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Children and adolescents with bipolar disorder are often referred to psychiatrists because of disruptive behaviors at home and in school. They exhibit poor academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and high rates of suicide attempts and completions.1,2 Many have comorbid psychiatric problems—particularly attention-deficit/hyperactivity disorder (ADHD).
Although few studies have examined this complex diagnosis, we do know that bipolar disorder presents differently in children and adolescents than in adults. Prodromal symptoms can appear early—before kindergarten in some children. Early recognition therefore is key to effectively treating these sick and often complicated patients.
How often a clinician encounters a child or adolescent with bipolar disorder depends largely on the practice setting (Box).1,3,4 Wherever you practice, however, you can recognize and treat pediatric bipolar disorder if you keep in mind that its presentation and disease progression differ from the adult type.
Pediatric versus adult symptoms
Prodromal symptoms—such as episodes of depressed mood or hopelessness and excessive mood lability—have been detected in youths who later were diagnosed with bipolar disorder. More than one-half of 494 adult members of the Depression and Bipolar Support Alliance have reported that they first exhibited signs of bipolar illness before age 19, with distribution by age as follows:
- 5% before age 5
- 12% at ages 5 to 9
- 14% at ages 10 to 14
- 28% at ages 15 to 19.5
Pediatric bipolar disorder is seen much more commonly in specialized psychiatric settings than in general practice.
Overall prevalence. A large, well-designed population study of mood disorders in adolescents reported a lifetime prevalence of 1% for bipolar spectrum disorders, including bipolar I, bipolar II, and cyclothymia.1 Most adolescents in the bipolar group (84%) reported a distinct period of elevated, expansive, or irritable mood that best fit DSM-IV criteria for bipolar disorder not otherwise specified (NOS). These adolescents—who represented an overall prevalence of 5.7%—had extremely high rates of psychosocial impairment and use of mental health services, similar to those with bipolar I disorder.
In specialized settings. Bipolar disorder is seen much more frequently in specialized settings, such as a pediatric psychopharmacology clinic, than in general psychiatric practice. For example:
- Among 262 children referred consecutively to a specialty pediatric psychopharmacology clinic, 16% met DSM-III-R criteria for mania.3
- In a special education class, 8 of 12 students met DSM-III-R criteria for a bipolar disorder.4
- In child and adolescent psychiatry inpatient units, it is not uncommon to find 30 to 40% of patients with a bipolar disorder.
Table 1
COMMON PRESENTING SYMPTOMS OF PEDIATRIC BIPOLAR DISORDER
| Episodes of depressed mood/hopelessness |
| Excessive mood lability |
| Periods of increased or decreased energy |
| Episodes of decreased need for sleep |
| Anger dyscontrol |
| Markedly irritable moods |
| Frequent argumentativeness |
| Bold/intrusive/demanding behaviors |
In a similar study,6 58 adult patients with bipolar I disorder reported an average interval of 9 to 12 years between the emergence of bipolar symptoms and the onset of a major affective disorder.
Common initial symptoms of pediatric bipolar disorder are listed in Table 1. Most of these symptoms occur in discrete episodes and represent a change from the child’s normal functioning.
Many children and adolescents are labeled “bipolar” without careful consideration of this disorder’s diagnostic complexities and subtypes. Bipolarity in young patients can be difficult to establish because of:
- variability of symptom expression, depending on the illness’ context and phase
- effects of development on symptom expression
- mood and behavioral effects of psychotropic medications the patient is taking.
Pediatric bipolar patients often present with a mixed or “dysphoric” picture characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania.3,7 Clinicians who evaluate children with pediatric bipolar disorders often try to fit them into the DSM-IV “rapid cycling” subtype. This subtype does not fit bipolar children very well, however, because they often lack clear episodes of mania. Rather, researchers are reporting that bipolar children cycle far more frequently than the four episodes/year in DSM-IV’s diagnostic criteria:
- Continuous, daily cycling from mania or hypomania to euthymia or depression was seen in 81% of a well-defined group of pediatric bipolar patients.7,8
- A high rate of rapid cycling and onset of a first manic episode at mean age 7 was reported in 90 children and adolescents (mean age 11) with bipolar I disorder.9
The picture that emerges from independent research groups is that multiple daily mood swings and irritability are much more common than euphoria in prepubertal children with bipolar disorder.8,10
Making the diagnosis
DSM-IV’s diagnostic classification system for bipolar disorders is complex, involving:
- five types of episodes (manic, hypomanic, mixed, depressed, unspecified)
- four severity levels (mild, moderate, severe without psychosis, severe with psychosis)
- and three course specifiers (with or without inter-episode recovery, seasonal pattern, rapid cycling).
