Nick C. Patel, PharmD, PhD

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Can monitoring help? Although consensus is lacking on the role and necessity of routine monitoring, serum valproate levels can help when you are seeking the most effective treatment for a bipolar patient (Table 1).⁵ Therapeutic monitoring also may help you assess medication adherence. In fact, monitoring may indirectly enhance adherence when the patient knows you will check serum valproate.

Table 1

4 situations where serum valproate monitoring may be clinically useful

To establish a baseline effective level in individual patients
To assess lack or loss of efficacy, including patient adherence
When drug-drug interactions increase or decrease valproate clearance (such as with aspirin, carbamazepine, felbamate, or phenytoin)5
When dose-dependent side effects occur (such as alopecia, elevated liver function, thrombocytopenia, or pancreatitis)

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Valproate was significantly more effective in groups with levels >71 mcg/mL, compared with placebo. Groups with serum valproate of 94 to 107 mcg/mL and >107 mcg/mL also showed greater response than did the group with ≤55 mcg/mL. Effect sizes for the 94 to 107 and >107 mcg/mL groups were –1.06 and –1.07 respectively, similar to 12-point decrease on the YMRS. A median 87 mcg/mL was associated with an effect size of –1.1.

 

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Compared with patients receiving placebo, those in the medium therapeutic group stayed in maintenance therapy significantly longer before discontinuing treatment for any reason or because of mania or depression. No significant differences were seen between the placebo and other 3 valproate groups or between the medium therapeutic and other 3 valproate groups.

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

Post hoc analysis of divalproex maintenance treatment data did not examine how soon patients discontinued treatment exclusively because of intolerance.¹³

 

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

	Serum valproate (mcg/mL)
	Lower level	Upper level	Comments
Acute mania	45 to 50	125	Upper level based on tolerability, not efficacy
Maintenance	75	100	Levels based primarily on retrospective analysis
Acute bipolar	Not established	Not established
* Based on available data

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

Related resources

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

Drug brand names

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

Disclosures

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Can monitoring help? Although consensus is lacking on the role and necessity of routine monitoring, serum valproate levels can help when you are seeking the most effective treatment for a bipolar patient (Table 1).⁵ Therapeutic monitoring also may help you assess medication adherence. In fact, monitoring may indirectly enhance adherence when the patient knows you will check serum valproate.

Table 1

4 situations where serum valproate monitoring may be clinically useful

To establish a baseline effective level in individual patients
To assess lack or loss of efficacy, including patient adherence
When drug-drug interactions increase or decrease valproate clearance (such as with aspirin, carbamazepine, felbamate, or phenytoin)5
When dose-dependent side effects occur (such as alopecia, elevated liver function, thrombocytopenia, or pancreatitis)

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Valproate was significantly more effective in groups with levels >71 mcg/mL, compared with placebo. Groups with serum valproate of 94 to 107 mcg/mL and >107 mcg/mL also showed greater response than did the group with ≤55 mcg/mL. Effect sizes for the 94 to 107 and >107 mcg/mL groups were –1.06 and –1.07 respectively, similar to 12-point decrease on the YMRS. A median 87 mcg/mL was associated with an effect size of –1.1.

 

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Compared with patients receiving placebo, those in the medium therapeutic group stayed in maintenance therapy significantly longer before discontinuing treatment for any reason or because of mania or depression. No significant differences were seen between the placebo and other 3 valproate groups or between the medium therapeutic and other 3 valproate groups.

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

Post hoc analysis of divalproex maintenance treatment data did not examine how soon patients discontinued treatment exclusively because of intolerance.¹³

 

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

	Serum valproate (mcg/mL)
	Lower level	Upper level	Comments
Acute mania	45 to 50	125	Upper level based on tolerability, not efficacy
Maintenance	75	100	Levels based primarily on retrospective analysis
Acute bipolar	Not established	Not established
* Based on available data

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

Related resources

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

Drug brand names

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

Disclosures

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Valproate’s well-accepted therapeutic range for treating epilepsy—50 to 100 mcg/mL—was adopted for bipolar disorder treatment without rigorous evaluation of serum levels and response relationships. Because most literature on monitoring serum valproate refers to its use as an anticonvulsant, you may wonder:

• When should I measure serum valproate in bipolar patients?
  
• What do serum valproate levels mean in their clinical care?
  

To answer these questions, we discuss when to monitor serum valproate, whether routinely or in specific situations. We then review studies that show how serum levels affect valproate’s efficacy and safety in three phases of bipolar disorder management: acute mania, maintenance therapy, and acute depression.

Is monitoring overused?

Some neurologists consider serum levels nonessential—and, in some cases, overused—when valproate is used as an anticonvulsant for healthy patients.^1,2 A multicenter, randomized controlled trial evaluating the impact of antiepileptic drug monitoring on patient outcomes³ supports this notion, at least in part. Serum monitoring did not improve therapeutic outcome, suggesting that patients with epilepsy could be satisfactorily treated by adjusting dosages based on clinical response.

On the other hand, American Psychiatric Association (APA) guidelines for bipolar disorder suggest routine serum monitoring every 6 months along with other hematologic and hepatic assessments, or more frequently if necessary. The APA recommends maintaining serum valproate levels of 50 to 125 mcg/mL when treating:

• acutely manic patients
  
• outpatients
  
• the elderly
  
• patients who are hypomanic or euthymic.⁴
  

Can monitoring help? Although consensus is lacking on the role and necessity of routine monitoring, serum valproate levels can help when you are seeking the most effective treatment for a bipolar patient (Table 1).⁵ Therapeutic monitoring also may help you assess medication adherence. In fact, monitoring may indirectly enhance adherence when the patient knows you will check serum valproate.

Table 1

4 situations where serum valproate monitoring may be clinically useful

To establish a baseline effective level in individual patients
To assess lack or loss of efficacy, including patient adherence
When drug-drug interactions increase or decrease valproate clearance (such as with aspirin, carbamazepine, felbamate, or phenytoin)5
When dose-dependent side effects occur (such as alopecia, elevated liver function, thrombocytopenia, or pancreatitis)

Effective levels in acute mania

In one of the first randomized, double-blind, placebo-controlled trials to examine valproate use in adults with acute mania, Pope et al⁶ used the epilepsy reference range to adjust dosages. Patients (n=17) initially received valproate, 750 mg/d, and dosages were then adjusted to serum levels of 50 to 100 mcg/mL. Nineteen patients received placebo. Mean (SD) baseline Young Mania Rating Scale (YMRS) scores for the valproate and placebo groups were 28.2 (5.8) and 28.6 (6.9), respectively.

