Evidence-Based Reviews

What’s the best treatment for comorbid ADHD/bipolar mania?

Current Psychiatry. 2005 April;4(4):27-37

How to stabilize mood without worsening ADHD symptoms.

References

1. Geller B, Cooper TB, Sun K, et al. Double-blind and placebo-controlled study of lithium for adolescent bipolar disorders with secondary substance dependency. J Am Acad Child Adolesc Psychiatry 1998;37(2):171-8.

2. Wozniak J, Biederman J, Kiely K, et al. Mania-like symptoms suggestive of childhood-onset bipolar disorder in clinically referred children. J Am Acad Child Adolesc Psychiatry 1995;34(7):867-76.

3. Kowatch RA, DelBello MP. Pediatric bipolar disorder: mood swings, irritability are diagnostic cues. Current Psychiatry 2003;2(3):40-7.

4. Quinn CA, Fristad MA. Defining and identifying early onset bipolar spectrum disorder. Curr Psychiatry Rep 2004;6(2):101-7.

5. Bhatara VS, Feil M, Hoagwood K, et al. Trends in combined pharmacotherapy with stimulants for children. Psychiatr Serv 2002;53(3):244.-

6. Zito JM, Safer DJ, dosReis S, et al. Psychotherapeutic medication patterns for youths with attention-deficit/hyperactivity disorder. Arch Pediatr Adolesc Med 1999;153(12):1257-63.

7. Wolf DV, Wagner KD. Bipolar disorder in children and adolescents. CNS Spectr 2003;8(12):954-9.

8. Carlson GA, Rapport MD, Kelly KL, Pataki CS. The effects of methylphenidate and lithium on attention and activity level. J Am Acad Child Adolesc Psychiatry 1992;31(2):262-70.

9. Biederman J, Mick E, Prince J, et al. Systematic chart review of the pharmacologic treatment of comorbid attention deficit hyperactivity disorder in youth with bipolar disorder. J Child Adolesc Psychopharmacol 1999;9(4):247-56.

10. Scheffer RE, Kowatch RA, Carmody T, Rush AJ. Randomized, placebo-controlled trial of mixed amphetamine salts for symptoms of comorbid ADHD in pediatric bipolar disorder after mood stabilization with divalproex sodium. Am J Psychiatry 2005;162(1):58-64.

11. Aman MG, Binder C, Turgay A. Risperidone effects in the presence/absence of psychostimulant medicine in children with ADHD, other disruptive behavioral disorders, and subaverage IQ. J Child Adolesc Psychopharmacology 2004;14(2):243-54.

12. Gadow KD, Sverd J, Sprafkin J, et al. Long-term methylphenidate therapy in children with comorbid attention-deficit hyperactivity disorder and chronic multiple tic disorder. Arch Gen Psychiatry 1999;56(4):330-6.

13. Gaffney GR, Perry PJ, Lund BC, et al. Risperidone versus clonidine in the treatment of children and adolescents with Tourette’s syndrome. J Am Acad Child Adolesc Psychiatry 2002;41(3):330-6.

14. Lombroso PJ, Scahill L, King RA, et al. Risperidone treatment of children and adolescents with chronic tic disorders: a preliminary report. J Am Acad Child Adolesc Psychiatry 1995;34(9):1147-52.

15. Frazier JA, Biederman J, Tohen M, et al. A prospective open-label treatment trial of olanzapine monotherapy in children and adolescents with bipolar disorder. J Child Adolesc Psychopharmacol 2001;11(3):239-50.

16. DelBello MP, Schwiers ML, Rosenberg HL, Strakowski SM. A double-blind, randomized, placebo-controlled study of quetiapine as adjunctive treatment for adolescent mania. J Am Acad Child Adolesc Psychiatry 2002;41(10):1216-23.

17. Frazier JA, Meyer MC, Biederman J, et al. Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry 1999;38(8):960-5.

18. Pavuluri MN, Henry DB, Devineni B, et al. A pharmacotherapy algorithm for stabilization and maintenance of pediatric bipolar disorder. J Am Acad Child Adolesc Psychiatry 2004;43(7):859-67.

19. Kowatch RA, Fristad M, Birmaher B, et al. Treatment guidelines for children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2005;44(3):213-35.

20. Findling RL, McNamara NK. Atypical antipsychotics in the treatment of children and adolescents: clinical applications. J Clin Psychiatry 2004;65(suppl 6):30-44.

21. Kowatch RA, Sethuraman G, Hume JH, et al. Combination pharmacotherapy in children and adolescents with bipolar disorder. Biol Psychiatry 2003;53(11):978-84.

22. Koehler-Troy C, Strober M, Malenbaum R. Methylphenidate-induced mania in a prepubertal child. J Clin Psychiatry 1986;47(11):566-7.

23. Craney J, Geller B. Clinical implications of antidepressant and stimulant use on switching from depression to mania in children. J Child Adolesc Psychopharmacol 2003;13(2):201-4.

24. Galanter CA, Carlson GA, Jensen PS, et al. Response to methylphenidate in children with attention deficit hyperactivity disorder and manic symptoms in the multimodal treatment study of children with attention deficit hyperactivity disorder titration trial. J Child Adolesc Psychopharmacol 2003;13(2):123-36.

25. Henderson TA, Hartman K. Aggression, mania, and hypomania induction associated with atomoxetine. Pediatrics 2004;114(3):895-6.

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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