychotic symptoms and mild to moderate chorea in patients with minimal bradykinesia. Start olanzapine at 2.5 mg/d and gradually increase to 5 to 10 mg/d as tolerated.¹⁴

Risperidone is effective for treating psychosis and chorea. It can be started at 0.5 to 1 mg/d, and gradually increased to 6 to 8 mg/d.¹⁴ The depot formulation of risperidone has been shown to be effective in HD, which may help patients adhere to their medication.¹⁸ Risperidone is a mid-high potency antipsychotic, and in our experience is best used to control psychotic symptoms in patients with moderate chorea and few or no symptoms of bradykinesia or rigidity.

Quetiapine reduces psychotic symptoms, agitation, irritability, and insomnia without worsening bradykinesia or rigidity,¹⁹ but it is not beneficial for chorea. It can be started at 12.5 mg/d and gradually increased for effect as tolerated, up to 600 mg/d (depending on indication), in 2 or 3 divided doses.¹⁴

Haloperidol is a high-potency typical antipsychotic and may help psychotic patients with severe chorea; it should not be used in patients with bradykinesia. Start haloperidol at 0.5 to 1 mg/d and gradually increase to 6 to 8 mg/d as tolerated.¹⁴ Because of higher likelihood of side effects with typical antipsychotics, we often reserve its use for patients whose psychosis does not respond to atypical agents.

Other antipsychotics. Aripiprazole in HD has been examined in only 2 single- patient case reports^20,21; the drug appeared to reduce psychosis and possibly chorea. Clozapine’s effectiveness for HD psychosis is not well known. It does not appear to be helpful for chorea and can cause agranulocytosis.²²

Because one of the hallmarks of HD is dementia, it is worth noting that the FDA has issued a “black-box” warning on the use of antipsychotic drugs in patients with dementia because of concerns regarding increased mortality. However, drawing specific conclusions is difficult because the FDA warning is based on studies that looked primarily at Alzheimer’s disease and vascular dementia, not HD.

Other pharmacotherapies

Tetrabenazine is the only FDA-approved drug for treating HD. However, it carries a “black-box” warning for increased risk of depression and suicidal ideation and is contraindicated in suicidal patients and those with untreated or inadequately treated depression.

Although several small trials have had conflicting results regarding its benefit, amantadine sometimes is used to treat chorea.^23-25 For more information about tetrabenazine and amantadine, see Box 3.

Box 3

Related Resources

• Huntington’s Disease Society of America. www.hdsa.org.
• Family Caregiver Alliance. Huntington’s disease. www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=574.
• Huntington Study Group. www.huntington-study-group.org.
• Huntington’s Disease Advocacy Center. www.hdac.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Wellbutrin XL, others
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Methylphenidate • Concerta, Ritalin, others
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tetrabenazine • Xenazine
• Venlafaxine XR • Effexor XR

Disclosures

Dr. Scher is a consultant to the advisory board for Lundbeck.

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatric symptoms are a common and debilitating manifestation of Huntington’s disease (HD), a progressive, inherited neurodegenerative disorder also characterized by chorea (involuntary, nonrepetitive movements) and cognitive decline. The prevalence of HD is 4 to 8 patients per 100,000 persons in most populations of European descent, with lower prevalence among non-Europeans.¹ HD is caused by an abnormal expansion of a trinucleotide (CAG) repeat sequence on chromosome 4, and is inherited in an autosomal dominant fashion, meaning a HD patient’s child has a 50% chance of inheriting the mutation. The expansion is located in the gene that encodes the “huntingtin” protein, the normal function of which is not well understood.

There’s no cure for HD, and treatments primarily are directed at symptom control. Psychiatric symptoms include depression, apathy, anxiety, and psychosis (Table).^2-4 Treating patients with HD can be challenging because most psychiatrists will see only a handful of patients with this multifaceted illness during their careers. See Box 1 for a case study of a patient with HD.

Table

Psychiatric symptoms of HD

Box 1

Psychiatric sequelae

In general, psychiatric symptoms of HD become increasingly prevalent over time (Box 2).^3,5 In a 2001 study of 52 HD patients by Paulsen et al,² 51 patients had ≥1 psychiatric symptom, such as dysphoria (69.2%), agitation (67.3%), irritability (65.4%), apathy (55.8%), and anxiety (51.9%); delusions (11.5%) and hallucinations (1.9%) were less prevalent.² Similarly, Thompson et al³ followed 111 HD patients for ≥3 years and all experienced psychiatric symptoms.

Box 2

Depressed mood and functional ability—not cognitive or motor symptoms⁶—are the 2 most critical factors linked to health-related quality of life in HD. Hamilton et al⁷ found that apathy or executive dysfunction in HD patients is strongly related to decline in ability to complete activities of daily living, and may be severely debilitating.

Apathy. Often mistaken for a symptom of depression, apathy’s presentation may resemble anhedonia or fatigue; however, research suggests that depression and apathy are distinct conditions. Naarding et al

Depression affects most HD patients, and often is most severe early in the disease course. Hubers et al⁸ found that 20% of 100 HD patients had suicidal ideation. The strongest predictor was depressed mood.

Sleep disturbances and daytime somnolence are common among HD patients, and patients with comorbid depression report more disturbed sleep. Managing disturbed sleep and daytime somnolence in HD, with emphasis on comorbid depression, may improve the quality of life of patients and their caregivers.⁹

Anxiety was present in >50% of HD patients in a study by Paulsen et al² and 37% evaluated by Craufurd et al.¹⁰ Craufurd et al¹⁰ also reported that 61% of patients were “physically tense and unable to relax.”

Among HD patients, 5% report obsessions and 10% report compulsive behaviors; these symptoms appear to become increasingly common as HD progresses.^4,10

Impulsivity and disinhibition. Craufurd et al¹⁰ found that 71% of HD patients experienced poor judgment and self-monitoring, 40% had poor temper control and verbal outbursts, 22% exhibited threatening behavior or violence, and 6% had disinhibited or inappropriate sexual behavior.¹⁰

Recent studies have shown higher rates of disinhibition in “presymptomatic” gene-positive subjects vs gene-negative controls, suggesting that these symptoms may arise early in HD.¹¹ Further, researchers demonstrated that patients lack symptom awareness and rate themselves as less impaired than their caregivers do.¹¹

In our clinical experience, impulsivity frequently is encountered and creates significant conflict between patients and their caregivers. We speculate that when coupled with depressive symptoms of HD, impulsivity and disinhibition may play an important role in the high rates of suicidality seen in these patients.

Psychosis. Delusions and hallucinations are less common in HD than other psychiatric symptoms. Craufurd et al¹⁰ reported 3% of HD patients had delusions, 3% had auditory hallucinations, 2% had tactile hallucinations, and no patients had visual hallucinations.

A few case reports and a small study by Tsuang et al¹² suggested that psychotic features in HD may be similar to those seen in paranoid schizophrenia. Tsuang et al¹² also noted that more severe HD-related psychosis tends to cluster in families, which suggests that susceptibility to HD psychosis may be heritable.

Treating psychiatric symptoms

High-quality randomized controlled trials of pharmacotherapies for psychiatric symptoms in HD patients are lacking. Decisions regarding which agents to use often are based on case reports or clinical experience. The suggestions below are based on available evidence and our clinical experience.

Depression. Depressive symptoms in HD seem to respond to conventional pharmacologic treatments for major depressive disorder (MDD). A small trial of venlafaxine extended-release (XR) in 26 HD patients with MDD showed statistically significant improvements in depressive symptoms; however, this trial was not blinded and did not have a placebo group.¹³ In addition, 1 in 5 patients developed significant side effects—nausea, irritability, or worsening chorea.¹³

Evidence for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants (TCAs) is lacking. Antidepressant choice should be based on patient response, side effect profile, and the need for secondary therapeutic effects.¹⁴

We often prescribe sertraline, citalopram, or escitalopram for our HD patients because of the relative absence of drug-drug interactions and favorable safety profile in medically and surgically ill patients. However, it’s important to tailor the treatment approach to your patient’s needs—eg, patients prone to forgetting their medicine may benefit from a drug with a longer half-life, such as fluoxetine. We avoid TCAs because of their anticholinergic effects, which may worsen dementia symptoms. Because HD patients have high rates of suicidality, agents that are highly toxic when taken in overdose should be used with caution.

One small study of HD patients with MDD or bipolar disorder showed clinical improvement in depressive symptoms after electroconvulsive therapy (ECT).¹⁵ Patients who suffered from comorbid delusions had the best improvements in mood.¹⁵ ECT likely is a good choice for HD patients who have failed several antidepressants, are suicidal, or who have depression with psychotic features.¹⁶

Apathy. A 2011 review concluded that no evidence-based recommendations regarding pharmacologic treatment for apathy in HD can be made because of lack of research.⁷ The Huntington’s Disease Society of America’s (HDSA) A Physician’s Guide to Managing Huntington’s Disease includes recommendations for treating apathy based on clinical experience.¹⁶ It suggests a nonsedating SSRI, followed by a trial of methylphenidate, pemoline, or dextroamphetamine if SSRIs were unsuccessful.

Anxiety. A small, open-label study of 11 patients found that olanzapine, 5 mg/d, significantly improved depression, anxiety, irritability, and obsessive behavior in HD patients.¹⁷

The HDSA guide suggests treating anxiety and obsessive-compulsive symptoms as you would in patients without HD. For anxiety, SSRIs and possibly a short-term trial of a low-dose benzodiazepine (ie, lorazepam, clonazepam) are suggested.¹⁶ Benzodiazepines may increase the risk of falls and delirium in this population. Anecdotally, buspirone is helpful in some patients, with a starting dose of 5 mg 2 to 3 times per day and increased to 20 to 30 mg/d in divided doses.¹⁶ For obsessive-compulsive symptoms, SSRIs are recommended; atypical antipsychotics are reserved for severe or refractory symptoms.¹⁶

Disinhibition and impulsivity. There’s no research on treating disinhibition and impulsivity in HD. In our clinical experience, atypical antipsychotics are the most helpful. Factors regarding choosing an agent and dosing levels are similar to those for psychotic symptoms.

Psychotic symptoms. Most studies of typical and atypical antipsychotics for HD psychosis have shown beneficial effects.^14,16-21 Neurologists frequently use these agents for managing chorea. Both neurologic and psychiatric features of the patient’s presentation must be considered when selecting a drug because treatment directed at 1 component of the disease may inadvertently exacerbate another. Specifically, higher potency antipsychotics (eg, haloperidol) are effective for chorea but can dramatically worsen bradykinesia; lower potency agents (eg, quetiapine) are less helpful for chorea but do not significantly worsen rigidity symptoms.

Olanzapine has been shown to improve chorea, anxiety, irritability, depression, sleep dysfunction, and weight loss in addition to psychotic symptoms.^14,17 We find that olanzapine treats a constellation of symptoms common among HD patients, and we prescribe it frequently. Because olanzapine is considered a mid-potency agent, we find it’s best suited for concurrent control of psychotic symptoms and mild to moderate chorea in patients with minimal bradykinesia. Start olanzapine at 2.5 mg/d and gradually increase to 5 to 10 mg/d as tolerated.¹⁴

Risperidone is effective for treating psychosis and chorea. It can be started at 0.5 to 1 mg/d, and gradually increased to 6 to 8 mg/d.¹⁴ The depot formulation of risperidone has been shown to be effective in HD, which may help patients adhere to their medication.¹⁸ Risperidone is a mid-high potency antipsychotic, and in our experience is best used to control psychotic symptoms in patients with moderate chorea and few or no symptoms of bradykinesia or rigidity.