Patients receiving valproate showed the greatest symptomatic improvement—as indicated by YMRS scores—within 1 to 4 days of achieving a serum level ≥50 mcg/mL. Serum valproate for all patients was maintained at >50 mcg/mL, which limits our ability to draw conclusions about a minimum level associated with efficacy.

Minimum threshold for efficacy. In another randomized, double-blind, placebo-controlled study of acute mania, Bowden et al⁷ compared the efficacy of divalproex (n=69) versus lithium (n=36) or placebo (n=74) given for 3 weeks. Patients met criteria for manic disorder using the Schedule for Affective Disorders and Schizophrenia (SADS) and had Mania Rating Scale scores (derived from the SADS) of at least 14.

Those in the divalproex group received 750 mg/d for 2 days, then 1,000 mg/d for 3 days. Dosages were then adjusted to target a serum level of 150 mcg/mL, unless limited by side effects. Mean serum valproate levels on days 8 and 21 were 77 and 93.2 mcg/mL, respectively. Marked improvement, defined as ≥50% reduction in Mania Rating Scale scores, was seen in 48% of the divalproex group, compared with 25% of the placebo group.

The authors then analyzed the relationship between serum valproate levels and clinical response and tolerability.⁸ At day 5, patients with serum valproate ≥45 mcg/mL were 2 to 7 times more likely to show 20% or greater improvement in SADS mania subscales (manic syndrome, and behavior and ideation).

This study provided a minimum threshold for valproate efficacy in bipolar mania—45 to 50 mcg/mL—but not a level above which further clinical benefit would not be gained.

Optimum serum ranges. Allen et al⁹ recently conducted a post hoc analysis of pooled intent-to-treat data from three randomized, fixed dose, placebo-controlled studies of divalproex for acute mania. Subjects were stratified into a placebo group (n=171) and six serum valproate ranges:

• ≤55 mcg/mL (n=35)
  
• >55 to 71.3 mcg/mL (n=32)
  
• >71.3 to 85 mcg/mL (n=36)
  
• >85 to 94 mcg/mL (n=34)
  
• >94 to 107 mcg/mL (n=33)
  
• >107 mcg/mL (n=33).
  

Valproate was significantly more effective in groups with levels >71 mcg/mL, compared with placebo. Groups with serum valproate of 94 to 107 mcg/mL and >107 mcg/mL also showed greater response than did the group with ≤55 mcg/mL. Effect sizes for the 94 to 107 and >107 mcg/mL groups were –1.06 and –1.07 respectively, similar to 12-point decrease on the YMRS. A median 87 mcg/mL was associated with an effect size of –1.1.

 

Loading for rapid response. Patients with acute mania may respond sooner when loading doses are used to attain therapeutic serum valproate levels.

Keck et al¹⁰ examined time to onset of improvement in adults with acute mania (N=19) receiving oral loading doses of valproate (20 mg/kg/d in divided doses for 5 days) to rapidly attain valproate levels ≥50 mcg/mL. Ten (53%) patients who received at least 1 loading dose showed a ≥50% reduction in MRS scores and the greatest improvement across the first 3 days.

Hirschfeld et al¹¹ also reported that patients’ symptoms began to improve sooner when divalproex was given at 30 mg/kg/d on days 1 and 2, and 20 mg/kg/d on days 3 to 10 (n=20), compared with standard titration (750 mg/d on days 1 and 2, and gradual dose titration on days 3 to 10 [n=20]).

Discussion. In acute mania, evidence suggests that patients with serum valproate ≥45 to 50 mcg/mL may show greater clinical improvement than patients with lower serum levels. Loading doses may achieve a minimum therapeutic serum level more quickly, yielding faster clinical improvement. A serum level >90 mcg/mL may confer additional benefit.

Although a minimum serum level has been recommended, no data have established a maximum level beyond which further clinical improvement would not be observed.

In maintenance therapy

What serum valproate levels are most effective for bipolar maintenance therapy? Some evidence is emerging.

Bowden et al¹² compared divalproex (n=187), lithium (n=90), and placebo (n=92) in a 52-week, double-blind, parallel-group study of bipolar adult outpatients who met recovery criteria 3 months after an index manic episode. Divalproex dosages were adjusted to achieve trough serum concentrations between 71 and 125 mcg/mL. Mean (SD) and median serum valproate levels were 84.8 (29.9) mcg/mL and 83.9 mcg/mL, respectively. Serum valproate levels significantly correlated with Mania Rating Scale scores. No minimum threshold for efficacy was reported.

Thirteen subjects in the divalproex group were then stratified into 4 categories:

• nontherapeutic (
• low therapeutic (50 to 74.9 mcg/mL)
  
• medium therapeutic (75 to 99.9 mcg/mL)
  
• high therapeutic (>100 mcg/mL).
  

Compared with patients receiving placebo, those in the medium therapeutic group stayed in maintenance therapy significantly longer before discontinuing treatment for any reason or because of mania or depression. No significant differences were seen between the placebo and other 3 valproate groups or between the medium therapeutic and other 3 valproate groups.

Discussion. Serum valproate levels of 75 to 100 mcg/mL may be most effective in preventing subsequent mood episodes with acceptable tolerability. Prospective, longitudinal studies are needed to better establish a therapeutic range for valproate in bipolar maintenance therapy.

In bipolar depression

Little evidence supports a therapeutic serum valproate range for treating acute bipolar depression.

In an 8-week, double-blind study, Davis et al¹⁴ randomly assigned adults with bipolar depression to divalproex (n=13) or placebo (n=12). Bipolar depression diagnoses were confirmed using the Structured Clinical Interview for DSM-IV, and patients were required to have a Hamilton Rating Scale for Depression (HRSD) score ≥16.

Valproate was started at 500 mg/d and titrated to serum levels of 50 to 150 mcg/mL. Mean (SD) serum valproate levels at weeks 4 and 8 were 80 (9.3) mcg/mL and 81 (19.2) mcg/mL, respectively. Remission rate (defined a priori as a >50% improvement and total HRSD score 15 In Sachs’ 8-week study, the mean (SD) valproate level was 61.5 (42.8) mcg/mL.

Discussion. The relationship between serum valproate and therapeutic efficacy in acute bipolar depression—and the range of levels considered therapeutic—are undefined. For now we recommend that individual patients’ clinical response and tolerability guide optimum serum valproate in acute bipolar depression (Box).¹⁶

Box

High levels and safety

High serum valproate levels may increase the risk and frequency of side effects. For example, serum levels >125 mcg/mL have been associated with:

• increased nausea, vomiting, dizziness, and sedation in acutely manic patients⁸
  
• weight gain and reduced platelets and white blood cells in patients receiving valproate as maintenance treatment.¹²
  

Post hoc analysis of divalproex maintenance treatment data did not examine how soon patients discontinued treatment exclusively because of intolerance.¹³

 

In the loading dose study by Hirschfeld et al,¹¹ patients receiving divalproex, 20 to 30 mg/kg/d, did not experience a higher frequency or severity of side effects compared with patients receiving standard titration. Keck et al¹⁰ also reported minimal valproate-related side effects in their open-label study. Neither study suggested an upper-limit valproate level associated with increased side effects.