Table 2
PEDIATRIC BIPOLAR DISORDER SUBTYPES: DIAGNOSTIC CHARACTERISTICS AND ASSOCIATED FEATURES
| DSM-IV subtype | Minimum duration of manic symptoms | Depression symptoms | Cardinal features |
|---|---|---|---|
| Bipolar I | Pure mixed or manic 1 week (or hospitalization needed) | Major depressive disorder presentation of bipolar may be the first disorder, particularly in adolescents | Multiple daily mood swings with severe irritability (mood lability) Short periods of euphoria Decreased need for sleep Hypersexuality Grandiosity Racing thoughts Pressured speech |
| Bipolar II | Hypomania 4 days | One or more prior episodes of major depressive disorder required, each with a duration of 2 weeks | Noticeable manic symptoms that do not cause significant dysfunction or lead to hospitalization |
| Cyclothymia | Hypomania cycling with depressive symptoms 1 year | Hypomania cycling with depressive symptoms, without manic, mixed, or major depressive episodes (1 year, with symptom-free intervals <2 months) | Chronic, low-level mood cycling |
| Bipolar NOS | < 4 days of bipolar symptoms | Rapid alternation (within days) between manic depressive symptoms without full manic, mixed, or major depressive episodes | May include hypomanic and episodes (but <4 days) without intercurrent depression May also be diagnosed when clinician determines bipolar disorder is present but cannot determine whether it is primary, due to a general medical condition, or substance-induced, such as severe mood lability secondary to fetal alcohol syndrome or alcohol-related neurodevelopmental disorder |
| NOS: not otherwise specified | |||
Table 3
COMPLICATING FACTORS IN PEDIATRIC BIPOLAR DISORDER
| Medical conditions that may mimic bipolar mania |
| Temporal lobe epilepsy |
| Hyperthyroidism |
| Closed or open head injury |
| Multiple sclerosis |
| Systemic lupus erythematosus |
| Alcohol-related neurodevelopmental disorder |
| Wilson’s disease (rare progressive disease caused by defective copper metabolism) |
| Medications that may increase mood cycling |
| Tricyclic antidepressants |
| Selective serotonin reuptake inhibitors |
| Serotonin and norepinephrine reuptake inhibitors |
| Aminophylline |
| Corticosteroids |
| Sympathomimetic amines, such as pseudoephedrine |
DSM-IV criteria for mania—which were developed from data on adults with bipolar disorders—do not take into account developmental differences between bipolar adults and bipolar children and adolescents.
Diagnostic characteristics of the pediatric bipolar disorder subtypes are compared in Table 2. Generally:
- Pediatric patients with bipolar I disorder have multiple daily mood swings, a “mixed” type of episode with short periods of euphoria and longer periods of irritability, and comorbidities such as ADHD, oppositional defiant disorder, or conduct disorder.3,11,12
- Bipolar II disorder presents more typically in adolescence and is usually noticed clinically as a major depressive episode. Past episodes of hypomania may have been missed unless a careful history was taken.
- Cyclothymia is difficult to diagnose because the hypomania and depressive symptoms are not as severe as in bipolar types I or II. Prospective mood charting can help the clinician diagnose cyclothymia (see “Related Resources”).
- Bipolar disorder NOS represents the largest group of patients with bipolar symptoms. This diagnosis is made when bipolar symptoms are present but not of sufficient severity or duration to warrant a diagnosis of bipolar I, II or cyclothymia. Bipolar NOS also can be diagnosed when a bipolar disorder is secondary to a general medical condition, such as fetal alcohol syndrome or alcohol-related neurodevelopmental disorder.