Quetiapine reduces psychotic symptoms, agitation, irritability, and insomnia without worsening bradykinesia or rigidity,¹⁹ but it is not beneficial for chorea. It can be started at 12.5 mg/d and gradually increased for effect as tolerated, up to 600 mg/d (depending on indication), in 2 or 3 divided doses.¹⁴

Haloperidol is a high-potency typical antipsychotic and may help psychotic patients with severe chorea; it should not be used in patients with bradykinesia. Start haloperidol at 0.5 to 1 mg/d and gradually increase to 6 to 8 mg/d as tolerated.¹⁴ Because of higher likelihood of side effects with typical antipsychotics, we often reserve its use for patients whose psychosis does not respond to atypical agents.

Other antipsychotics. Aripiprazole in HD has been examined in only 2 single- patient case reports^20,21; the drug appeared to reduce psychosis and possibly chorea. Clozapine’s effectiveness for HD psychosis is not well known. It does not appear to be helpful for chorea and can cause agranulocytosis.²²

Because one of the hallmarks of HD is dementia, it is worth noting that the FDA has issued a “black-box” warning on the use of antipsychotic drugs in patients with dementia because of concerns regarding increased mortality. However, drawing specific conclusions is difficult because the FDA warning is based on studies that looked primarily at Alzheimer’s disease and vascular dementia, not HD.

Other pharmacotherapies

Tetrabenazine is the only FDA-approved drug for treating HD. However, it carries a “black-box” warning for increased risk of depression and suicidal ideation and is contraindicated in suicidal patients and those with untreated or inadequately treated depression.

Although several small trials have had conflicting results regarding its benefit, amantadine sometimes is used to treat chorea.^23-25 For more information about tetrabenazine and amantadine, see Box 3.

Box 3

Related Resources

• Huntington’s Disease Society of America. www.hdsa.org.
• Family Caregiver Alliance. Huntington’s disease. www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=574.
• Huntington Study Group. www.huntington-study-group.org.
• Huntington’s Disease Advocacy Center. www.hdac.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Wellbutrin XL, others
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Methylphenidate • Concerta, Ritalin, others
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tetrabenazine • Xenazine
• Venlafaxine XR • Effexor XR

Disclosures

Dr. Scher is a consultant to the advisory board for Lundbeck.

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Psychiatric symptoms are a common and debilitating manifestation of Huntington’s disease (HD), a progressive, inherited neurodegenerative disorder also characterized by chorea (involuntary, nonrepetitive movements) and cognitive decline. The prevalence of HD is 4 to 8 patients per 100,000 persons in most populations of European descent, with lower prevalence among non-Europeans.¹ HD is caused by an abnormal expansion of a trinucleotide (CAG) repeat sequence on chromosome 4, and is inherited in an autosomal dominant fashion, meaning a HD patient’s child has a 50% chance of inheriting the mutation. The expansion is located in the gene that encodes the “huntingtin” protein, the normal function of which is not well understood.

There’s no cure for HD, and treatments primarily are directed at symptom control. Psychiatric symptoms include depression, apathy, anxiety, and psychosis (Table).^2-4 Treating patients with HD can be challenging because most psychiatrists will see only a handful of patients with this multifaceted illness during their careers. See Box 1 for a case study of a patient with HD.

Table

Psychiatric symptoms of HD

Box 1

Psychiatric sequelae

In general, psychiatric symptoms of HD become increasingly prevalent over time (Box 2).^3,5 In a 2001 study of 52 HD patients by Paulsen et al,² 51 patients had ≥1 psychiatric symptom, such as dysphoria (69.2%), agitation (67.3%), irritability (65.4%), apathy (55.8%), and anxiety (51.9%); delusions (11.5%) and hallucinations (1.9%) were less prevalent.² Similarly, Thompson et al³ followed 111 HD patients for ≥3 years and all experienced psychiatric symptoms.

Box 2

Depressed mood and functional ability—not cognitive or motor symptoms⁶—are the 2 most critical factors linked to health-related quality of life in HD. Hamilton et al⁷ found that apathy or executive dysfunction in HD patients is strongly related to decline in ability to complete activities of daily living, and may be severely debilitating.

Apathy. Often mistaken for a symptom of depression, apathy’s presentation may resemble anhedonia or fatigue; however, research suggests that depression and apathy are distinct conditions. Naarding et al

Depression affects most HD patients, and often is most severe early in the disease course. Hubers et al⁸ found that 20% of 100 HD patients had suicidal ideation. The strongest predictor was depressed mood.

Sleep disturbances and daytime somnolence are common among HD patients, and patients with comorbid depression report more disturbed sleep. Managing disturbed sleep and daytime somnolence in HD, with emphasis on comorbid depression, may improve the quality of life of patients and their caregivers.⁹

Anxiety was present in >50% of HD patients in a study by Paulsen et al² and 37% evaluated by Craufurd et al.¹⁰ Craufurd et al¹⁰ also reported that 61% of patients were “physically tense and unable to relax.”

Among HD patients, 5% report obsessions and 10% report compulsive behaviors; these symptoms appear to become increasingly common as HD progresses.^4,10

Impulsivity and disinhibition. Craufurd et al¹⁰ found that 71% of HD patients experienced poor judgment and self-monitoring, 40% had poor temper control and verbal outbursts, 22% exhibited threatening behavior or violence, and 6% had disinhibited or inappropriate sexual behavior.¹⁰

Recent studies have shown higher rates of disinhibition in “presymptomatic” gene-positive subjects vs gene-negative controls, suggesting that these symptoms may arise early in HD.¹¹ Further, researchers demonstrated that patients lack symptom awareness and rate themselves as less impaired than their caregivers do.¹¹

In our clinical experience, impulsivity frequently is encountered and creates significant conflict between patients and their caregivers. We speculate that when coupled with depressive symptoms of HD, impulsivity and disinhibition may play an important role in the high rates of suicidality seen in these patients.

Psychosis. Delusions and hallucinations are less common in HD than other psychiatric symptoms. Craufurd et al¹⁰ reported 3% of HD patients had delusions, 3% had auditory hallucinations, 2% had tactile hallucinations, and no patients had visual hallucinations.

A few case reports and a small study by Tsuang et al¹² suggested that psychotic features in HD may be similar to those seen in paranoid schizophrenia. Tsuang et al¹² also noted that more severe HD-related psychosis tends to cluster in families, which suggests that susceptibility to HD psychosis may be heritable.

Treating psychiatric symptoms

High-quality randomized controlled trials of pharmacotherapies for psychiatric symptoms in HD patients are lacking. Decisions regarding which agents to use often are based on case reports or clinical experience. The suggestions below are based on available evidence and our clinical experience.

Depression. Depressive symptoms in HD seem to respond to conventional pharmacologic treatments for major depressive disorder (MDD). A small trial of venlafaxine extended-release (XR) in 26 HD patients with MDD showed statistically significant improvements in depressive symptoms; however, this trial was not blinded and did not have a placebo group.¹³ In addition, 1 in 5 patients developed significant side effects—nausea, irritability, or worsening chorea.¹³

Evidence for selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors, and tricyclic antidepressants (TCAs) is lacking. Antidepressant choice should be based on patient response, side effect profile, and the need for secondary therapeutic effects.¹⁴

We often prescribe sertraline, citalopram, or escitalopram for our HD patients because of the relative absence of drug-drug interactions and favorable safety profile in medically and surgically ill patients. However, it’s important to tailor the treatment approach to your patient’s needs—eg, patients prone to forgetting their medicine may benefit from a drug with a longer half-life, such as fluoxetine. We avoid TCAs because of their anticholinergic effects, which may worsen dementia symptoms. Because HD patients have high rates of suicidality, agents that are highly toxic when taken in overdose should be used with caution.

One small study of HD patients with MDD or bipolar disorder showed clinical improvement in depressive symptoms after electroconvulsive therapy (ECT).¹⁵ Patients who suffered from comorbid delusions had the best improvements in mood.¹⁵ ECT likely is a good choice for HD patients who have failed several antidepressants, are suicidal, or who have depression with psychotic features.¹⁶

Apathy. A 2011 review concluded that no evidence-based recommendations regarding pharmacologic treatment for apathy in HD can be made because of lack of research.⁷ The Huntington’s Disease Society of America’s (HDSA) A Physician’s Guide to Managing Huntington’s Disease includes recommendations for treating apathy based on clinical experience.¹⁶ It suggests a nonsedating SSRI, followed by a trial of methylphenidate, pemoline, or dextroamphetamine if SSRIs were unsuccessful.

Anxiety. A small, open-label study of 11 patients found that olanzapine, 5 mg/d, significantly improved depression, anxiety, irritability, and obsessive behavior in HD patients.¹⁷

The HDSA guide suggests treating anxiety and obsessive-compulsive symptoms as you would in patients without HD. For anxiety, SSRIs and possibly a short-term trial of a low-dose benzodiazepine (ie, lorazepam, clonazepam) are suggested.¹⁶ Benzodiazepines may increase the risk of falls and delirium in this population. Anecdotally, buspirone is helpful in some patients, with a starting dose of 5 mg 2 to 3 times per day and increased to 20 to 30 mg/d in divided doses.¹⁶ For obsessive-compulsive symptoms, SSRIs are recommended; atypical antipsychotics are reserved for severe or refractory symptoms.¹⁶

Disinhibition and impulsivity. There’s no research on treating disinhibition and impulsivity in HD. In our clinical experience, atypical antipsychotics are the most helpful. Factors regarding choosing an agent and dosing levels are similar to those for psychotic symptoms.

Psychotic symptoms. Most studies of typical and atypical antipsychotics for HD psychosis have shown beneficial effects.^14,16-21 Neurologists frequently use these agents for managing chorea. Both neurologic and psychiatric features of the patient’s presentation must be considered when selecting a drug because treatment directed at 1 component of the disease may inadvertently exacerbate another. Specifically, higher potency antipsychotics (eg, haloperidol) are effective for chorea but can dramatically worsen bradykinesia; lower potency agents (eg, quetiapine) are less helpful for chorea but do not significantly worsen rigidity symptoms.

Olanzapine has been shown to improve chorea, anxiety, irritability, depression, sleep dysfunction, and weight loss in addition to psychotic symptoms.^14,17 We find that olanzapine treats a constellation of symptoms common among HD patients, and we prescribe it frequently. Because olanzapine is considered a mid-potency agent, we find it’s best suited for concurrent control of psychotic symptoms and mild to moderate chorea in patients with minimal bradykinesia. Start olanzapine at 2.5 mg/d and gradually increase to 5 to 10 mg/d as tolerated.¹⁴

Risperidone is effective for treating psychosis and chorea. It can be started at 0.5 to 1 mg/d, and gradually increased to 6 to 8 mg/d.¹⁴ The depot formulation of risperidone has been shown to be effective in HD, which may help patients adhere to their medication.¹⁸ Risperidone is a mid-high potency antipsychotic, and in our experience is best used to control psychotic symptoms in patients with moderate chorea and few or no symptoms of bradykinesia or rigidity.

Quetiapine reduces psychotic symptoms, agitation, irritability, and insomnia without worsening bradykinesia or rigidity,¹⁹ but it is not beneficial for chorea. It can be started at 12.5 mg/d and gradually increased for effect as tolerated, up to 600 mg/d (depending on indication), in 2 or 3 divided doses.¹⁴

Haloperidol is a high-potency typical antipsychotic and may help psychotic patients with severe chorea; it should not be used in patients with bradykinesia. Start haloperidol at 0.5 to 1 mg/d and gradually increase to 6 to 8 mg/d as tolerated.¹⁴ Because of higher likelihood of side effects with typical antipsychotics, we often reserve its use for patients whose psychosis does not respond to atypical agents.