Discussion. Serum valproate >125 mcg/mL has been associated with increased side effects (Table 2), but more studies are needed.

Table 2

For bipolar disorder, suggested serum valproate therapeutic ranges*

	Serum valproate (mcg/mL)
	Lower level	Upper level	Comments
Acute mania	45 to 50	125	Upper level based on tolerability, not efficacy
Maintenance	75	100	Levels based primarily on retrospective analysis
Acute bipolar	Not established	Not established
* Based on available data

Clinical recommendations

Carefully consider when to monitor serum valproate levels in your patients with bipolar disorder:

• Obtaining routine serum levels can be expensive, and no data support the cost-effectiveness of this approach in bipolar disorder.
  
• Individualize valproate dosing; a specific patient’s therapeutic range may differ from another’s or from those published in the literature or used by a clinical laboratory.
  
• Monitoring serum valproate levels does not replace the need to adjust dosages based on patients’ therapeutic response and tolerance.
  

Related resources

• American Psychiatric Association. Practice guideline for the treatment of patients with bipolar disorder (revision). Am J Psychiatry2002; 159(suppl 4):1–50.
  
• Depression and Bipolar Support Alliance. www.dbsalliance.org.
  

Drug brand names

• Carbamazepine • Tegretol, Equetro
  
• Divalproex sodium • Depakote
  
• Felbamate • Felbatol
  
• Phenytoin • Dilantin
  

Disclosures

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

Dr. Patel is a consultant to and speaker for Eli Lilly and Co. and a speaker for Pfizer.

Dr. Keck receives research support from or is a consultant to or advisor for Abbott Laboratories, AstraZeneca Pharmaceuticals, Bristol-Myers Squibb Co., GlaxoSmithKline, Janssen Pharmaceutica, Eli Lilly and Co., Organon, Ortho-McNeil Pharmaceutical, Merck & Co., Pfizer, Shire, and UCB Pharma.

Comorbid attention-deficit/hyperactivity disorder (ADHD) is nearly universal in youths with bipolar disorder (BPD),¹ and comorbid mania has been noted in 16% of children with ADHD.² Choosing medication for these complex patients is difficult because psychostimulants may worsen mania and mood stabilizers may not resolve ADHD symptoms. Yet, very little information exists on combining psychostimulants with mood stabilizers or atypical antipsychotics.

This article offers evidence to help you decide:

• which to treat first—ADHD or BPD
• how to individualize combination therapy.

CHALLENGES OF COMORBIDITY

Differential diagnosis. ADHD and bipolar disorder (BPD) symptoms overlap, and experts disagree on which symptoms indicate co-existing ADHD and BPD. Multiple daily mood swings and irritability are commonly found in prepubertal BPD.³ Recent reviews address differential diagnosis and specific assessment tools;^3-5 after careful evaluation, then focus on treatment.

Treating comorbid ADHD and BPD usually requires more than one medication, and use of multiple drugs in children and adolescents is becoming increasingly common.^6,7

PSYCHOSTIMULANTS AND MOOD STABILIZERS

Small, uncontrolled studies of children and adolescents with comorbid ADHD and BPD have shown that treatment with a mood stabilizer and a psychostimulant can control both sets of symptoms. For example:

• Lithium (serum levels 0.7 to 1.1 mEq/L) plus methylphenidate (10 to 20 mg/d) improved attention and hyperactivity symptoms more effectively than either agent alone in 7 children (6 boys, 1 girl) ages 6 to 10 hospitalized with disruptive behavioral disorders and BPD or major depression.⁸
• A retrospective analysis of 38 children (ages 3 to 16; 84% male) with BPD found that ADHD symptoms were 7.5 times more likely to improve if mood was stabilized before rather than after ADHD treatment with tricyclic antidepressants.⁹

The efficacy of combining a mood stabilizer and psychostimulant has been confirmed by only one controlled study—a randomized, placebo-controlled trial of mixed amphetamine salts in divalproex-treated patients.¹⁰ Forty patients (ages 6 to 17; 83% male) with BPD and ADHD received open-label divalproex (median dosage 750 mg/d) for 8 weeks. Thirty patients whose manic symptoms were significantly reduced entered a 4-week, double-blind, crossover trial of mixed amphetamine salts, 10 mg/d, or placebo.

Following this double-blind phase, 23 patients received open-label divalproex plus mixed amphetamine salts for 12 weeks. The Young Mania Rating Scale and Clinical Global Impression-Improvement scale were used to assess manic and ADHD symptoms during all three study phases.

Manic symptoms in patients treated with divalproex monotherapy improved significantly, but ADHD symptoms did not. ADHD symptoms improved more with divalproex plus mixed amphetamine salts than with divalproex plus placebo. One patient experienced manic symptom exacerbation with combination therapy.

PSYCHOSTIMULANTS AND ANTIPSYCHOTICS

Combinations of psychostimulants and atypical antipsychotics are commonly used in children and adolescents with comorbid psychiatric and behavioral disorders, such as ADHD and disruptive behavioral disorders (oppositional defiant disorder, conduct disorder). In 78 children ages 5 to 12 (83% male) with comorbid ADHD and a disruptive behavioral disorder, disruptive behavior and hyperactivity improved significantly with risperidone alone or with a psychostimulant.¹¹

Combined psychostimulant/atypical antipsychotic therapy may help youths with comorbid ADHD and Tourette syndrome. Methylphenidate can reduce ADHD symptoms without exacerbating tics,¹² and risperidone can treat tic disorders, even in patients with comorbid ADHD.^13,14 No controlled trials have examined psychostimulant and atypical antipsychotic combinations in these patients, however.

Atypical antipsychotics have been shown to be effective in treating adult BPD, and limited data suggest the same to be true in pediatric patients. Olanzapine, quetiapine, and risperidone have been shown to reduce manic symptoms in children and adolescents (Table 1).^15-17 Atypical antipsychotics, however, have been associated with metabolic side effects, including weight gain, hyperglycemia, hyperlipidemia, and hyperprolactinemia.

To date, no study has systematically evaluated combination psychostimulant and atypical antipsychotic treatment in comorbid ADHD and BPD. In the olanzapine and risperidone studies,^15,17 concomitant psychostimulant use was permitted and did not affect manic symptom response.

