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.
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.
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|
|YMRS: Young Mania Rating Scale|
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