Other antipsychotics. Aripiprazole in HD has been examined in only 2 single- patient case reports^20,21; the drug appeared to reduce psychosis and possibly chorea. Clozapine’s effectiveness for HD psychosis is not well known. It does not appear to be helpful for chorea and can cause agranulocytosis.²²

Because one of the hallmarks of HD is dementia, it is worth noting that the FDA has issued a “black-box” warning on the use of antipsychotic drugs in patients with dementia because of concerns regarding increased mortality. However, drawing specific conclusions is difficult because the FDA warning is based on studies that looked primarily at Alzheimer’s disease and vascular dementia, not HD.

Other pharmacotherapies

Tetrabenazine is the only FDA-approved drug for treating HD. However, it carries a “black-box” warning for increased risk of depression and suicidal ideation and is contraindicated in suicidal patients and those with untreated or inadequately treated depression.

Although several small trials have had conflicting results regarding its benefit, amantadine sometimes is used to treat chorea.^23-25 For more information about tetrabenazine and amantadine, see Box 3.

Box 3

Related Resources

• Huntington’s Disease Society of America. www.hdsa.org.
• Family Caregiver Alliance. Huntington’s disease. www.caregiver.org/caregiver/jsp/content_node.jsp?nodeid=574.
• Huntington Study Group. www.huntington-study-group.org.
• Huntington’s Disease Advocacy Center. www.hdac.org.

Drug Brand Names

• Amantadine • Symmetrel
• Aripiprazole • Abilify
• Bupropion • Wellbutrin, Wellbutrin XL, others
• Buspirone • BuSpar
• Citalopram • Celexa
• Clonazepam • Klonopin
• Clozapine • Clozaril
• Dextroamphetamine • Dexedrine
• Escitalopram • Lexapro
• Fluoxetine • Prozac
• Haloperidol • Haldol
• Lorazepam • Ativan
• Methylphenidate • Concerta, Ritalin, others
• Mirtazapine • Remeron
• Olanzapine • Zyprexa
• Pemoline • Cylert
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Sertraline • Zoloft
• Tetrabenazine • Xenazine
• Venlafaxine XR • Effexor XR

Disclosures

Dr. Scher is a consultant to the advisory board for Lundbeck.

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
My patient stopped antipsychotic medication, experienced a recurrence of paranoid schizophrenia, and now is involuntarily hospitalized. During her admission assessment, she said she had a “psychiatric advance directive.” I obtained the document, which says she refuses psychopharmacologic treatment under any circumstances. Without medication, she might take years to recover. How should I proceed?
Submitted by “Dr. Y”

Most psychiatrists who regularly practice hospital-based care know their state’s legal procedures for forcing psychotic, civilly committed patients to take medication to relieve their acute symptoms. In most jurisdictions, courts will order medication over a patient’s objection after finding that the patient lacks competence to refuse antipsychotic therapy and that the proposed treatment is in the patient’s best interest.¹

But if a patient has a psychiatric advance directive (PAD) that opposes psychotropic medication, things may become complicated. To decide what to do if a patient’s PAD precludes administering a treatment you think is necessary, you should understand:

• what PADs do
• what courts have said about PADs
• what your state’s laws say about PADs
• where and when to seek legal advice.

What are advance directives?

An advance directive (or “declaration”) for health care (ADHC) is a legal document executed by a competent individual that states preferences regarding medical treatment should that individual become incapable of making or expressing decisions.^2-4 An ADHC may be a “living will” that lays out instructions for specific health care situations or a “durable power of attorney” (DPOA) that designates a proxy decision maker, or it may include elements of both. In 1990, the U.S. Congress passed the Patient Self-Determination Act,⁵ which required health care institutions that receive Medicare or Medicaid to ask patients whether they have ADHCs and to give patients information about state laws governing ADHCs.

Modeled after medical advance directives, PADs let competent individuals declare their wishes should they need psychiatric treatment during a period of decision-making incapacity.^3,4 At least 25 states have advance directive statutes specific to psychiatry.⁶ Depending on the state, PADs may allow individuals to assert their preferences regarding psychotropic medication, electroconvulsive therapy (ECT), alternatives to hospitalization, location and length of voluntary hospitalization, the treating psychiatrist, seclusion and restraint, emergency medications, and visitors.

Prevalence and praise

The prevalence of PADs is unknown. A 2006 survey of 1,011 psychiatric outpatients in California, Florida, Illinois, Massachusetts, and North Carolina by Swanson et al⁷ found only 4% to 13% of patients previously executed a PAD. However, most participants said that if given the opportunity and assistance, they would create a PAD.⁷

Psychiatric advocacy groups have lauded the development of PADs. For example, the National Alliance on Mental Illness’ position is that “PADs should be considered as a way to empower consumers to take a more active role in their treatment, and as a way to avoid conflicts over treatment and medication issues.”⁸ Proponents suggest that PADs:

• promote autonomy
• foster communication between patients and treatment providers
• increase compliance with medication
• reduce involuntary treatment and judicial involvement.^4,8

Mental Health America launched My Plan, My Life: My Psychiatric Advance Directive in September 2011 to increase public awareness of the availability of PADs.⁹ Therefore, it is safe to assume that most psychiatrists will encounter patients with PADs.

What if a PAD blocks treatment?

What happens when an adult such as Dr. Y’s patient has a PAD that precludes effective treatment? A similar situation led to Hargrave v Vermont.¹⁰

Nancy Hargrave, a Vermont woman with schizophrenia and a history of psychiatric hospitalizations, executed a DPOA—Vermont does not have a separate statute for PADs—in which she explicitly refused “any and all anti-psychotic, neuroleptic, psychotropic, or psychoactive medications,” and ECT.¹⁰

In anticipation of situations like this, Vermont’s legislature passed Act 114, a 1998 state law that required caregivers to abide by the DPOAs of civilly committed individuals and mentally ill prisoners for 45 days.¹⁰ After this time, a court may override the advance directive and allow involuntary medication administration if a patient “ha[d] not experienced a significant clinical improvement in his or her mental state, and remain[ed] incompetent.”¹⁰

In 1999, Hargrave sued the state of Vermont and other parties in federal court, alleging that Act 114 constituted discrimination under Title II of the Americans with Disabilities Act¹¹ because Act 114 excluded her from participating in the “services, programs, or activities of a public entity,” namely, the use of her DPOA under Vermont state law.¹⁰ The federal district court sided with Hargrave, concluding that “Act 114 was facially discriminatory against mentally disabled individuals.” One year later, the U.S. Court of Appeals for the Second Circuit affirmed the district court’s ruling.

Surprisingly, no other court has adjudicated this issue. However, in Second Circuit states—Vermont, New York, and Connecticut—DPOAs of mentally ill patients cannot be abrogated. This is an unsettling notion for many psychiatrists, because, as Paul Appelbaum, MD, explains, “Advance directives may now constitute an ironclad bulwark against future involuntary treatment with medication—except in emergencies—even for incompetent, committed patients and even when the alternative is long-term institutional care.”¹² Other scholars have pointed out that giving physicians an avenue to override or disregard patients’ directives would negate their intended purpose, which is to have one’s competently expressed wishes followed when one’s decision-making capacity is compromised.^6,13

Doctors’ duties

How you should respond to an involuntary patient’s PAD depends on which state you practice in. A physician’s obligation to comply with a patient’s PAD depends on state law, and most states with PAD laws provide some latitude or options if physicians believe they should not comply with a patient’s wishes.^6,13Table 1^14-18 cites examples of statutory language regarding a physician’s duty to comply with a PAD.

A survey of 164 psychiatrists in North Carolina provides some insight into psychiatrists’ perceptions of PADs.¹⁹ After reading a hypothetical scenario about a mentally ill individual whose PAD expressed refusal of hospitalization or treatment with antipsychotics, 47% of the psychiatrists chose to override the PAD. The authors found that “PAD override was more likely among psychiatrists who worked in hospital emergency departments; those who were concerned about patients’ violence risk and lack of insight; and those who were legally defensive.”

In addition to addressing conflicts between patients’ PADs and doctors’ views about proper treatment, some state laws also contain clauses that spell out the limits of physician liability in cases of physician compliance or noncompliance with PADs. Excerpts from 2 such laws appear in Table 2.^16-17

Table 1

Examples of state laws on compliance with psychiatric advance directives

Table 2

Excerpts from state laws on PAD-related liability

Related Resources

• National Resource Center on Psychiatric Advance Directives. www.nrc-pad.org.
• Duke University Program on Psychiatric Advance Directives. http://pad.duhs.duke.edu.
• Hung EK, McNiel DE, Binder RL. Covert medication in psychiatric emergencies: is it ever ethically permissible? J Am Acad Psychiatry Law. 2012;40(2):239-245.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
My patient stopped antipsychotic medication, experienced a recurrence of paranoid schizophrenia, and now is involuntarily hospitalized. During her admission assessment, she said she had a “psychiatric advance directive.” I obtained the document, which says she refuses psychopharmacologic treatment under any circumstances. Without medication, she might take years to recover. How should I proceed?
Submitted by “Dr. Y”

Most psychiatrists who regularly practice hospital-based care know their state’s legal procedures for forcing psychotic, civilly committed patients to take medication to relieve their acute symptoms. In most jurisdictions, courts will order medication over a patient’s objection after finding that the patient lacks competence to refuse antipsychotic therapy and that the proposed treatment is in the patient’s best interest.¹

But if a patient has a psychiatric advance directive (PAD) that opposes psychotropic medication, things may become complicated. To decide what to do if a patient’s PAD precludes administering a treatment you think is necessary, you should understand:

• what PADs do
• what courts have said about PADs
• what your state’s laws say about PADs
• where and when to seek legal advice.

What are advance directives?

An advance directive (or “declaration”) for health care (ADHC) is a legal document executed by a competent individual that states preferences regarding medical treatment should that individual become incapable of making or expressing decisions.^2-4 An ADHC may be a “living will” that lays out instructions for specific health care situations or a “durable power of attorney” (DPOA) that designates a proxy decision maker, or it may include elements of both. In 1990, the U.S. Congress passed the Patient Self-Determination Act,⁵ which required health care institutions that receive Medicare or Medicaid to ask patients whether they have ADHCs and to give patients information about state laws governing ADHCs.

Modeled after medical advance directives, PADs let competent individuals declare their wishes should they need psychiatric treatment during a period of decision-making incapacity.^3,4 At least 25 states have advance directive statutes specific to psychiatry.⁶ Depending on the state, PADs may allow individuals to assert their preferences regarding psychotropic medication, electroconvulsive therapy (ECT), alternatives to hospitalization, location and length of voluntary hospitalization, the treating psychiatrist, seclusion and restraint, emergency medications, and visitors.

Prevalence and praise

The prevalence of PADs is unknown. A 2006 survey of 1,011 psychiatric outpatients in California, Florida, Illinois, Massachusetts, and North Carolina by Swanson et al⁷ found only 4% to 13% of patients previously executed a PAD. However, most participants said that if given the opportunity and assistance, they would create a PAD.⁷

Psychiatric advocacy groups have lauded the development of PADs. For example, the National Alliance on Mental Illness’ position is that “PADs should be considered as a way to empower consumers to take a more active role in their treatment, and as a way to avoid conflicts over treatment and medication issues.”⁸ Proponents suggest that PADs:

• promote autonomy
• foster communication between patients and treatment providers
• increase compliance with medication
• reduce involuntary treatment and judicial involvement.^4,8

Mental Health America launched My Plan, My Life: My Psychiatric Advance Directive in September 2011 to increase public awareness of the availability of PADs.⁹ Therefore, it is safe to assume that most psychiatrists will encounter patients with PADs.

What if a PAD blocks treatment?