Table 1

Atypical antipsychotic studies in pediatric bipolar disorder

Drug and mean dosage	Study design	Sample characteristics	Efficacy measures	Results
Olanzapine15 9.6±4.3 mg/d	8-week, open-label monotherapy	23 patients, mean age 10±3 yrs, 57% male	≥30% decrease on YMRS	Response rate 61%
Quetiapine16 432 mg/d	6-week, randomized, placebo-controlled, adjunctive (+DVP)	30 patients, mean age 14±2 yrs, 53% male	≥50% decrease on YMRS	Response rates: DVP + placebo 53% DVP + quetiapine 87%
Risperidone17 1.7±1.3 mg/d	Retrospective, adjunctive	28 patients, mean age 10±4 yrs, 97% male	≤2 on CGI-I	Response rate 82%
CGI-I: Clinical Global Impressions-Improvement scale
DVP: divalproex
YMRS: Young Mania Rating Scale

WHICH COMBINATION?

Which combination treatment—psychostimulant plus mood stabilizer, psychostimulant plus atypical antipsychotic, or psychostimulant plus both mood stabilizer and atypical antipsychotic—is most appropriate for a child or adolescent with comorbid ADHD and BPD? Recommended treatment strategies are based on studies of pediatric and adult BPD and expert consensus.^18,19

 

Consider the type of bipolar episode (Table 2).

For initial treatment of youths with BPD manic or mixed without psychosis, recent guidelines by Kowatch et al suggest using mood-stabilizer or atypical antipsychotic monotherapy. Youths who are more severely ill or present with psychosis may respond more favorably to a mood stabilizer plus an atypical antipsychotic.^16,19

Individual patient traits will also determine whether a mood stabilizer or atypical antipsychotic is used and which agent within either medication class is chosen. For example:

• If the patient is aggressive, risperidone may reduce aggression and manic symptoms. Among the atypicals, risperidone has the most evidence suggesting efficacy for aggressive behaviors in youths across psychiatric conditions.²⁰
• If an atypical antipsychotic is warranted and the patient’s weight is an issue, ziprasidone or aripiprazole would be preferred. These agents are considered weight-neutral compared with other atypicals.²⁰

Other factors to consider include medication side effects, interactions, adherence, and cost.

Table 2

Mood stabilizer, atypical antipsychotic, or both with ADHD therapy?

Type of bipolar episode	Recommended psychotropics
Manic or mixed episode with psychosis	Mood stabilizer + atypical antipsychotic
Manic or mixed episode without psychosis	Mood stabilizer or atypical antipsychotic monotherapy first if no response, switch to the other monotherapy if partial response, augment one with the other
Prominent irritability without psychosis	Atypical antipsychotic
Source: Adapted from references 18 and 19

WHICH TO TREAT FIRST?

If the child or adolescent with comorbid ADHD and BPD has acute manic symptoms, available data and expert opinion recommend starting treatment with a mood stabilizer or atypical antipsychotic.^9,19,21 If ADHD symptoms persist after mood stabilization, a psychostimulant trial is warranted.

In practice, however, youngsters usually present with ADHD symptoms first. Psychostimulant treatment is initiated, ADHD symptoms are controlled, and the child’s academic and social functioning improve. Bipolar symptoms emerge later, often heralded by a depressive or mixed episode. Is it necessary to discontinue the psychostimulant and risk worsening ADHD symptoms before starting a mood stabilizer or atypical antipsychotic?

Clinical lore and one case report suggest that psychostimulants may destabilize mood.^22,23 A 10-year-old boy with severe hyperactivity and family history of BPD experienced manic symptoms—rapid and pressured speech, grandiose delusions of identity, and tangentiality of thought processes—during methylphenidate treatment.²²

Conversely, an analysis²⁴ of children ages 7 to 10 from the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD contradicts these assumptions. Although a clinical diagnosis of BPD was not assigned, 29 children (83% male) met the Diagnostic Interview Schedule for Children proxy for mania, 32 (88% male) met the Child Behavior Checklist proxy, and 7 met both proxies for mania.

The first month of methylphenidate treatment did not increase irritability, mood symptoms, or mania in the 54 children with ADHD and manic symptoms, compared with children with ADHD alone. The authors concluded that clinicians should not categorically avoid using stimulants in children with ADHD and some manic symptoms.

In a study by Pavuluri et al¹⁸ of pediatric bipolar type I disorder, 17 patients (mean age 11±4 years) received mood stabilizers—following a drug therapy algorithm that included risperidone—and typically received a psychostimulant after mood stabilization. This group was compared with 17 patients receiving “treatment as usual.”

The usual-treatment group remained on psychostimulant therapy after BPD intervention with a mood stabilizer and was less likely to receive an atypical antipsychotic. The algorithm treatment group showed better outcomes overall, specifically for mania and aggression.

Clearly, more studies are needed to determine the optimum treatment sequence with psychostimulants and mood stabilizers in youths with comorbid ADHD and BPD. With either approach, routinely monitor patients treated with psychostimulants for emerging or worsening bipolar symptoms.

LESSONS FROM CLINICAL EXPERIENCE

Nonstimulants. Using psychostimulants is appropriate for ADHD in patients with stable bipolar symptoms. Evidence for using nonstimulants such as clonidine, guanfacine, or atomoxetine is less clear.

In a naturalistic study of 153 children and adolescent outpatients treated with atomoxetine, 51 (33%) experienced irritability, aggression, mania, or hypomania. Of these patients, 31 (61%) had a family history of a mood disorder, and 41 (80%) had a personal history of mood symptoms.²⁵ Although these findings suggest that atomoxetine may be associated with mood exacerbation and hypomania, additional data are needed to determine whether atomoxetine may be used for ADHD symptoms in youths with comorbid BPD.

Atypical antipsychotics. Mood stabilization—particularly with atypical antipsychotics—often can address comorbid disruptive behaviors and aggressive symptoms. Combinations of atypical antipsychotics with psychostimulants are largely devoid of drug-drug interactions and metabolic interference, making them uncomplicated to use.

Though published studies of pediatric BPD have focused on three atypical antipsychotics—olanzapine, quetiapine, and risperidone—any agent in this class can be used in this population, with the choice often depending on how side effects are likely to affect individual patients (Table 3 ).

 

Pharmacologic attributes may also determine which atypical antipsychotic is used. For example, ziprasidone’s serotonergic profile—with serotonin-1A receptor agonism and serotonin-1D antagonism—may make it useful for patients with mixed states and bipolar depression.²⁶ Aripiprazole offers potential synergism of dopamine agonism with psychostimulant therapy, which could be useful for treating both disruptive behaviors and ADHD.