Differential diagnosis. Medications and medical disorders may exacerbate or mimic pediatric bipolar symptoms (Table 3), so it is important to assess these potential confounds before initiating treatment. Psychiatric comorbidities also frequently complicate the presentation of pediatric bipolar disorder and its response to treatment (Table 4). ADHD is the most common comorbidity, with rates as high as 98% in bipolar children.3,13
Outcomes
Long-term outcomes of children and adolescents with bipolar disorders have not been well studied. In the only prospective follow-up investigation of adolescent inpatients with mania, Strober et al found that most of 54 patients (96%) recovered from an index affective episode, but nearly one-half (44%) experienced one or more relapses within 5 years.14 The rate of recovery varied according to the index episode’s polarity. Recovery was faster in patients with pure mania or mixed states, and multiple relapses occurred more frequently in those with mixed or cycling episodes. Twenty percent of the patients attempted suicide.
Recently, Geller et al reported the results of the first large, prospective, follow-up study of children with bipolar disorder.15 In 89 outpatients (mean age 11) with bipolar I disorder, comprehensive assessments at baseline and at 6, 12, 18, and 24 months showed that 65% recovered from mania but 55% relapsed after recovery. Mean time to recovery was 36 weeks, and relapse occurred after a mean of 28.6 weeks. Children living with their intact biological families were twice as likely to recover as those in other living arrangements.
The poor outcomes of these bipolar children highlight the need for earlier recognition and more effective treatments.
Treating acute mania
Many psychotropic medications used to treat adults with bipolar disorders are also used for children and adolescents. To date, only two double-blind, placebo-controlled studies13,16 and one uncontrolled maintenance treatment study17 have examined treatment of acute mania in pediatric bipolar disorder.
Lithium is the most studied medication for pediatric bipolar disorder and the only FDA-approved medication for treating acute mania and bipolar disorder in patients ages 12 to 18. Approximately 40 to 50% of children and adolescents with bipolar disorder respond to lithium monotherapy.18,19
In general, lithium should be titrated to 30 mg/kg/d in two or three divided doses; this typically produces a serum level of 0.8 to 1.2 mEq/L. Common side effects in children and adolescents include nausea, polyuria, polydipsia, tremor, acne, and weight gain. Lithium levels and thyroid function should be monitored, as in adult patients.
Only one prospective, placebo-controlled study has examined lithium use in children and adolescents with bipolar disorders. Twenty-five adolescents with comorbid bipolar and substance use disorders were treated with lithium or placebo for 6 weeks. Positive urine toxicology screens decreased significantly, and global assessment of functioning improved in 46% of those receiving lithium vs. 8% of those receiving placebo.13 This study demonstrated lithium’s efficacy in treating bipolar adolescents with comorbid substance abuse but did not measure its effect on mood.
Risk factors for poor lithium response in children and adolescents with bipolar disorder include prepubertal onset and comorbid ADHD.20
Divalproex. No placebo-controlled studies of antiepileptics in pediatric bipolar disorder have been published. Open-label studies of divalproex have reported response rates of 53 to 82% in manic adolescents.18, 21-23 Several case reports and series have described successful use of carbamazepine as monotherapy and adjunctive treatment in children and adolescents with bipolar disorder.24,25
Table 4
RATES OF COMMON COMORBIDITIES IN PEDIATRIC BIPOLAR DISORDERS
| Disorder | Children (prepubertal) | Adolescents |
|---|---|---|
| ADHD | 70 to 90% | 30 to 60% |
| Anxiety disorders | 20 to 30% | 30 to 40% |
| Conduct disorders | 20 to 30% | 30 to 50% |
| Oppositional defiant disorder | 60 to 80% | 20 to 30% |
| Substance abuse | 10% | 40 to 80% |
| Learning disabilities | 30 to 40% | 30 to 40% |
One 6-week, random-assignment, prospective study compared lithium, divalproex, and carbamazepine in treating 42 acutely manic or hypomanic patients ages 8 to 18.18 In this open study, all three mood stabilizers demonstrated efficacy in treating a mixed or manic episode in youths with bipolar I or II disorder. Response rates—based on a 50% improvement in Young Mania Rating Scale baseline scores—were divalproex 53%, lithium 38%, and carbamazepine 38%.
In general, divalproex is started at 20 mg/kg/d, which typically produces a serum level of 80 to 120 μg/ml. Common side effects in children include weight gain, nausea, sedation, and tremor.