What happens when an adult such as Dr. Y’s patient has a PAD that precludes effective treatment? A similar situation led to Hargrave v Vermont.¹⁰

Nancy Hargrave, a Vermont woman with schizophrenia and a history of psychiatric hospitalizations, executed a DPOA—Vermont does not have a separate statute for PADs—in which she explicitly refused “any and all anti-psychotic, neuroleptic, psychotropic, or psychoactive medications,” and ECT.¹⁰

In anticipation of situations like this, Vermont’s legislature passed Act 114, a 1998 state law that required caregivers to abide by the DPOAs of civilly committed individuals and mentally ill prisoners for 45 days.¹⁰ After this time, a court may override the advance directive and allow involuntary medication administration if a patient “ha[d] not experienced a significant clinical improvement in his or her mental state, and remain[ed] incompetent.”¹⁰

In 1999, Hargrave sued the state of Vermont and other parties in federal court, alleging that Act 114 constituted discrimination under Title II of the Americans with Disabilities Act¹¹ because Act 114 excluded her from participating in the “services, programs, or activities of a public entity,” namely, the use of her DPOA under Vermont state law.¹⁰ The federal district court sided with Hargrave, concluding that “Act 114 was facially discriminatory against mentally disabled individuals.” One year later, the U.S. Court of Appeals for the Second Circuit affirmed the district court’s ruling.

Surprisingly, no other court has adjudicated this issue. However, in Second Circuit states—Vermont, New York, and Connecticut—DPOAs of mentally ill patients cannot be abrogated. This is an unsettling notion for many psychiatrists, because, as Paul Appelbaum, MD, explains, “Advance directives may now constitute an ironclad bulwark against future involuntary treatment with medication—except in emergencies—even for incompetent, committed patients and even when the alternative is long-term institutional care.”¹² Other scholars have pointed out that giving physicians an avenue to override or disregard patients’ directives would negate their intended purpose, which is to have one’s competently expressed wishes followed when one’s decision-making capacity is compromised.^6,13

Doctors’ duties

How you should respond to an involuntary patient’s PAD depends on which state you practice in. A physician’s obligation to comply with a patient’s PAD depends on state law, and most states with PAD laws provide some latitude or options if physicians believe they should not comply with a patient’s wishes.^6,13Table 1^14-18 cites examples of statutory language regarding a physician’s duty to comply with a PAD.

A survey of 164 psychiatrists in North Carolina provides some insight into psychiatrists’ perceptions of PADs.¹⁹ After reading a hypothetical scenario about a mentally ill individual whose PAD expressed refusal of hospitalization or treatment with antipsychotics, 47% of the psychiatrists chose to override the PAD. The authors found that “PAD override was more likely among psychiatrists who worked in hospital emergency departments; those who were concerned about patients’ violence risk and lack of insight; and those who were legally defensive.”

In addition to addressing conflicts between patients’ PADs and doctors’ views about proper treatment, some state laws also contain clauses that spell out the limits of physician liability in cases of physician compliance or noncompliance with PADs. Excerpts from 2 such laws appear in Table 2.^16-17

Table 1

Examples of state laws on compliance with psychiatric advance directives

Table 2

Excerpts from state laws on PAD-related liability

Related Resources

• National Resource Center on Psychiatric Advance Directives. www.nrc-pad.org.
• Duke University Program on Psychiatric Advance Directives. http://pad.duhs.duke.edu.
• Hung EK, McNiel DE, Binder RL. Covert medication in psychiatric emergencies: is it ever ethically permissible? J Am Acad Psychiatry Law. 2012;40(2):239-245.

Disclosure

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

Discuss this article at www.facebook.com/CurrentPsychiatry

Dear Dr. Mossman:
My patient stopped antipsychotic medication, experienced a recurrence of paranoid schizophrenia, and now is involuntarily hospitalized. During her admission assessment, she said she had a “psychiatric advance directive.” I obtained the document, which says she refuses psychopharmacologic treatment under any circumstances. Without medication, she might take years to recover. How should I proceed?
Submitted by “Dr. Y”

Most psychiatrists who regularly practice hospital-based care know their state’s legal procedures for forcing psychotic, civilly committed patients to take medication to relieve their acute symptoms. In most jurisdictions, courts will order medication over a patient’s objection after finding that the patient lacks competence to refuse antipsychotic therapy and that the proposed treatment is in the patient’s best interest.¹

But if a patient has a psychiatric advance directive (PAD) that opposes psychotropic medication, things may become complicated. To decide what to do if a patient’s PAD precludes administering a treatment you think is necessary, you should understand:

• what PADs do
• what courts have said about PADs
• what your state’s laws say about PADs
• where and when to seek legal advice.

What are advance directives?

An advance directive (or “declaration”) for health care (ADHC) is a legal document executed by a competent individual that states preferences regarding medical treatment should that individual become incapable of making or expressing decisions.^2-4 An ADHC may be a “living will” that lays out instructions for specific health care situations or a “durable power of attorney” (DPOA) that designates a proxy decision maker, or it may include elements of both. In 1990, the U.S. Congress passed the Patient Self-Determination Act,⁵ which required health care institutions that receive Medicare or Medicaid to ask patients whether they have ADHCs and to give patients information about state laws governing ADHCs.

Modeled after medical advance directives, PADs let competent individuals declare their wishes should they need psychiatric treatment during a period of decision-making incapacity.^3,4 At least 25 states have advance directive statutes specific to psychiatry.⁶ Depending on the state, PADs may allow individuals to assert their preferences regarding psychotropic medication, electroconvulsive therapy (ECT), alternatives to hospitalization, location and length of voluntary hospitalization, the treating psychiatrist, seclusion and restraint, emergency medications, and visitors.

Prevalence and praise

The prevalence of PADs is unknown. A 2006 survey of 1,011 psychiatric outpatients in California, Florida, Illinois, Massachusetts, and North Carolina by Swanson et al⁷ found only 4% to 13% of patients previously executed a PAD. However, most participants said that if given the opportunity and assistance, they would create a PAD.⁷

Psychiatric advocacy groups have lauded the development of PADs. For example, the National Alliance on Mental Illness’ position is that “PADs should be considered as a way to empower consumers to take a more active role in their treatment, and as a way to avoid conflicts over treatment and medication issues.”⁸ Proponents suggest that PADs:

• promote autonomy
• foster communication between patients and treatment providers
• increase compliance with medication
• reduce involuntary treatment and judicial involvement.^4,8

Mental Health America launched My Plan, My Life: My Psychiatric Advance Directive in September 2011 to increase public awareness of the availability of PADs.⁹ Therefore, it is safe to assume that most psychiatrists will encounter patients with PADs.

What if a PAD blocks treatment?

What happens when an adult such as Dr. Y’s patient has a PAD that precludes effective treatment? A similar situation led to Hargrave v Vermont.¹⁰

Nancy Hargrave, a Vermont woman with schizophrenia and a history of psychiatric hospitalizations, executed a DPOA—Vermont does not have a separate statute for PADs—in which she explicitly refused “any and all anti-psychotic, neuroleptic, psychotropic, or psychoactive medications,” and ECT.¹⁰

In anticipation of situations like this, Vermont’s legislature passed Act 114, a 1998 state law that required caregivers to abide by the DPOAs of civilly committed individuals and mentally ill prisoners for 45 days.¹⁰ After this time, a court may override the advance directive and allow involuntary medication administration if a patient “ha[d] not experienced a significant clinical improvement in his or her mental state, and remain[ed] incompetent.”¹⁰

In 1999, Hargrave sued the state of Vermont and other parties in federal court, alleging that Act 114 constituted discrimination under Title II of the Americans with Disabilities Act¹¹ because Act 114 excluded her from participating in the “services, programs, or activities of a public entity,” namely, the use of her DPOA under Vermont state law.¹⁰ The federal district court sided with Hargrave, concluding that “Act 114 was facially discriminatory against mentally disabled individuals.” One year later, the U.S. Court of Appeals for the Second Circuit affirmed the district court’s ruling.

Surprisingly, no other court has adjudicated this issue. However, in Second Circuit states—Vermont, New York, and Connecticut—DPOAs of mentally ill patients cannot be abrogated. This is an unsettling notion for many psychiatrists, because, as Paul Appelbaum, MD, explains, “Advance directives may now constitute an ironclad bulwark against future involuntary treatment with medication—except in emergencies—even for incompetent, committed patients and even when the alternative is long-term institutional care.”¹² Other scholars have pointed out that giving physicians an avenue to override or disregard patients’ directives would negate their intended purpose, which is to have one’s competently expressed wishes followed when one’s decision-making capacity is compromised.^6,13

Doctors’ duties

How you should respond to an involuntary patient’s PAD depends on which state you practice in. A physician’s obligation to comply with a patient’s PAD depends on state law, and most states with PAD laws provide some latitude or options if physicians believe they should not comply with a patient’s wishes.^6,13Table 1^14-18 cites examples of statutory language regarding a physician’s duty to comply with a PAD.

A survey of 164 psychiatrists in North Carolina provides some insight into psychiatrists’ perceptions of PADs.¹⁹ After reading a hypothetical scenario about a mentally ill individual whose PAD expressed refusal of hospitalization or treatment with antipsychotics, 47% of the psychiatrists chose to override the PAD. The authors found that “PAD override was more likely among psychiatrists who worked in hospital emergency departments; those who were concerned about patients’ violence risk and lack of insight; and those who were legally defensive.”

In addition to addressing conflicts between patients’ PADs and doctors’ views about proper treatment, some state laws also contain clauses that spell out the limits of physician liability in cases of physician compliance or noncompliance with PADs. Excerpts from 2 such laws appear in Table 2.^16-17

Table 1

Examples of state laws on compliance with psychiatric advance directives

Table 2

Excerpts from state laws on PAD-related liability

Related Resources

• National Resource Center on Psychiatric Advance Directives. www.nrc-pad.org.
• Duke University Program on Psychiatric Advance Directives. http://pad.duhs.duke.edu.
• Hung EK, McNiel DE, Binder RL. Covert medication in psychiatric emergencies: is it ever ethically permissible? J Am Acad Psychiatry Law. 2012;40(2):239-245.

Disclosure

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

A review of the patient’s blood pressure since admission indicated consistently elevated systolic and diastolic pressures, on average, of 170/105 mm Hg. Additionally, his serum potassium levels ranged from 2.4 to 3.1 mmol/L (normal 3.5-5.1 mmol/L).

A detailed medical history and review of previous records revealed that an initial diagnosis of hypertension had been made during a routine sports physical at age 14, although the patient was cleared for full activity. Over the previous year, the patient said he had gained weight—much of it in the abdomen—and experienced sleep disturbances, increasing fatigability, muscle weakness, hair loss, and declining performance in his high school sports. In addition, he had noticed increased facial flushing and sweating.

On physical exam, we noted an obese male (height 5’5’’, weight 191.5 lb, BMI 30.86 kg/m²) with the following vital signs: temperature 97.9°F, pulse 105 bpm, and blood pressure 177/111 mm Hg. Pertinent physical exam findings outside of his surgical site included diffusely thinning hair, moon facies, facial plethora, increased supraclavicular and dorsocervical fat pads, thoracic and abdominal striae, thinned skin overlying his upper and lower extremities, and lower extremity edema ( FIGURE 1 ). All other exam findings were within normal limits.

Initial blood chemistry lab results revealed hyperglycemia (290 mg/dL; random normal, <200 mg/dL), hypokalemia (3.0 mmol/L; normal, 3.5-5.4 mmol/L), hypochloremia (96 mmol/L; normal, 98-107 mmol/L), and a mean corpuscular volume of 101.2 fL (normal, 80-100 fL). The patient also had a white blood cell (WBC) count of 14,400/mcL with a predominance of neutrophils and 6 bands, and a high sensitivity C-reactive protein level of 7.5 mg/dL (normal, <0.748 mg/dL).

FIGURE 1
The signs were all there

WHAT ADDITIONAL TESTING WOULD YOU ORDER?
WHAT IS YOUR PRESUMPTIVE DIAGNOSIS?