Table 3

Using atypical antipsychotics to treat comorbid ADHD/bipolar disorder

Drug	Target dosage (mg/d)	Side effects	Useful in…
Aripiprazole	10 to 15	Nausea, vomiting	Comorbid disruptive behavioral disorders, maintenance stabilization
Olanzapine	10 to 20	Weight gain, hyperlipidemia, hyperglycemia, sedation	Maintenance stabilization
Quetiapine	400 to 600	Weight gain, sedation	Mixed states, bipolar depression
Risperidone	1 to 2	Weight gain, hyperprolactinemia, extrapyramidal symptoms	Comorbid disruptive behavioral disorders, including aggression
Ziprasidone	80 to 120	Cardiac abnormalities, akathisia	Mixed states, bipolar depression

Related resources

• Child and Adolescent Bipolar Foundation. www.bpkids.org
• Children and Adults with Attention-Deficit Hyperactivity Disorder (CHADD). www.chadd.org
• Findling RF, Kowatch RA, Post RM. P ediatric bipolar disorders: a handbook for clinicians. London: Martin Dunitz Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Aripiprazole • Abilify
• Divalproex • Depakote
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Patel is a consultant to Eli Lilly and Co. and a speaker for Eli Lilly and Co. and Pfizer Inc.

Dr. Sallee receives research support from Otsuka America Pharmaceutical, Pfizer Inc., and Bristol-Myers Squibb Co. and is a consultant or speaker for Eli Lilly and Co, Otsuka America Pharmaceutical, and Pfizer Inc.

Comorbid attention-deficit/hyperactivity disorder (ADHD) is nearly universal in youths with bipolar disorder (BPD),¹ and comorbid mania has been noted in 16% of children with ADHD.² Choosing medication for these complex patients is difficult because psychostimulants may worsen mania and mood stabilizers may not resolve ADHD symptoms. Yet, very little information exists on combining psychostimulants with mood stabilizers or atypical antipsychotics.

This article offers evidence to help you decide:

• which to treat first—ADHD or BPD
• how to individualize combination therapy.

CHALLENGES OF COMORBIDITY

Differential diagnosis. ADHD and bipolar disorder (BPD) symptoms overlap, and experts disagree on which symptoms indicate co-existing ADHD and BPD. Multiple daily mood swings and irritability are commonly found in prepubertal BPD.³ Recent reviews address differential diagnosis and specific assessment tools;^3-5 after careful evaluation, then focus on treatment.

Treating comorbid ADHD and BPD usually requires more than one medication, and use of multiple drugs in children and adolescents is becoming increasingly common.^6,7

PSYCHOSTIMULANTS AND MOOD STABILIZERS

Small, uncontrolled studies of children and adolescents with comorbid ADHD and BPD have shown that treatment with a mood stabilizer and a psychostimulant can control both sets of symptoms. For example:

• Lithium (serum levels 0.7 to 1.1 mEq/L) plus methylphenidate (10 to 20 mg/d) improved attention and hyperactivity symptoms more effectively than either agent alone in 7 children (6 boys, 1 girl) ages 6 to 10 hospitalized with disruptive behavioral disorders and BPD or major depression.⁸
• A retrospective analysis of 38 children (ages 3 to 16; 84% male) with BPD found that ADHD symptoms were 7.5 times more likely to improve if mood was stabilized before rather than after ADHD treatment with tricyclic antidepressants.⁹

The efficacy of combining a mood stabilizer and psychostimulant has been confirmed by only one controlled study—a randomized, placebo-controlled trial of mixed amphetamine salts in divalproex-treated patients.¹⁰ Forty patients (ages 6 to 17; 83% male) with BPD and ADHD received open-label divalproex (median dosage 750 mg/d) for 8 weeks. Thirty patients whose manic symptoms were significantly reduced entered a 4-week, double-blind, crossover trial of mixed amphetamine salts, 10 mg/d, or placebo.

Following this double-blind phase, 23 patients received open-label divalproex plus mixed amphetamine salts for 12 weeks. The Young Mania Rating Scale and Clinical Global Impression-Improvement scale were used to assess manic and ADHD symptoms during all three study phases.

Manic symptoms in patients treated with divalproex monotherapy improved significantly, but ADHD symptoms did not. ADHD symptoms improved more with divalproex plus mixed amphetamine salts than with divalproex plus placebo. One patient experienced manic symptom exacerbation with combination therapy.

PSYCHOSTIMULANTS AND ANTIPSYCHOTICS

Combinations of psychostimulants and atypical antipsychotics are commonly used in children and adolescents with comorbid psychiatric and behavioral disorders, such as ADHD and disruptive behavioral disorders (oppositional defiant disorder, conduct disorder). In 78 children ages 5 to 12 (83% male) with comorbid ADHD and a disruptive behavioral disorder, disruptive behavior and hyperactivity improved significantly with risperidone alone or with a psychostimulant.¹¹

Combined psychostimulant/atypical antipsychotic therapy may help youths with comorbid ADHD and Tourette syndrome. Methylphenidate can reduce ADHD symptoms without exacerbating tics,¹² and risperidone can treat tic disorders, even in patients with comorbid ADHD.^13,14 No controlled trials have examined psychostimulant and atypical antipsychotic combinations in these patients, however.

Atypical antipsychotics have been shown to be effective in treating adult BPD, and limited data suggest the same to be true in pediatric patients. Olanzapine, quetiapine, and risperidone have been shown to reduce manic symptoms in children and adolescents (Table 1).^15-17 Atypical antipsychotics, however, have been associated with metabolic side effects, including weight gain, hyperglycemia, hyperlipidemia, and hyperprolactinemia.

To date, no study has systematically evaluated combination psychostimulant and atypical antipsychotic treatment in comorbid ADHD and BPD. In the olanzapine and risperidone studies,^15,17 concomitant psychostimulant use was permitted and did not affect manic symptom response.

Table 1

Atypical antipsychotic studies in pediatric bipolar disorder

Drug and mean dosage	Study design	Sample characteristics	Efficacy measures	Results
Olanzapine15 9.6±4.3 mg/d	8-week, open-label monotherapy	23 patients, mean age 10±3 yrs, 57% male	≥30% decrease on YMRS	Response rate 61%
Quetiapine16 432 mg/d	6-week, randomized, placebo-controlled, adjunctive (+DVP)	30 patients, mean age 14±2 yrs, 53% male	≥50% decrease on YMRS	Response rates: DVP + placebo 53% DVP + quetiapine 87%
Risperidone17 1.7±1.3 mg/d	Retrospective, adjunctive	28 patients, mean age 10±4 yrs, 97% male	≤2 on CGI-I	Response rate 82%
CGI-I: Clinical Global Impressions-Improvement scale
DVP: divalproex
YMRS: Young Mania Rating Scale

WHICH COMBINATION?