A possible association between divalproex and polycystic ovary syndrome (PCOS) has been reported in women with epilepsy.26 The mechanism for PCOS has been hypothesized to be obesity secondary to divalproex, resulting in elevated insulin and androgen levels. Recently, Rasgon et al27 reported that epilepsy—and not the anticonvulsants used to treat it—may increase the risk of PCOS. In contrast, O’Donovan et al reported higher rates of menstrual irregularities and PCOS in women with bipolar disorder who were taking divalproex than in those who were not taking divalproex and in healthy controls.28
Until we learn more about this association, clinicians should monitor bipolar female adolescents treated with divalproex for any signs of PCOS, which include menstrual abnormalities, hirsutism, and acne.
Carbamazepine is used widely for seizure management but less commonly than divalproex in pediatric bipolar disorder. This anticonvulsant must be titrated slowly and requires frequent monitoring of blood levels, which can be a problem in children with needle phobia.
Carbamazepine is usually titrated to 15 mg/kg/d to produce a serum level of 7 to 10 μg/ml. Its most common side effects are sedation, rash, nausea, and hyponatremia. Aplastic anemia and severe dermatologic reactions, such as Stevens-Johnson syndrome, occur uncommonly.28
Atypical antipsychotics. Recent case series and open-label reports suggest that atypical antipsychotics such as clozapine,29 risperidone,30 olanzapine,31-33 and quetiapine16 are effective in treating pediatric bipolar disorder. However, clinically significant weight gain may be associated with the use of olanzapine and risperidone.34 Ziprasidone may increase QTc prolongation, and safety data are limited in children and adolescents. Therefore, ziprasidone should be used with caution in pediatric bipolar disorder, and ECGs should be monitored.
In the only double-blind, placebo-controlled study of an atypical antipsychotic in pediatric bipolar disorder, manic symptoms were more greatly reduced in 15 adolescents given quetiapine plus divalproex than in 15 patients who received divalproex alone. Quetiapine was titrated to 450 mg/d across 7 days and was well-tolerated. The findings suggest that a mood stabilizer plus an atypical antipsychotic may be more effective than a mood stabilizer alone for treating adolescent mania.16
Long-term treatment
In addition to treating acute affective episodes, lithium may also help prevent recurrent affective episodes in younger patients. In the only maintenance treatment study for pediatric bipolar disorder, Strober et al prospectively evaluated 37 adolescents whose bipolar disorder had been stabilized with lithium during hospitalization.17 After 18 months of follow-up, 35% of patients had discontinued lithium, and their relapse rate was 92% (compared with 38% in patients who were lithium-compliant.
It is reasonable to maintain a child or adolescent who has had a single manic episode on mood-stabilizing treatment for several years and then—if the patient is euthymic and asymptomatic—to slowly taper the mood stabilizer(s) over several months. If mood symptoms recur, the agent(s) should be reintroduced.
If a child with bipolar disorder does not respond or only partially responds to a mood stabilizer, it may be necessary to add a second mood stabilizer or an atypical antipsychotic. A bipolar child or adolescent with psychotic symptoms should be maintained on an antipsychotic (typical or atypical) for at least 1 month, even if the psychosis has resolved.35
Treatment of comorbid ADHD. Most children with bipolar disorder have comorbid ADHD, and mood stabilization is necessary prior to starting stimulant medications.36 In bipolar patients, sustained-release psychostimulants may reduce rebound symptoms more effectively than immediate-release formulations. Typical dosages for a child with bipolar disorder and ADHD would be Concerta, 36 mg/d, or Adderall XR, 10 to 20 mg/d.
Psychosocial interventions
Most psychotherapeutic interventions have not been systematically studied in pediatric bipolar disorder but may be beneficial. In a recent study, Fristad et al reported the efficacy of multifamily psychoeducational group therapy for treating bipolar children and adolescents and their families.37
Other useful psychosocial tactics include:
- Minimize periods of overstimulation (for example, these patients do not do well at shopping malls).
- Maintain good sleep hygiene.
- Address medication nonadherence immediately.
- Discuss the risk of substance abuse with the patient.
- Encourage mood charting by the patient and or parent.