Suspecting Cushing’s syndrome, we ordered cortisol and ACTH

Based on our initial findings, we ordered a 24-hour urinary free cortisol and plasma adrenocorticotropic hormone (ACTH) level—both of which had to be sent to outside laboratories. We also ordered a computed tomography (CT) scan of the patient’s adrenal glands and magnetic resonance imaging (MRI) of his pituitary gland.

The CT scan revealed mild hyperplasia of the adrenal glands bilaterally; the MRI demonstrated a 7 × 6 × 6 mm pituitary microadenoma ( FIGURE 2 ) in the anterior portion of the gland. In addition, a 6 × 6 × 1 mm lesion was noted—thought to be a Rathke’s cleft (Pars intermedia) cyst by the reviewing radiologist.

The patient’s initial cortisol and ACTH lab work revealed a urinary cortisol level of 5089.2 mcg/24 h (normal, 3-55 mcg/24 h) and an ACTH level of 216 pg/mL (normal, 9-57 pg/mL for ages 3-17 years).

We diagnosed Cushing’s syndrome in this patient.

FIGURE 2
MRI reveals pituitary microadenoma

Differentiating between ACTH-dependent and -independent Cushing’s syndrome
Cushing’s syndrome is a constellation of signs and symptoms caused by an overproduction of cortisol, which results in a variety of abnormalities in the hypothalamic-pituitary-adrenal axis. In general, the syndrome is differentiated as either ACTH-dependent or ACTH-independent, based on the underlying cause.¹ Examples of ACTH-dependent Cushing’s syndrome include pituitary adenoma (formally classified as Cushing’s disease) and ectopic ACTH or corticotrophin-releasing hormone-producing tumors. Examples of ACTH-independent Cushing’s syndrome include adrenal adenoma or carcinoma and exogenous glucocorticoid therapy.²

Clinical manifestations include obesity, hypertension (usually with some degree of concurrent hypokalemia), skin abnormalities (eg, plethora, hirsutism, violaceous striae), musculoskeletal weakness, neuropsychiatric symptoms (eg, depression), gonadal dysfunction, and metabolic derangements, including glucose intolerance, diabetes, and hyperlipidemia. In children, a near universal decrease in linear growth secondary to hypercortisolism is seen.³

Investigating a suspected case of Cushing’s syndrome can be divided into 2 stages: confirming the diagnosis and establishing the etiology. The following tests can be used to make the diagnosis: 24-hour urinary free cortisol, low-dose dexamethasone suppression, and late-night salivary cortisol. Several of these tests require late-night administration that necessitates hospital admission. These tests are typically followed by a CT scan of the patient’s adrenal glands and/or an MRI of the patient’s pituitary gland to evaluate the etiology. Additionally, as demonstrated by the patient described here, ongoing issues with hypertension, metabolic abnormalities, and hyperglycemia may require intensive intervention and management.⁴

Don't be fooled
Potential complications in diagnosing the syndrome, however, can cloud an accurate diagnosis—especially early in the disease process. In addition to biochemical similarities between Cushing’s syndrome and obesity, depression, and alcoholism, ACTH-dependent Cushing’s syndrome can undergo cyclical or intermittent activity and can remain in remission for years.¹ Also, ectopic ACTH-secreting tumors may, by virtue of their small size and location, go undetected.

Don’t try to lower BP through usual means
Hypertension, a hallmark finding in approximately 80% of adults and 47% of children with Cushing’s syndrome,⁵ stems from hypercortisol-driven pathologic changes in the mechanisms controlling plasma volume, peripheral vascular resistance, and cardiac output. In addition, these cortisol-driven changes have a direct effect on mineralocorticoid and glucocorticoid receptors within the central nervous system. Secondary effects such as insulin resistance and the development of sleep apnea further complicate the management of this generally treatment-resistant hypertension. Lastly, specific mechanisms such as the cross-reactivity of excess glucocorticoids with mineralocorticoid receptors acting on targets within the kidney, can also lead to metabolic derangements, such as profound hypokalemia and metabolic alkalosis.

Thus, controlling hypertension and the metabolic changes seen in Cushing’s syndrome often requires addressing the underlying hypercortisolism rather than achieving normotension and normal serum electrolytes through the usual means.⁵

Treatment puts our patient back on track
Our patient was transferred to a tertiary care hospital for further management and consultation with endocrinology and neurosurgery. He was started on high-dose ketoconazole, an imidazole-derivative antifungal medication that acts to inhibit adrenal steroidogenesis and has been used successfully in patients with Cushing’s syndrome.^6,7 (Ketoconazole is typically dosed at 400-1200 mg/d⁷ and can be used for >6 months to 1 year, or temporarily in advance of surgery.)

Our patient underwent successful transsphenoidal adenectomy by neurosurgery, and his blood pressure, serum electrolytes, and serum glucose returned to normal levels. He is about to begin his senior year in high school.

CORRESPONDENCE Michael Barna, MD, Department of Family Medicine, Naval Hospital Camp Pendleton, Box 555191, Camp Pendleton, CA 92055; [email protected]

A review of the patient’s blood pressure since admission indicated consistently elevated systolic and diastolic pressures, on average, of 170/105 mm Hg. Additionally, his serum potassium levels ranged from 2.4 to 3.1 mmol/L (normal 3.5-5.1 mmol/L).

A detailed medical history and review of previous records revealed that an initial diagnosis of hypertension had been made during a routine sports physical at age 14, although the patient was cleared for full activity. Over the previous year, the patient said he had gained weight—much of it in the abdomen—and experienced sleep disturbances, increasing fatigability, muscle weakness, hair loss, and declining performance in his high school sports. In addition, he had noticed increased facial flushing and sweating.

On physical exam, we noted an obese male (height 5’5’’, weight 191.5 lb, BMI 30.86 kg/m²) with the following vital signs: temperature 97.9°F, pulse 105 bpm, and blood pressure 177/111 mm Hg. Pertinent physical exam findings outside of his surgical site included diffusely thinning hair, moon facies, facial plethora, increased supraclavicular and dorsocervical fat pads, thoracic and abdominal striae, thinned skin overlying his upper and lower extremities, and lower extremity edema ( FIGURE 1 ). All other exam findings were within normal limits.

Initial blood chemistry lab results revealed hyperglycemia (290 mg/dL; random normal, <200 mg/dL), hypokalemia (3.0 mmol/L; normal, 3.5-5.4 mmol/L), hypochloremia (96 mmol/L; normal, 98-107 mmol/L), and a mean corpuscular volume of 101.2 fL (normal, 80-100 fL). The patient also had a white blood cell (WBC) count of 14,400/mcL with a predominance of neutrophils and 6 bands, and a high sensitivity C-reactive protein level of 7.5 mg/dL (normal, <0.748 mg/dL).

FIGURE 1
The signs were all there

WHAT ADDITIONAL TESTING WOULD YOU ORDER?
WHAT IS YOUR PRESUMPTIVE DIAGNOSIS?

Suspecting Cushing’s syndrome, we ordered cortisol and ACTH

Based on our initial findings, we ordered a 24-hour urinary free cortisol and plasma adrenocorticotropic hormone (ACTH) level—both of which had to be sent to outside laboratories. We also ordered a computed tomography (CT) scan of the patient’s adrenal glands and magnetic resonance imaging (MRI) of his pituitary gland.

The CT scan revealed mild hyperplasia of the adrenal glands bilaterally; the MRI demonstrated a 7 × 6 × 6 mm pituitary microadenoma ( FIGURE 2 ) in the anterior portion of the gland. In addition, a 6 × 6 × 1 mm lesion was noted—thought to be a Rathke’s cleft (Pars intermedia) cyst by the reviewing radiologist.

The patient’s initial cortisol and ACTH lab work revealed a urinary cortisol level of 5089.2 mcg/24 h (normal, 3-55 mcg/24 h) and an ACTH level of 216 pg/mL (normal, 9-57 pg/mL for ages 3-17 years).

We diagnosed Cushing’s syndrome in this patient.

FIGURE 2
MRI reveals pituitary microadenoma

Differentiating between ACTH-dependent and -independent Cushing’s syndrome
Cushing’s syndrome is a constellation of signs and symptoms caused by an overproduction of cortisol, which results in a variety of abnormalities in the hypothalamic-pituitary-adrenal axis. In general, the syndrome is differentiated as either ACTH-dependent or ACTH-independent, based on the underlying cause.¹ Examples of ACTH-dependent Cushing’s syndrome include pituitary adenoma (formally classified as Cushing’s disease) and ectopic ACTH or corticotrophin-releasing hormone-producing tumors. Examples of ACTH-independent Cushing’s syndrome include adrenal adenoma or carcinoma and exogenous glucocorticoid therapy.²

Clinical manifestations include obesity, hypertension (usually with some degree of concurrent hypokalemia), skin abnormalities (eg, plethora, hirsutism, violaceous striae), musculoskeletal weakness, neuropsychiatric symptoms (eg, depression), gonadal dysfunction, and metabolic derangements, including glucose intolerance, diabetes, and hyperlipidemia. In children, a near universal decrease in linear growth secondary to hypercortisolism is seen.³

Investigating a suspected case of Cushing’s syndrome can be divided into 2 stages: confirming the diagnosis and establishing the etiology. The following tests can be used to make the diagnosis: 24-hour urinary free cortisol, low-dose dexamethasone suppression, and late-night salivary cortisol. Several of these tests require late-night administration that necessitates hospital admission. These tests are typically followed by a CT scan of the patient’s adrenal glands and/or an MRI of the patient’s pituitary gland to evaluate the etiology. Additionally, as demonstrated by the patient described here, ongoing issues with hypertension, metabolic abnormalities, and hyperglycemia may require intensive intervention and management.⁴

Don't be fooled
Potential complications in diagnosing the syndrome, however, can cloud an accurate diagnosis—especially early in the disease process. In addition to biochemical similarities between Cushing’s syndrome and obesity, depression, and alcoholism, ACTH-dependent Cushing’s syndrome can undergo cyclical or intermittent activity and can remain in remission for years.¹ Also, ectopic ACTH-secreting tumors may, by virtue of their small size and location, go undetected.

Don’t try to lower BP through usual means
Hypertension, a hallmark finding in approximately 80% of adults and 47% of children with Cushing’s syndrome,⁵ stems from hypercortisol-driven pathologic changes in the mechanisms controlling plasma volume, peripheral vascular resistance, and cardiac output. In addition, these cortisol-driven changes have a direct effect on mineralocorticoid and glucocorticoid receptors within the central nervous system. Secondary effects such as insulin resistance and the development of sleep apnea further complicate the management of this generally treatment-resistant hypertension. Lastly, specific mechanisms such as the cross-reactivity of excess glucocorticoids with mineralocorticoid receptors acting on targets within the kidney, can also lead to metabolic derangements, such as profound hypokalemia and metabolic alkalosis.

Thus, controlling hypertension and the metabolic changes seen in Cushing’s syndrome often requires addressing the underlying hypercortisolism rather than achieving normotension and normal serum electrolytes through the usual means.⁵

Treatment puts our patient back on track
Our patient was transferred to a tertiary care hospital for further management and consultation with endocrinology and neurosurgery. He was started on high-dose ketoconazole, an imidazole-derivative antifungal medication that acts to inhibit adrenal steroidogenesis and has been used successfully in patients with Cushing’s syndrome.^6,7 (Ketoconazole is typically dosed at 400-1200 mg/d⁷ and can be used for >6 months to 1 year, or temporarily in advance of surgery.)

Our patient underwent successful transsphenoidal adenectomy by neurosurgery, and his blood pressure, serum electrolytes, and serum glucose returned to normal levels. He is about to begin his senior year in high school.