Which combination treatment—psychostimulant plus mood stabilizer, psychostimulant plus atypical antipsychotic, or psychostimulant plus both mood stabilizer and atypical antipsychotic—is most appropriate for a child or adolescent with comorbid ADHD and BPD? Recommended treatment strategies are based on studies of pediatric and adult BPD and expert consensus.^18,19

 

Consider the type of bipolar episode (Table 2).

For initial treatment of youths with BPD manic or mixed without psychosis, recent guidelines by Kowatch et al suggest using mood-stabilizer or atypical antipsychotic monotherapy. Youths who are more severely ill or present with psychosis may respond more favorably to a mood stabilizer plus an atypical antipsychotic.^16,19

Individual patient traits will also determine whether a mood stabilizer or atypical antipsychotic is used and which agent within either medication class is chosen. For example:

• If the patient is aggressive, risperidone may reduce aggression and manic symptoms. Among the atypicals, risperidone has the most evidence suggesting efficacy for aggressive behaviors in youths across psychiatric conditions.²⁰
• If an atypical antipsychotic is warranted and the patient’s weight is an issue, ziprasidone or aripiprazole would be preferred. These agents are considered weight-neutral compared with other atypicals.²⁰

Other factors to consider include medication side effects, interactions, adherence, and cost.

Table 2

Mood stabilizer, atypical antipsychotic, or both with ADHD therapy?

Type of bipolar episode	Recommended psychotropics
Manic or mixed episode with psychosis	Mood stabilizer + atypical antipsychotic
Manic or mixed episode without psychosis	Mood stabilizer or atypical antipsychotic monotherapy first if no response, switch to the other monotherapy if partial response, augment one with the other
Prominent irritability without psychosis	Atypical antipsychotic
Source: Adapted from references 18 and 19

WHICH TO TREAT FIRST?

If the child or adolescent with comorbid ADHD and BPD has acute manic symptoms, available data and expert opinion recommend starting treatment with a mood stabilizer or atypical antipsychotic.^9,19,21 If ADHD symptoms persist after mood stabilization, a psychostimulant trial is warranted.

In practice, however, youngsters usually present with ADHD symptoms first. Psychostimulant treatment is initiated, ADHD symptoms are controlled, and the child’s academic and social functioning improve. Bipolar symptoms emerge later, often heralded by a depressive or mixed episode. Is it necessary to discontinue the psychostimulant and risk worsening ADHD symptoms before starting a mood stabilizer or atypical antipsychotic?

Clinical lore and one case report suggest that psychostimulants may destabilize mood.^22,23 A 10-year-old boy with severe hyperactivity and family history of BPD experienced manic symptoms—rapid and pressured speech, grandiose delusions of identity, and tangentiality of thought processes—during methylphenidate treatment.²²

Conversely, an analysis²⁴ of children ages 7 to 10 from the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD contradicts these assumptions. Although a clinical diagnosis of BPD was not assigned, 29 children (83% male) met the Diagnostic Interview Schedule for Children proxy for mania, 32 (88% male) met the Child Behavior Checklist proxy, and 7 met both proxies for mania.

The first month of methylphenidate treatment did not increase irritability, mood symptoms, or mania in the 54 children with ADHD and manic symptoms, compared with children with ADHD alone. The authors concluded that clinicians should not categorically avoid using stimulants in children with ADHD and some manic symptoms.

In a study by Pavuluri et al¹⁸ of pediatric bipolar type I disorder, 17 patients (mean age 11±4 years) received mood stabilizers—following a drug therapy algorithm that included risperidone—and typically received a psychostimulant after mood stabilization. This group was compared with 17 patients receiving “treatment as usual.”

The usual-treatment group remained on psychostimulant therapy after BPD intervention with a mood stabilizer and was less likely to receive an atypical antipsychotic. The algorithm treatment group showed better outcomes overall, specifically for mania and aggression.

Clearly, more studies are needed to determine the optimum treatment sequence with psychostimulants and mood stabilizers in youths with comorbid ADHD and BPD. With either approach, routinely monitor patients treated with psychostimulants for emerging or worsening bipolar symptoms.

LESSONS FROM CLINICAL EXPERIENCE

Nonstimulants. Using psychostimulants is appropriate for ADHD in patients with stable bipolar symptoms. Evidence for using nonstimulants such as clonidine, guanfacine, or atomoxetine is less clear.

In a naturalistic study of 153 children and adolescent outpatients treated with atomoxetine, 51 (33%) experienced irritability, aggression, mania, or hypomania. Of these patients, 31 (61%) had a family history of a mood disorder, and 41 (80%) had a personal history of mood symptoms.²⁵ Although these findings suggest that atomoxetine may be associated with mood exacerbation and hypomania, additional data are needed to determine whether atomoxetine may be used for ADHD symptoms in youths with comorbid BPD.

Atypical antipsychotics. Mood stabilization—particularly with atypical antipsychotics—often can address comorbid disruptive behaviors and aggressive symptoms. Combinations of atypical antipsychotics with psychostimulants are largely devoid of drug-drug interactions and metabolic interference, making them uncomplicated to use.

Though published studies of pediatric BPD have focused on three atypical antipsychotics—olanzapine, quetiapine, and risperidone—any agent in this class can be used in this population, with the choice often depending on how side effects are likely to affect individual patients (Table 3 ).

 

Pharmacologic attributes may also determine which atypical antipsychotic is used. For example, ziprasidone’s serotonergic profile—with serotonin-1A receptor agonism and serotonin-1D antagonism—may make it useful for patients with mixed states and bipolar depression.²⁶ Aripiprazole offers potential synergism of dopamine agonism with psychostimulant therapy, which could be useful for treating both disruptive behaviors and ADHD.

Table 3

Using atypical antipsychotics to treat comorbid ADHD/bipolar disorder

Drug	Target dosage (mg/d)	Side effects	Useful in…
Aripiprazole	10 to 15	Nausea, vomiting	Comorbid disruptive behavioral disorders, maintenance stabilization
Olanzapine	10 to 20	Weight gain, hyperlipidemia, hyperglycemia, sedation	Maintenance stabilization
Quetiapine	400 to 600	Weight gain, sedation	Mixed states, bipolar depression
Risperidone	1 to 2	Weight gain, hyperprolactinemia, extrapyramidal symptoms	Comorbid disruptive behavioral disorders, including aggression
Ziprasidone	80 to 120	Cardiac abnormalities, akathisia	Mixed states, bipolar depression

Related resources

• Child and Adolescent Bipolar Foundation. www.bpkids.org
• Children and Adults with Attention-Deficit Hyperactivity Disorder (CHADD). www.chadd.org
• Findling RF, Kowatch RA, Post RM. P ediatric bipolar disorders: a handbook for clinicians. London: Martin Dunitz Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Aripiprazole • Abilify
• Divalproex • Depakote
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Patel is a consultant to Eli Lilly and Co. and a speaker for Eli Lilly and Co. and Pfizer Inc.