- Mood charts appropriate for pediatric patients.
- Child and Adolescent Bipolar Foundation. www.cabf.org
- Findling RF, Kowatch RA, Post RM. Pediatric bipolar disorders: a handbook for clinicians. London, Martin Dunitz Press, 2002.
- Geller B, DelBello MP (eds). Child and early adolescent bipolar disorder: theory, assessment, and treatment. New York: Guilford Publications, 2002.
Drug brand names
- Clozapine • Clozaril
- Divalproex sodium • Depakote
- Olanzapine • Zyprexa
- Risperidone • Risperdal
- Quetiapine • Seroquel
- Ziprasidone • Geodon
Disclosure
Dr. Kowatch receives grant support from, serves as a consultant to, or is on the speakers bureau of Novartis Pharmaceuticals Corp., Abbott Laboratories, Solvay Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, GlaxoSmithKline, and AstraZeneca Pharmaceuticals.
Dr. DelBello receives grant support from, serves as a consultant to, or is on the speakers bureau of Abbott Laboratories, AstraZeneca Pharmaceuticals, Eli Lilly and Co., Ortho-McNeil Pharmaceutical, Shire Pharmaceutical Group, Janssen Pharmaceutica, Pfizer Inc., and GlaxoSmithKline.
1. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 1995;34:454-63.
2. Nottelmann E. National Institute of Mental Health Research Roundtable on Prepubertal Bipolar Disorder. J Am Acad Child Adolesc Psychiatry 2001;40:871-8.
3. 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.
4. Isaac G. Misdiagnosed bipolar disorder in adolescents in a special educational school and treatment program. J Clin Psychiatry 1992;53(4):133-6.
5. Lish JD, Dime-Meenan S, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994;31(4):281-94.
6. Egeland JA, Hostetter AM, Pauls DL, Sussex JN. Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories. J Am Acad Child Adolesc Psychiatry 2000;39(Oct):1245-52.
7. Geller B, Sun K, Zimerman B, Luby J, Frazier J, Williams M. Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 1995;34:259-68.
8. Geller B, Zimerman B, Williams M, et al. Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2000;10:157-64.
9. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3:202-10.
10. Wozniak J, Biederman J. Childhood mania: insights into diagnostic and treatment issues. J Assoc Acad Minor Phys 1997;8(4):78-84.
11. West SA, McElroy SL, Strakowski SM, et al. Attention-deficit/hyperactivity disorder in adolescent mania. Am J Psychiatry 1995;152(2):271-3.
12. Kovacs M, Pollock M. Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J Am Acad Child Adolesc Psychiatry 1995;34(6):715-23.
13. 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.
14. Strober M, Schmidt-Lackner S, Freeman R, Bower S, Lampert C, DeAntonio M. Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 1995;34(6):724-31.
15. Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M, Zimerman B. Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002;159(6):927-33.
16. DelBello M, Schwiers M, Rosenberg H, Strakowski S. Quetiapine as adjunctive treatment for adolescent mania associated with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2002;41(10):1216-23.
17. Strober M, Morrell W, Lampert C, Burroughs J. Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study. Am J Psychiatry 1990;147(4):457-61.
18. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium and carbamazepine in children and adolescents with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2000;39(6):713-20.
19. Youngerman J, Canino IA. Lithium carbonate use in children and adolescents. A survey of the literature. Arch Gen Psychiatry 1978;35(2):216-24.
20. Strober M. Mixed mania associated with tricyclic antidepressant therapy in prepubertal delusional depression: three cases. J Child Adolesc Psychopharmacol 1998;8:181-5.
21. Wagner KD, Weller E, Biederman J, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002;41(10):1224-30.
22. West SA, Keck PE, Jr, McElroy SL, et al. Open trial of valproate in the treatment of adolescent mania. J Child Adolesc Psychopharmacol 1994;4:263-7.
23. Papatheodorou G, Kutcher SP, Katic M, Szalai JP. The efficacy and safety of divalproex sodium in the treatment of acute mania in adolescents and young adults: an open clinical trial. J Clin Psychopharmacol 1995;15(2):110-6.
24. Evans RW, Clay TH, Gualtieri CT. Carbamazepine in pediatric psychiatry. J Am Acad Child Adolesc Psychiatry 1987;26(1):2-8.