CORRESPONDENCE Michael Barna, MD, Department of Family Medicine, Naval Hospital Camp Pendleton, Box 555191, Camp Pendleton, CA 92055; [email protected]

A review of the patient’s blood pressure since admission indicated consistently elevated systolic and diastolic pressures, on average, of 170/105 mm Hg. Additionally, his serum potassium levels ranged from 2.4 to 3.1 mmol/L (normal 3.5-5.1 mmol/L).

A detailed medical history and review of previous records revealed that an initial diagnosis of hypertension had been made during a routine sports physical at age 14, although the patient was cleared for full activity. Over the previous year, the patient said he had gained weight—much of it in the abdomen—and experienced sleep disturbances, increasing fatigability, muscle weakness, hair loss, and declining performance in his high school sports. In addition, he had noticed increased facial flushing and sweating.

On physical exam, we noted an obese male (height 5’5’’, weight 191.5 lb, BMI 30.86 kg/m²) with the following vital signs: temperature 97.9°F, pulse 105 bpm, and blood pressure 177/111 mm Hg. Pertinent physical exam findings outside of his surgical site included diffusely thinning hair, moon facies, facial plethora, increased supraclavicular and dorsocervical fat pads, thoracic and abdominal striae, thinned skin overlying his upper and lower extremities, and lower extremity edema ( FIGURE 1 ). All other exam findings were within normal limits.

Initial blood chemistry lab results revealed hyperglycemia (290 mg/dL; random normal, <200 mg/dL), hypokalemia (3.0 mmol/L; normal, 3.5-5.4 mmol/L), hypochloremia (96 mmol/L; normal, 98-107 mmol/L), and a mean corpuscular volume of 101.2 fL (normal, 80-100 fL). The patient also had a white blood cell (WBC) count of 14,400/mcL with a predominance of neutrophils and 6 bands, and a high sensitivity C-reactive protein level of 7.5 mg/dL (normal, <0.748 mg/dL).

FIGURE 1
The signs were all there

WHAT ADDITIONAL TESTING WOULD YOU ORDER?
WHAT IS YOUR PRESUMPTIVE DIAGNOSIS?

Suspecting Cushing’s syndrome, we ordered cortisol and ACTH

Based on our initial findings, we ordered a 24-hour urinary free cortisol and plasma adrenocorticotropic hormone (ACTH) level—both of which had to be sent to outside laboratories. We also ordered a computed tomography (CT) scan of the patient’s adrenal glands and magnetic resonance imaging (MRI) of his pituitary gland.

The CT scan revealed mild hyperplasia of the adrenal glands bilaterally; the MRI demonstrated a 7 × 6 × 6 mm pituitary microadenoma ( FIGURE 2 ) in the anterior portion of the gland. In addition, a 6 × 6 × 1 mm lesion was noted—thought to be a Rathke’s cleft (Pars intermedia) cyst by the reviewing radiologist.

The patient’s initial cortisol and ACTH lab work revealed a urinary cortisol level of 5089.2 mcg/24 h (normal, 3-55 mcg/24 h) and an ACTH level of 216 pg/mL (normal, 9-57 pg/mL for ages 3-17 years).

We diagnosed Cushing’s syndrome in this patient.

FIGURE 2
MRI reveals pituitary microadenoma

Differentiating between ACTH-dependent and -independent Cushing’s syndrome
Cushing’s syndrome is a constellation of signs and symptoms caused by an overproduction of cortisol, which results in a variety of abnormalities in the hypothalamic-pituitary-adrenal axis. In general, the syndrome is differentiated as either ACTH-dependent or ACTH-independent, based on the underlying cause.¹ Examples of ACTH-dependent Cushing’s syndrome include pituitary adenoma (formally classified as Cushing’s disease) and ectopic ACTH or corticotrophin-releasing hormone-producing tumors. Examples of ACTH-independent Cushing’s syndrome include adrenal adenoma or carcinoma and exogenous glucocorticoid therapy.²

Clinical manifestations include obesity, hypertension (usually with some degree of concurrent hypokalemia), skin abnormalities (eg, plethora, hirsutism, violaceous striae), musculoskeletal weakness, neuropsychiatric symptoms (eg, depression), gonadal dysfunction, and metabolic derangements, including glucose intolerance, diabetes, and hyperlipidemia. In children, a near universal decrease in linear growth secondary to hypercortisolism is seen.³

Investigating a suspected case of Cushing’s syndrome can be divided into 2 stages: confirming the diagnosis and establishing the etiology. The following tests can be used to make the diagnosis: 24-hour urinary free cortisol, low-dose dexamethasone suppression, and late-night salivary cortisol. Several of these tests require late-night administration that necessitates hospital admission. These tests are typically followed by a CT scan of the patient’s adrenal glands and/or an MRI of the patient’s pituitary gland to evaluate the etiology. Additionally, as demonstrated by the patient described here, ongoing issues with hypertension, metabolic abnormalities, and hyperglycemia may require intensive intervention and management.⁴

Don't be fooled
Potential complications in diagnosing the syndrome, however, can cloud an accurate diagnosis—especially early in the disease process. In addition to biochemical similarities between Cushing’s syndrome and obesity, depression, and alcoholism, ACTH-dependent Cushing’s syndrome can undergo cyclical or intermittent activity and can remain in remission for years.¹ Also, ectopic ACTH-secreting tumors may, by virtue of their small size and location, go undetected.

Don’t try to lower BP through usual means
Hypertension, a hallmark finding in approximately 80% of adults and 47% of children with Cushing’s syndrome,⁵ stems from hypercortisol-driven pathologic changes in the mechanisms controlling plasma volume, peripheral vascular resistance, and cardiac output. In addition, these cortisol-driven changes have a direct effect on mineralocorticoid and glucocorticoid receptors within the central nervous system. Secondary effects such as insulin resistance and the development of sleep apnea further complicate the management of this generally treatment-resistant hypertension. Lastly, specific mechanisms such as the cross-reactivity of excess glucocorticoids with mineralocorticoid receptors acting on targets within the kidney, can also lead to metabolic derangements, such as profound hypokalemia and metabolic alkalosis.

Thus, controlling hypertension and the metabolic changes seen in Cushing’s syndrome often requires addressing the underlying hypercortisolism rather than achieving normotension and normal serum electrolytes through the usual means.⁵

Treatment puts our patient back on track
Our patient was transferred to a tertiary care hospital for further management and consultation with endocrinology and neurosurgery. He was started on high-dose ketoconazole, an imidazole-derivative antifungal medication that acts to inhibit adrenal steroidogenesis and has been used successfully in patients with Cushing’s syndrome.^6,7 (Ketoconazole is typically dosed at 400-1200 mg/d⁷ and can be used for >6 months to 1 year, or temporarily in advance of surgery.)

Our patient underwent successful transsphenoidal adenectomy by neurosurgery, and his blood pressure, serum electrolytes, and serum glucose returned to normal levels. He is about to begin his senior year in high school.

CORRESPONDENCE Michael Barna, MD, Department of Family Medicine, Naval Hospital Camp Pendleton, Box 555191, Camp Pendleton, CA 92055; [email protected]

When assessing possible onychomycosis, conventional practice is to take samples from the most proximal infected area. But this approach is usually technically difficult and may cause discomfort to patients.^1-6 We therefore sought to determine the optimal location for fungal sampling from the distal part of the affected nail.

Methods

To assess the accuracy of distal sampling in diagnosing distal and lateral subungual onychomycosis (DLSO) of the toenails, we reevaluated 106 patients with DLSO previously confirmed by microscopic visualization of fungi in potassium hydroxide (KOH) solution and by fungal culture of specimens obtained using the proximal sampling approach.

Before we obtained our samples, we cleaned the nails with alcohol and pared the most distal part of the nails in an effort to eliminate contaminant molds and bacteria. Using a 1- or 2-mm curette, we took specimens first from the distal nail bed and, second, from the distal underside of the nail plate ( FIGURE ). We separated specimens for use in either direct KOH visualization or in fungal culture using Sabouraud’s Dextrose agar (Novamed; Jerusalem, Israel), which contains chloramphenicol or streptomycin and penicillin to prevent contamination.

FIGURE
Distal sampling for distal and lateral subungual onychomycosis

Statistical analyses
We recorded sociodemographic characteristics and fungal culture results in basic descriptive (prevalence) tables. In univariate analysis, we used t-tests to compare the means of continuous variables (eg, age, duration of fungal infection). To assess the distribution of categorical parameters (eg, sex) and to gauge the efficacy of the different probing techniques, we used chi-square (χ²) tests. We analyzed coded data using SPSS (Chicago, IL) for Windows software, version 12.

We conducted the study according to the rules of the local Helsinki Committee.

Results

We examined 106 patients with DLSO, of which 65 (61.3%) were male and 41 (38.7%) were female, ages 23 to 72 years (mean age, 44.6). The duration of fungal infection ranged from 3 to 30 years, with a mean of 14.9 years. In 70.8% of cases, the infection involved the first toenail. Duration of the fungal disease did not differ significantly between the sexes.

KOH test results were positive for 84 (79.2%) specimens from the distal nail bed, and for only 60 (56.6%) specimens from the distal underside of the nail plate (P=.0007); culture results were positive for 93 (87.7%) and 76 (71.7%) specimens, respectively (P=.0063). Combining results from both locations (all positive samples from the nail bed, plus positive samples from the nail underside when results from the nail bed were negative) yielded confirmation with KOH testing in 92 (86.8%) patients and with culture in 100 (94.3%) patients. There were no statistically significant differences between the combined results of both locations and the results from the distal nail bed alone (KOH, P=.143; culture, P=.149) ( TABLE ).

TABLE
Accuracy of distal sampling in 106 patients with confirmed DLSO

Discussion

In DLSO, most dermatophyte species invade the middle and ventral layers of the nail plate adjacent to the nail bed, where the keratin is soft and close to the living cells below. In fact, the nail bed is probably the primary invasion site of dermatophytes, and it acts as a reservoir for continual reinfection of the growing nail.⁷ Obtaining confirmation of fungal infection before initiating antifungal treatment is the gold standard in clinical practice, given that antifungal agents have potentially serious adverse effects, that treatment is expensive, and that medicolegal issues exist.⁸

The standard methods used to detect a fungal nail infection are direct microscopy with KOH preparation and fungal culture. The KOH test is the simplest, least expensive method used in the detection of fungi, but it cannot identify the specific pathogen. Fungal speciation is done by culture. More accurate histopathologic evaluation is possible with periodic acid-Schiff stain, immunofluorescent microscopy with calcofluor stain, or polymerase chain reaction, but these techniques are more expensive and less feasible in outpatient clinics.⁹

The diagnostic accuracy of the KOH test and fungal culture ranges from 50% to 70%, depending on the experience of the laboratory technician and the methods used to collect and prepare the sample.^8-10 It is better to take samples from the most proximal infected area by curettage or drilling, but this technique is usually more difficult than a distal approach, should be performed by skilled personnel, and may cause discomfort to patients.^3,5,6

Our recommendation for practice. Earlier studies suggested that nail specimens should be taken from the nail bed.^11-13 We sampled the nail bed first in our study because, in trying to determine an optimal location for sampling, we wanted to avoid contaminating nail-bed specimens with debris from the underside of the nail. In practice, however, we suggest that, in cases of suspected DLSO, clinicians first obtain specimens from the distal underside of the nail, and then collect all remaining material from the distal part of the nail bed. This technique is simple and can easily be performed in an office setting. If test results are negative but DLSO remains clinically likely, test a second sample after a week or 2.

CORRESPONDENCE Boaz Amichai, MD, Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel; [email protected]

When assessing possible onychomycosis, conventional practice is to take samples from the most proximal infected area. But this approach is usually technically difficult and may cause discomfort to patients.^1-6 We therefore sought to determine the optimal location for fungal sampling from the distal part of the affected nail.