Dr. Sallee receives research support from Otsuka America Pharmaceutical, Pfizer Inc., and Bristol-Myers Squibb Co. and is a consultant or speaker for Eli Lilly and Co, Otsuka America Pharmaceutical, and Pfizer Inc.

Comorbid attention-deficit/hyperactivity disorder (ADHD) is nearly universal in youths with bipolar disorder (BPD),¹ and comorbid mania has been noted in 16% of children with ADHD.² Choosing medication for these complex patients is difficult because psychostimulants may worsen mania and mood stabilizers may not resolve ADHD symptoms. Yet, very little information exists on combining psychostimulants with mood stabilizers or atypical antipsychotics.

This article offers evidence to help you decide:

• which to treat first—ADHD or BPD
• how to individualize combination therapy.

CHALLENGES OF COMORBIDITY

Differential diagnosis. ADHD and bipolar disorder (BPD) symptoms overlap, and experts disagree on which symptoms indicate co-existing ADHD and BPD. Multiple daily mood swings and irritability are commonly found in prepubertal BPD.³ Recent reviews address differential diagnosis and specific assessment tools;^3-5 after careful evaluation, then focus on treatment.

Treating comorbid ADHD and BPD usually requires more than one medication, and use of multiple drugs in children and adolescents is becoming increasingly common.^6,7

PSYCHOSTIMULANTS AND MOOD STABILIZERS

Small, uncontrolled studies of children and adolescents with comorbid ADHD and BPD have shown that treatment with a mood stabilizer and a psychostimulant can control both sets of symptoms. For example:

• Lithium (serum levels 0.7 to 1.1 mEq/L) plus methylphenidate (10 to 20 mg/d) improved attention and hyperactivity symptoms more effectively than either agent alone in 7 children (6 boys, 1 girl) ages 6 to 10 hospitalized with disruptive behavioral disorders and BPD or major depression.⁸
• A retrospective analysis of 38 children (ages 3 to 16; 84% male) with BPD found that ADHD symptoms were 7.5 times more likely to improve if mood was stabilized before rather than after ADHD treatment with tricyclic antidepressants.⁹

The efficacy of combining a mood stabilizer and psychostimulant has been confirmed by only one controlled study—a randomized, placebo-controlled trial of mixed amphetamine salts in divalproex-treated patients.¹⁰ Forty patients (ages 6 to 17; 83% male) with BPD and ADHD received open-label divalproex (median dosage 750 mg/d) for 8 weeks. Thirty patients whose manic symptoms were significantly reduced entered a 4-week, double-blind, crossover trial of mixed amphetamine salts, 10 mg/d, or placebo.

Following this double-blind phase, 23 patients received open-label divalproex plus mixed amphetamine salts for 12 weeks. The Young Mania Rating Scale and Clinical Global Impression-Improvement scale were used to assess manic and ADHD symptoms during all three study phases.

Manic symptoms in patients treated with divalproex monotherapy improved significantly, but ADHD symptoms did not. ADHD symptoms improved more with divalproex plus mixed amphetamine salts than with divalproex plus placebo. One patient experienced manic symptom exacerbation with combination therapy.

PSYCHOSTIMULANTS AND ANTIPSYCHOTICS

Combinations of psychostimulants and atypical antipsychotics are commonly used in children and adolescents with comorbid psychiatric and behavioral disorders, such as ADHD and disruptive behavioral disorders (oppositional defiant disorder, conduct disorder). In 78 children ages 5 to 12 (83% male) with comorbid ADHD and a disruptive behavioral disorder, disruptive behavior and hyperactivity improved significantly with risperidone alone or with a psychostimulant.¹¹

Combined psychostimulant/atypical antipsychotic therapy may help youths with comorbid ADHD and Tourette syndrome. Methylphenidate can reduce ADHD symptoms without exacerbating tics,¹² and risperidone can treat tic disorders, even in patients with comorbid ADHD.^13,14 No controlled trials have examined psychostimulant and atypical antipsychotic combinations in these patients, however.

Atypical antipsychotics have been shown to be effective in treating adult BPD, and limited data suggest the same to be true in pediatric patients. Olanzapine, quetiapine, and risperidone have been shown to reduce manic symptoms in children and adolescents (Table 1).^15-17 Atypical antipsychotics, however, have been associated with metabolic side effects, including weight gain, hyperglycemia, hyperlipidemia, and hyperprolactinemia.

To date, no study has systematically evaluated combination psychostimulant and atypical antipsychotic treatment in comorbid ADHD and BPD. In the olanzapine and risperidone studies,^15,17 concomitant psychostimulant use was permitted and did not affect manic symptom response.

Table 1

Atypical antipsychotic studies in pediatric bipolar disorder

Drug and mean dosage	Study design	Sample characteristics	Efficacy measures	Results
Olanzapine15 9.6±4.3 mg/d	8-week, open-label monotherapy	23 patients, mean age 10±3 yrs, 57% male	≥30% decrease on YMRS	Response rate 61%
Quetiapine16 432 mg/d	6-week, randomized, placebo-controlled, adjunctive (+DVP)	30 patients, mean age 14±2 yrs, 53% male	≥50% decrease on YMRS	Response rates: DVP + placebo 53% DVP + quetiapine 87%
Risperidone17 1.7±1.3 mg/d	Retrospective, adjunctive	28 patients, mean age 10±4 yrs, 97% male	≤2 on CGI-I	Response rate 82%
CGI-I: Clinical Global Impressions-Improvement scale
DVP: divalproex
YMRS: Young Mania Rating Scale

WHICH COMBINATION?

Which combination treatment—psychostimulant plus mood stabilizer, psychostimulant plus atypical antipsychotic, or psychostimulant plus both mood stabilizer and atypical antipsychotic—is most appropriate for a child or adolescent with comorbid ADHD and BPD? Recommended treatment strategies are based on studies of pediatric and adult BPD and expert consensus.^18,19

 

Consider the type of bipolar episode (Table 2).