25. Puente RM. The use of carbamazepine in the treatment of behavioural disorders in children. In: Birkmayer W (ed). Epileptic seizures - behaviour - pain. Baltimore: University Park Press, 1975;243-52.
26. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329(19):1383-8.
27. Rasgon NL, Altshuler LL, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000;61:173-8.
28. O'Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 2002;63:322-30.
29. Kowatch RA, Suppes T, Gilfillan SK, et al. Clozapine treatment of children and adolescents with bipolar disorder and schizophrenia: a clinical case series. J Child Adolesc Psychopharmacol 1995;5(4):241-53.
30. Frazier J, Meyer M, et al. Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry 1999;38:960-5.
31. Soutullo C, Sorter M, Foster K, et al. Olanzapine in the treatment of adolescent acute mania: a report of seven cases. J Affect Disord. 1999;53:279-83.
32. Khouzam H, El-Gabalawi F. Treatment of bipolar I disorder in an adolescent with olanzapine. J Child Adolesc Psychopharmacol 2000;10:147-51.
33. Chang K, Ketter T. Mood stabilizer augmentation with olanzapine in acutely manic children. J Child Adolesc Psychopharmacol 2000;10:45-9.
34. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 2002;41:337-43.
35. Kafantaris V, Dicker R, et al. Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania. J Child Adolesc Psychopharmacol 2001;11:409-13.
36. 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.
37. Fristad MA, Goldberg-Arnold JS. Working with families of children with early-onset bipolar disorder. In: Geller B, DelBello M (eds). Child and early adolescent bipolar disorder: Theory, assessment, and treatment. New York: Guilford Publications, 2002.
Children and adolescents with bipolar disorder are often referred to psychiatrists because of disruptive behaviors at home and in school. They exhibit poor academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and high rates of suicide attempts and completions.1,2 Many have comorbid psychiatric problems—particularly attention-deficit/hyperactivity disorder (ADHD).
Although few studies have examined this complex diagnosis, we do know that bipolar disorder presents differently in children and adolescents than in adults. Prodromal symptoms can appear early—before kindergarten in some children. Early recognition therefore is key to effectively treating these sick and often complicated patients.
How often a clinician encounters a child or adolescent with bipolar disorder depends largely on the practice setting (Box).1,3,4 Wherever you practice, however, you can recognize and treat pediatric bipolar disorder if you keep in mind that its presentation and disease progression differ from the adult type.
Pediatric versus adult symptoms
Prodromal symptoms—such as episodes of depressed mood or hopelessness and excessive mood lability—have been detected in youths who later were diagnosed with bipolar disorder. More than one-half of 494 adult members of the Depression and Bipolar Support Alliance have reported that they first exhibited signs of bipolar illness before age 19, with distribution by age as follows:
- 5% before age 5
- 12% at ages 5 to 9
- 14% at ages 10 to 14
- 28% at ages 15 to 19.5
Pediatric bipolar disorder is seen much more commonly in specialized psychiatric settings than in general practice.
Overall prevalence. A large, well-designed population study of mood disorders in adolescents reported a lifetime prevalence of 1% for bipolar spectrum disorders, including bipolar I, bipolar II, and cyclothymia.1 Most adolescents in the bipolar group (84%) reported a distinct period of elevated, expansive, or irritable mood that best fit DSM-IV criteria for bipolar disorder not otherwise specified (NOS). These adolescents—who represented an overall prevalence of 5.7%—had extremely high rates of psychosocial impairment and use of mental health services, similar to those with bipolar I disorder.
In specialized settings. Bipolar disorder is seen much more frequently in specialized settings, such as a pediatric psychopharmacology clinic, than in general psychiatric practice. For example:
- Among 262 children referred consecutively to a specialty pediatric psychopharmacology clinic, 16% met DSM-III-R criteria for mania.3
- In a special education class, 8 of 12 students met DSM-III-R criteria for a bipolar disorder.4
- In child and adolescent psychiatry inpatient units, it is not uncommon to find 30 to 40% of patients with a bipolar disorder.