Methods

To assess the accuracy of distal sampling in diagnosing distal and lateral subungual onychomycosis (DLSO) of the toenails, we reevaluated 106 patients with DLSO previously confirmed by microscopic visualization of fungi in potassium hydroxide (KOH) solution and by fungal culture of specimens obtained using the proximal sampling approach.

Before we obtained our samples, we cleaned the nails with alcohol and pared the most distal part of the nails in an effort to eliminate contaminant molds and bacteria. Using a 1- or 2-mm curette, we took specimens first from the distal nail bed and, second, from the distal underside of the nail plate ( FIGURE ). We separated specimens for use in either direct KOH visualization or in fungal culture using Sabouraud’s Dextrose agar (Novamed; Jerusalem, Israel), which contains chloramphenicol or streptomycin and penicillin to prevent contamination.

FIGURE
Distal sampling for distal and lateral subungual onychomycosis

Statistical analyses
We recorded sociodemographic characteristics and fungal culture results in basic descriptive (prevalence) tables. In univariate analysis, we used t-tests to compare the means of continuous variables (eg, age, duration of fungal infection). To assess the distribution of categorical parameters (eg, sex) and to gauge the efficacy of the different probing techniques, we used chi-square (χ²) tests. We analyzed coded data using SPSS (Chicago, IL) for Windows software, version 12.

We conducted the study according to the rules of the local Helsinki Committee.

Results

We examined 106 patients with DLSO, of which 65 (61.3%) were male and 41 (38.7%) were female, ages 23 to 72 years (mean age, 44.6). The duration of fungal infection ranged from 3 to 30 years, with a mean of 14.9 years. In 70.8% of cases, the infection involved the first toenail. Duration of the fungal disease did not differ significantly between the sexes.

KOH test results were positive for 84 (79.2%) specimens from the distal nail bed, and for only 60 (56.6%) specimens from the distal underside of the nail plate (P=.0007); culture results were positive for 93 (87.7%) and 76 (71.7%) specimens, respectively (P=.0063). Combining results from both locations (all positive samples from the nail bed, plus positive samples from the nail underside when results from the nail bed were negative) yielded confirmation with KOH testing in 92 (86.8%) patients and with culture in 100 (94.3%) patients. There were no statistically significant differences between the combined results of both locations and the results from the distal nail bed alone (KOH, P=.143; culture, P=.149) ( TABLE ).

TABLE
Accuracy of distal sampling in 106 patients with confirmed DLSO

Discussion

In DLSO, most dermatophyte species invade the middle and ventral layers of the nail plate adjacent to the nail bed, where the keratin is soft and close to the living cells below. In fact, the nail bed is probably the primary invasion site of dermatophytes, and it acts as a reservoir for continual reinfection of the growing nail.⁷ Obtaining confirmation of fungal infection before initiating antifungal treatment is the gold standard in clinical practice, given that antifungal agents have potentially serious adverse effects, that treatment is expensive, and that medicolegal issues exist.⁸

The standard methods used to detect a fungal nail infection are direct microscopy with KOH preparation and fungal culture. The KOH test is the simplest, least expensive method used in the detection of fungi, but it cannot identify the specific pathogen. Fungal speciation is done by culture. More accurate histopathologic evaluation is possible with periodic acid-Schiff stain, immunofluorescent microscopy with calcofluor stain, or polymerase chain reaction, but these techniques are more expensive and less feasible in outpatient clinics.⁹

The diagnostic accuracy of the KOH test and fungal culture ranges from 50% to 70%, depending on the experience of the laboratory technician and the methods used to collect and prepare the sample.^8-10 It is better to take samples from the most proximal infected area by curettage or drilling, but this technique is usually more difficult than a distal approach, should be performed by skilled personnel, and may cause discomfort to patients.^3,5,6

Our recommendation for practice. Earlier studies suggested that nail specimens should be taken from the nail bed.^11-13 We sampled the nail bed first in our study because, in trying to determine an optimal location for sampling, we wanted to avoid contaminating nail-bed specimens with debris from the underside of the nail. In practice, however, we suggest that, in cases of suspected DLSO, clinicians first obtain specimens from the distal underside of the nail, and then collect all remaining material from the distal part of the nail bed. This technique is simple and can easily be performed in an office setting. If test results are negative but DLSO remains clinically likely, test a second sample after a week or 2.

CORRESPONDENCE Boaz Amichai, MD, Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel; [email protected]

When assessing possible onychomycosis, conventional practice is to take samples from the most proximal infected area. But this approach is usually technically difficult and may cause discomfort to patients.^1-6 We therefore sought to determine the optimal location for fungal sampling from the distal part of the affected nail.

Methods

To assess the accuracy of distal sampling in diagnosing distal and lateral subungual onychomycosis (DLSO) of the toenails, we reevaluated 106 patients with DLSO previously confirmed by microscopic visualization of fungi in potassium hydroxide (KOH) solution and by fungal culture of specimens obtained using the proximal sampling approach.

Before we obtained our samples, we cleaned the nails with alcohol and pared the most distal part of the nails in an effort to eliminate contaminant molds and bacteria. Using a 1- or 2-mm curette, we took specimens first from the distal nail bed and, second, from the distal underside of the nail plate ( FIGURE ). We separated specimens for use in either direct KOH visualization or in fungal culture using Sabouraud’s Dextrose agar (Novamed; Jerusalem, Israel), which contains chloramphenicol or streptomycin and penicillin to prevent contamination.

FIGURE
Distal sampling for distal and lateral subungual onychomycosis

Statistical analyses
We recorded sociodemographic characteristics and fungal culture results in basic descriptive (prevalence) tables. In univariate analysis, we used t-tests to compare the means of continuous variables (eg, age, duration of fungal infection). To assess the distribution of categorical parameters (eg, sex) and to gauge the efficacy of the different probing techniques, we used chi-square (χ²) tests. We analyzed coded data using SPSS (Chicago, IL) for Windows software, version 12.

We conducted the study according to the rules of the local Helsinki Committee.

Results

We examined 106 patients with DLSO, of which 65 (61.3%) were male and 41 (38.7%) were female, ages 23 to 72 years (mean age, 44.6). The duration of fungal infection ranged from 3 to 30 years, with a mean of 14.9 years. In 70.8% of cases, the infection involved the first toenail. Duration of the fungal disease did not differ significantly between the sexes.

KOH test results were positive for 84 (79.2%) specimens from the distal nail bed, and for only 60 (56.6%) specimens from the distal underside of the nail plate (P=.0007); culture results were positive for 93 (87.7%) and 76 (71.7%) specimens, respectively (P=.0063). Combining results from both locations (all positive samples from the nail bed, plus positive samples from the nail underside when results from the nail bed were negative) yielded confirmation with KOH testing in 92 (86.8%) patients and with culture in 100 (94.3%) patients. There were no statistically significant differences between the combined results of both locations and the results from the distal nail bed alone (KOH, P=.143; culture, P=.149) ( TABLE ).

TABLE
Accuracy of distal sampling in 106 patients with confirmed DLSO

Discussion

In DLSO, most dermatophyte species invade the middle and ventral layers of the nail plate adjacent to the nail bed, where the keratin is soft and close to the living cells below. In fact, the nail bed is probably the primary invasion site of dermatophytes, and it acts as a reservoir for continual reinfection of the growing nail.⁷ Obtaining confirmation of fungal infection before initiating antifungal treatment is the gold standard in clinical practice, given that antifungal agents have potentially serious adverse effects, that treatment is expensive, and that medicolegal issues exist.⁸

The standard methods used to detect a fungal nail infection are direct microscopy with KOH preparation and fungal culture. The KOH test is the simplest, least expensive method used in the detection of fungi, but it cannot identify the specific pathogen. Fungal speciation is done by culture. More accurate histopathologic evaluation is possible with periodic acid-Schiff stain, immunofluorescent microscopy with calcofluor stain, or polymerase chain reaction, but these techniques are more expensive and less feasible in outpatient clinics.⁹

The diagnostic accuracy of the KOH test and fungal culture ranges from 50% to 70%, depending on the experience of the laboratory technician and the methods used to collect and prepare the sample.^8-10 It is better to take samples from the most proximal infected area by curettage or drilling, but this technique is usually more difficult than a distal approach, should be performed by skilled personnel, and may cause discomfort to patients.^3,5,6

Our recommendation for practice. Earlier studies suggested that nail specimens should be taken from the nail bed.^11-13 We sampled the nail bed first in our study because, in trying to determine an optimal location for sampling, we wanted to avoid contaminating nail-bed specimens with debris from the underside of the nail. In practice, however, we suggest that, in cases of suspected DLSO, clinicians first obtain specimens from the distal underside of the nail, and then collect all remaining material from the distal part of the nail bed. This technique is simple and can easily be performed in an office setting. If test results are negative but DLSO remains clinically likely, test a second sample after a week or 2.

CORRESPONDENCE Boaz Amichai, MD, Department of Dermatology, Sheba Medical Center, Tel-Hashomer, Israel; [email protected]

Cardiovascular disease (CVD) is the principal cause of death in the United States.¹ As the population grows older and obesity and diabetes become increasingly prevalent, the prevalence of CVD is also expected to rise.^2,3 Fortunately, many CVD events can be prevented or delayed by modifying risk factors such as hyperlipidemia, hypertension, and smoking. Interventions associated with a reduction in risk have led to a reduction in CVD events^4,5 and contributed to a steady decline in cardiac deaths.⁶

Control of platelet aggregation is a cornerstone of primary CVD prevention.⁷ In an outpatient setting, this usually translates into identifying patients who are at high risk for a CVD event and advising them to take low-dose aspirin daily or every other day. Although not without controversy,^8,9 the US Preventive Services Task Force (USPSTF) recommends regular aspirin use for primary CVD prevention for middle-aged to older men at high risk for myocardial infarction (MI) and women at high risk for ischemic stroke.¹⁰

The efficacy of this intervention is proven: In primary prevention trials, regular aspirin use is associated with a 14% reduction in the likelihood of CVD events over 7 years.¹¹ What’s more, aspirin therapy, as recommended by the USPSTF, is among the most cost-effective clinic-based preventive measures.¹²

In 2004, 41% of US adults age 40 or older reported taking aspirin regularly¹³ —an increase of approximately 20% since 1999.¹⁴ More recent data from a national population-based cohort study found that 41% of adults ages 45 to 90 years who did not have CVD but were at moderate to high risk for a CVD event reported taking aspirin ≥3 days per week.¹⁵ In the same study, almost one-fourth of those at low CVD risk also reported regular aspirin use.

While regular aspirin use for primary CVD prevention has been on the rise,^13,14 the extent to which this intervention has penetrated various segments of the population is unclear. Several studies have found that aspirin use is consistently highest among those who are older, male, and white.^15-17 Other socioeconomic variables (eg, education level, employment, marital status) have received little attention. And no previous study has used national guidelines for aspirin therapy to stratify samples.

A look at overuse and underuse. To ensure that aspirin therapy for primary CVD prevention is directed at those who are most likely to benefit from it, a better understanding of variables associated with both aspirin overuse and underuse is needed. This area of research is important, in part because direct-to-consumer aspirin marketing may be particularly influential among groups at low risk for CVD—for whom the risk of excess bleeding outweighs the potential for disease prevention.^13,18

This study was undertaken to examine the association between specific sociodemographic variables and aspirin use among a representative sample of Wisconsin adults without CVD, looking both at those for whom aspirin therapy is indicated and those for whom it is not indicated based on national guidelines.

Methods

Design
We used a cross-sectional design, with data from the Survey of the Health of Wisconsin (SHOW),¹⁹ an annual survey of Wisconsin residents ages 21 to 74 years. SHOW uses a 2-stage stratified cluster sampling design to select households, with all age-eligible household members invited to participate. Recruitment for the annual survey consists of general community-wide announcements, as well as an initial letter and up to 6 visits to the randomly selected households to encourage participation.