For initial treatment of youths with BPD manic or mixed without psychosis, recent guidelines by Kowatch et al suggest using mood-stabilizer or atypical antipsychotic monotherapy. Youths who are more severely ill or present with psychosis may respond more favorably to a mood stabilizer plus an atypical antipsychotic.^16,19

Individual patient traits will also determine whether a mood stabilizer or atypical antipsychotic is used and which agent within either medication class is chosen. For example:

• If the patient is aggressive, risperidone may reduce aggression and manic symptoms. Among the atypicals, risperidone has the most evidence suggesting efficacy for aggressive behaviors in youths across psychiatric conditions.²⁰
• If an atypical antipsychotic is warranted and the patient’s weight is an issue, ziprasidone or aripiprazole would be preferred. These agents are considered weight-neutral compared with other atypicals.²⁰

Other factors to consider include medication side effects, interactions, adherence, and cost.

Table 2

Mood stabilizer, atypical antipsychotic, or both with ADHD therapy?

Type of bipolar episode	Recommended psychotropics
Manic or mixed episode with psychosis	Mood stabilizer + atypical antipsychotic
Manic or mixed episode without psychosis	Mood stabilizer or atypical antipsychotic monotherapy first if no response, switch to the other monotherapy if partial response, augment one with the other
Prominent irritability without psychosis	Atypical antipsychotic
Source: Adapted from references 18 and 19

WHICH TO TREAT FIRST?

If the child or adolescent with comorbid ADHD and BPD has acute manic symptoms, available data and expert opinion recommend starting treatment with a mood stabilizer or atypical antipsychotic.^9,19,21 If ADHD symptoms persist after mood stabilization, a psychostimulant trial is warranted.

In practice, however, youngsters usually present with ADHD symptoms first. Psychostimulant treatment is initiated, ADHD symptoms are controlled, and the child’s academic and social functioning improve. Bipolar symptoms emerge later, often heralded by a depressive or mixed episode. Is it necessary to discontinue the psychostimulant and risk worsening ADHD symptoms before starting a mood stabilizer or atypical antipsychotic?

Clinical lore and one case report suggest that psychostimulants may destabilize mood.^22,23 A 10-year-old boy with severe hyperactivity and family history of BPD experienced manic symptoms—rapid and pressured speech, grandiose delusions of identity, and tangentiality of thought processes—during methylphenidate treatment.²²

Conversely, an analysis²⁴ of children ages 7 to 10 from the National Institute of Mental Health Multimodal Treatment Study of Children with ADHD contradicts these assumptions. Although a clinical diagnosis of BPD was not assigned, 29 children (83% male) met the Diagnostic Interview Schedule for Children proxy for mania, 32 (88% male) met the Child Behavior Checklist proxy, and 7 met both proxies for mania.

The first month of methylphenidate treatment did not increase irritability, mood symptoms, or mania in the 54 children with ADHD and manic symptoms, compared with children with ADHD alone. The authors concluded that clinicians should not categorically avoid using stimulants in children with ADHD and some manic symptoms.

In a study by Pavuluri et al¹⁸ of pediatric bipolar type I disorder, 17 patients (mean age 11±4 years) received mood stabilizers—following a drug therapy algorithm that included risperidone—and typically received a psychostimulant after mood stabilization. This group was compared with 17 patients receiving “treatment as usual.”

The usual-treatment group remained on psychostimulant therapy after BPD intervention with a mood stabilizer and was less likely to receive an atypical antipsychotic. The algorithm treatment group showed better outcomes overall, specifically for mania and aggression.

Clearly, more studies are needed to determine the optimum treatment sequence with psychostimulants and mood stabilizers in youths with comorbid ADHD and BPD. With either approach, routinely monitor patients treated with psychostimulants for emerging or worsening bipolar symptoms.

LESSONS FROM CLINICAL EXPERIENCE

Nonstimulants. Using psychostimulants is appropriate for ADHD in patients with stable bipolar symptoms. Evidence for using nonstimulants such as clonidine, guanfacine, or atomoxetine is less clear.

In a naturalistic study of 153 children and adolescent outpatients treated with atomoxetine, 51 (33%) experienced irritability, aggression, mania, or hypomania. Of these patients, 31 (61%) had a family history of a mood disorder, and 41 (80%) had a personal history of mood symptoms.²⁵ Although these findings suggest that atomoxetine may be associated with mood exacerbation and hypomania, additional data are needed to determine whether atomoxetine may be used for ADHD symptoms in youths with comorbid BPD.

Atypical antipsychotics. Mood stabilization—particularly with atypical antipsychotics—often can address comorbid disruptive behaviors and aggressive symptoms. Combinations of atypical antipsychotics with psychostimulants are largely devoid of drug-drug interactions and metabolic interference, making them uncomplicated to use.

Though published studies of pediatric BPD have focused on three atypical antipsychotics—olanzapine, quetiapine, and risperidone—any agent in this class can be used in this population, with the choice often depending on how side effects are likely to affect individual patients (Table 3 ).

 

Pharmacologic attributes may also determine which atypical antipsychotic is used. For example, ziprasidone’s serotonergic profile—with serotonin-1A receptor agonism and serotonin-1D antagonism—may make it useful for patients with mixed states and bipolar depression.²⁶ Aripiprazole offers potential synergism of dopamine agonism with psychostimulant therapy, which could be useful for treating both disruptive behaviors and ADHD.

Table 3

Using atypical antipsychotics to treat comorbid ADHD/bipolar disorder

Drug	Target dosage (mg/d)	Side effects	Useful in…
Aripiprazole	10 to 15	Nausea, vomiting	Comorbid disruptive behavioral disorders, maintenance stabilization
Olanzapine	10 to 20	Weight gain, hyperlipidemia, hyperglycemia, sedation	Maintenance stabilization
Quetiapine	400 to 600	Weight gain, sedation	Mixed states, bipolar depression
Risperidone	1 to 2	Weight gain, hyperprolactinemia, extrapyramidal symptoms	Comorbid disruptive behavioral disorders, including aggression
Ziprasidone	80 to 120	Cardiac abnormalities, akathisia	Mixed states, bipolar depression

Related resources

• Child and Adolescent Bipolar Foundation. www.bpkids.org
• Children and Adults with Attention-Deficit Hyperactivity Disorder (CHADD). www.chadd.org
• Findling RF, Kowatch RA, Post RM. P ediatric bipolar disorders: a handbook for clinicians. London: Martin Dunitz Press, 2002.

Drug brand names

• Atomoxetine • Strattera
• Aripiprazole • Abilify
• Divalproex • Depakote
• Olanzapine • Zyprexa
• Quetiapine • Seroquel
• Risperidone • Risperdal
• Ziprasidone • Geodon

Disclosures

Dr. Patel is a consultant to Eli Lilly and Co. and a speaker for Eli Lilly and Co. and Pfizer Inc.

Dr. Sallee receives research support from Otsuka America Pharmaceutical, Pfizer Inc., and Bristol-Myers Squibb Co. and is a consultant or speaker for Eli Lilly and Co, Otsuka America Pharmaceutical, and Pfizer Inc.