By the end of 2010, SHOW had 1572 enrollees—about 53% of all eligible invitees. The demographic profile of SHOW enrollees was similar to US census data for all Wisconsin adults during the same time frame.¹⁹ All SHOW procedures were approved by the University of Wisconsin Institutional Review Board, and all participants provided informed consent.

Study sample
Our analyses were based on data provided by SHOW participants who were screened and enrolled between 2008 and 2010. To be included in our study, participants had to be between the ages of 35 and 74 years; not pregnant, on active military duty, or institutionalized; and have no personal history of CVD (myocardial infarction, angina, stroke, or transient ischemic attack) or CVD risk equivalent (type 1 or type 2 diabetes) at the time of recruitment. Data on key study variables had to be available, as well. (We used 35 years as the lower age limit because of the very low likelihood of CVD in younger individuals.)

We stratified the analytical sample (N=831) into 2 groups—participants for whom aspirin therapy was indicated and those for whom it was not indicated—in order to examine aspirin’s appropriate (recommended) and inappropriate use.

Measures
Outcome. The outcome variable was aspirin use. SHOW had asked participants how often they took aspirin. Similar to the methods used by Sanchez et al,¹⁵ we classified those who reported taking aspirin most (≥4) days of the week as regular aspirin users. All others were classified as nonregular aspirin users. Participants were not asked about the daily dose or weekly volume of aspirin.

Variables
Sociodemographic variables considered in our analysis were age, sex, race/ethnicity, education level, marital/partner status, employment status, health insurance, and region of residence within Wisconsin.

All participants underwent physical examinations, conducted as part of SHOW, at either a permanent or mobile exam center. Blood pressure was measured after a 5-minute rest period in a seated position, and the average of the last 2 out of 3 consecutive measurements was reported. Body mass index (BMI) was calculated, and blood samples were obtained by venipuncture, processed immediately, and sent to the Marshfield Clinic laboratory for measuring total and high-density lipoprotein (HDL) cholesterol.

Indications for aspirin therapy. We stratified the sample by those who were and those who were not candidates for aspirin therapy for primary CVD prevention based on the latest guidelines from the USPSTF ( FIGURE ).¹⁰ The Task Force recommends aspirin therapy for men ages 45 to 74 years with a moderate or greater 10-year risk of a coronary heart disease (CHD) event and women ages 55 to 74 years with a moderate or greater 10-year risk of stroke. We used the global CVD risk equation derived from the Framingham Heart Study (based on age, sex, smoking status, systolic blood pressure, and total and HDL cholesterol) to calculate each participant’s 10-year risk and, thus, determine whether aspirin therapy was or was not indicated.²⁰ Total and HDL cholesterol values were missing for 94 participants in the analytical sample; their 10-year CVD risk was estimated using BMI, a reasonable alternative to more conventional CVD risk prediction when laboratory values are unavailable.²¹

FIGURE
Study (SHOW) sample, stratified based on aspirin indication¹⁰

Statistical analyses
All analytical procedures were conducted using Statistical Analysis Software (SAS Version 9.2; Cary, NC). A complete-case framework was used.

We used multivariate logistic regression for survey data (PROC SURVEYLOGISTIC; SAS Institute, Cary, NC) to examine the association between aspirin use and sociodemographic variables. Two separate analyses were conducted, one of participants for whom aspirin therapy was indicated and the other for participants for whom it was not. The outcomes were modeled dichotomously, as regular vs nonregular aspirin users, and a collinearity check was done. ²¹

Initially, we created univariate models to gauge the crude relationship between each variable and aspirin use. Any variable with P<.20 in its univariate association with regular aspirin use was considered for inclusion in the final multivariate regression model. In the multivariate analyses, we sequentially eliminated variables with the weakest association with aspirin use until only significant (P<.10) independent predictors remained. Appropriate weighting was applied based on survey strata and cluster structure.¹⁹

Results

Of the 831 participants who met the eligibility criteria for our analysis, 268 (32%) had an aspirin indication. TABLE 1 shows the key characteristics of the analytical sample, stratified by those for whom aspirin was indicated and those for whom it was not. The sample was primarily middle-aged (mean age 52.4±0.36) and non-Hispanic white (93%). Compared with those for whom aspirin therapy was not indicated, the group with an aspirin indication was significantly older (56.9 vs 50.3) and had a significantly higher proportion of males (97% vs 19%). As expected, those for whom aspirin was indicated were also at higher risk for CHD and stroke, most notably as a result of significantly higher systolic BP (131.9 vs 121.5 mm Hg) and lower HDL cholesterol (42.5 vs 52.6 mg/dL) compared with participants without an aspirin indication.

TABLE 1
Study sample, by sociodemographic variable and aspirin indication

When aspirin was indicated, use was linked to age and sex
In the group with an aspirin indication (n=268), 83 (31%) reported taking aspirin most days of the week. The initial examination of sociodemographic variables showed that age, sex, and employment status demonstrated significant univariate associations with regular aspirin use ( TABLE 2 ). In the multivariate model, however, the odds of regular aspirin use were significantly greater among participants who were older (odds ratio [OR], 1.07; P<.001) or female (OR, 3.49; P=.021) compared with participants who were younger or male, respectively.

TABLE 2
Participants who have an aspirin indication: Association between sociodemographic variables and regular aspirin use

When aspirin was not indicated, age and sex still affected use
Among the 563 participants for whom aspirin therapy was not indicated, 102 (18%) reported taking aspirin regularly. Age, sex, race/ethnicity, health insurance, and employment ( TABLE 3 ), as well as region of residence and study enrollment year, had significant univariate associations with regular aspirin use; these variables were tested for potential inclusion in the multivariate model. In the final multivariate regression model, the odds of regular aspirin use were significantly greater among participants who were older (OR, 1.07; P<.001) and significantly lower among participants who were Hispanic or nonwhite (OR, 0.32; P=.063).

TABLE 3
Participants who do not have an aspirin indication: Association between sociodemographic variables and regular aspirin use

Discussion

Aspirin was generally underutilized in the group with significant CVD risk (n=268) in our study, with slightly less than a third of participants for whom aspirin therapy was indicated taking it most days of the week. Despite trends of increased aspirin use among US adults in recent years,¹⁵ aspirin therapy in the 2008-2010 SHOW sample was lower than in 2005 to 2008. It was also lower than national estimates of aspirin use for primary CVD prevention^15,22 —but about 20% higher than estimates of overall aspirin use in Wisconsin 20 years ago.²³ Consistent with previous research, the final adjusted model and sensitivity analysis indicated that older individuals were more likely to take aspirin regularly.

Contrary to the findings in some previous studies,^15-17 however, our analysis suggested that women had a higher adjusted odds of regular aspirin use compared with men. This result should be interpreted with extreme caution, however, because so few females (9 of 464 [3%]) met the current USPSTF criteria for aspirin therapy for primary CVD prevention. The previous USPSTF guidelines^24,25 were less conservative, with a lower minimum age and threshold for CVD risk for women. The revision is the likely result of recent primary prevention trials¹⁰ that found regular aspirin use provided less cardioprotection for younger women.

The sample without an aspirin indication—roughly twice the size of the group with an aspirin indication (563 vs 268), which is reflective of the general population of Wisconsin—was useful in highlighting inappropriate use. There were clear indications of aspirin overuse in this group, with 18% of the sample reporting that they took aspirin regularly. The finding that inappropriate aspirin use was more likely in non-Hispanic whites vs minorities is similar to the result of an earlier study in which blacks, Hispanics, and Chinese Americans with low CVD risk were much less likely to report regular aspirin use compared with whites at low risk.¹⁵

The main concern with regular aspirin use in those for whom it is not indicated for primary CVD prevention is the risk of upper gastrointestinal bleeding and, less commonly, hemorrhagic stroke.²⁶ To illustrate this point, consider the following: About 10% of SHOW participants ages 35 to 74 years had no history of CVD and no indication for aspirin therapy based on the latest USPSTF guidelines, but took aspirin regularly nonetheless. Extrapolating those numbers to the entire state of Wisconsin would suggest that approximately 270,000 state residents have a similar profile. Assuming an extra 1.3 major bleeding events per 1000 person-years of regular aspirin use (as a meta-analysis of studies of adverse events associated with antiplatelet therapy found),²⁷ that would translate into an estimated 350 major bleeding events per year in Wisconsin that are attributable to aspirin overuse.

In view of the current USPSTF recommendations,¹⁰ aspirin is not optimally utilized by Wisconsin residents for the primary prevention of CVD. Aspirin therapy is not used enough by those with a high CVD risk, who could derive substantial vascular disease protection from it. Conversely, aspirin therapy is overused by those with a low CVD risk, for whom the risk of major bleeding is significantly higher than the potential for vascular disease protection. Furthermore, younger individuals at high CVD risk appear to be least likely to take aspirin regularly.

Recommendations
The strongest modifiable predictor of regular aspirin use is a recommendation from a clinician.¹³ Therefore, we recommend stronger primary care initiatives to ensure that patients are screened for aspirin use more frequently, particularly middle-aged men at high CVD risk. This clinic-based initiative could reach a larger proportion of the general population when combined with broader, community-oriented CVD preventive services.²⁸

More precise marketing and education are also needed. Because aspirin is a low-cost over-the-counter product that leads the consumer market for analgesics,²⁹ the general public (and older, non-Hispanic whites, in particular) needs to be better informed about the risks of medically inappropriate aspirin use for primary CVD prevention.

Study limitations
Selection and measurement biases were among the chief study limitations.

Study (SHOW) enrollment rate was slightly above 50%, with steady increases in enrollment each year (from 46% in 2008-2009 to 56% in 2010) due to expanded recruitment and consolidation of field operations.

Aspirin use was self-reported, and SHOW did not capture the reason for taking it (eg, CVD prevention or pain management). Some evidence of overreporting of aspirin use among older individuals exists,³⁰ suggesting that a more objective measure of aspirin use (eg, pill bottle verification or blood platelet aggregation test) could yield different results.

Certain confounders were not measured, most notably contraindications to aspirin (eg, genetic platelet abnormalities). Such findings could explain some patterns of aspirin use in both strata, as up to 10% of any given population has a contraindication to aspirin due to allergy, intolerance, gastrointestinal ulcer, concomitant anticoagulant medication, or other high bleeding risk.^18,31 Few of these variables were known about our sample.

TABLE 4W (available below) provides a breakdown of some possible aspirin contraindications, as well as possible reasons other than primary CVD prevention for regular aspirin use. Because clinical judgment is often required to assess the degree of severity of a given health condition in order to deem it an aspirin contraindication, these findings could not reliably be used to reclassify participants. We present them simply for hypothesis generation.

Some data collection predates the current USPSTF guidelines,¹⁰ which could have resulted in a misclassification of participants’ aspirin indication. However, sensitivity analyses restricted to the 2010 sample alone—the only one with data collection after the newer guidelines were released—did not reveal any meaningful differences.

Other methodological limitations include the less racially diverse population of Wisconsin compared with other parts of the country and the sample size, which did not permit testing for statistical interactions and perhaps resulted in larger confidence intervals for some associations (eg, race/ethnicity) relative to the population as a whole.

TABLE 4W
Possible reasons for aspirin use—or contraindication— by aspirin indication*

Acknowledgement

The authors thank Matt Walsh, PhD, for his assistance in creating the analytical dataset, as well as Sally Steward-Townsend, Susan Wright, Bri Deyo, Bethany Varley, and the rest of the Survey of the Health of Wisconsin staff.

CORRESPONDENCE Jeffrey J. VanWormer, PhD, Epidemiology Research Center, Marshfield Clinic Research Foundation, 1000 North Oak Avenue, Marshfield, WI 54449; [email protected]