Table 1
COMMON PRESENTING SYMPTOMS OF PEDIATRIC BIPOLAR DISORDER
| Episodes of depressed mood/hopelessness |
| Excessive mood lability |
| Periods of increased or decreased energy |
| Episodes of decreased need for sleep |
| Anger dyscontrol |
| Markedly irritable moods |
| Frequent argumentativeness |
| Bold/intrusive/demanding behaviors |
In a similar study,6 58 adult patients with bipolar I disorder reported an average interval of 9 to 12 years between the emergence of bipolar symptoms and the onset of a major affective disorder.
Common initial symptoms of pediatric bipolar disorder are listed in Table 1. Most of these symptoms occur in discrete episodes and represent a change from the child’s normal functioning.
Many children and adolescents are labeled “bipolar” without careful consideration of this disorder’s diagnostic complexities and subtypes. Bipolarity in young patients can be difficult to establish because of:
- variability of symptom expression, depending on the illness’ context and phase
- effects of development on symptom expression
- mood and behavioral effects of psychotropic medications the patient is taking.
Pediatric bipolar patients often present with a mixed or “dysphoric” picture characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania.3,7 Clinicians who evaluate children with pediatric bipolar disorders often try to fit them into the DSM-IV “rapid cycling” subtype. This subtype does not fit bipolar children very well, however, because they often lack clear episodes of mania. Rather, researchers are reporting that bipolar children cycle far more frequently than the four episodes/year in DSM-IV’s diagnostic criteria:
- Continuous, daily cycling from mania or hypomania to euthymia or depression was seen in 81% of a well-defined group of pediatric bipolar patients.7,8
- A high rate of rapid cycling and onset of a first manic episode at mean age 7 was reported in 90 children and adolescents (mean age 11) with bipolar I disorder.9
The picture that emerges from independent research groups is that multiple daily mood swings and irritability are much more common than euphoria in prepubertal children with bipolar disorder.8,10
Making the diagnosis
DSM-IV’s diagnostic classification system for bipolar disorders is complex, involving:
- five types of episodes (manic, hypomanic, mixed, depressed, unspecified)
- four severity levels (mild, moderate, severe without psychosis, severe with psychosis)
- and three course specifiers (with or without inter-episode recovery, seasonal pattern, rapid cycling).
Table 2
PEDIATRIC BIPOLAR DISORDER SUBTYPES: DIAGNOSTIC CHARACTERISTICS AND ASSOCIATED FEATURES
| DSM-IV subtype | Minimum duration of manic symptoms | Depression symptoms | Cardinal features |
|---|---|---|---|
| Bipolar I | Pure mixed or manic 1 week (or hospitalization needed) | Major depressive disorder presentation of bipolar may be the first disorder, particularly in adolescents | Multiple daily mood swings with severe irritability (mood lability) Short periods of euphoria Decreased need for sleep Hypersexuality Grandiosity Racing thoughts Pressured speech |
| Bipolar II | Hypomania 4 days | One or more prior episodes of major depressive disorder required, each with a duration of 2 weeks | Noticeable manic symptoms that do not cause significant dysfunction or lead to hospitalization |
| Cyclothymia | Hypomania cycling with depressive symptoms 1 year | Hypomania cycling with depressive symptoms, without manic, mixed, or major depressive episodes (1 year, with symptom-free intervals <2 months) | Chronic, low-level mood cycling |
| Bipolar NOS | < 4 days of bipolar symptoms | Rapid alternation (within days) between manic depressive symptoms without full manic, mixed, or major depressive episodes | May include hypomanic and episodes (but <4 days) without intercurrent depression May also be diagnosed when clinician determines bipolar disorder is present but cannot determine whether it is primary, due to a general medical condition, or substance-induced, such as severe mood lability secondary to fetal alcohol syndrome or alcohol-related neurodevelopmental disorder |
| NOS: not otherwise specified | |||
Table 3
COMPLICATING FACTORS IN PEDIATRIC BIPOLAR DISORDER
| Medical conditions that may mimic bipolar mania |
| Temporal lobe epilepsy |
| Hyperthyroidism |
| Closed or open head injury |
| Multiple sclerosis |
| Systemic lupus erythematosus |
| Alcohol-related neurodevelopmental disorder |
| Wilson’s disease (rare progressive disease caused by defective copper metabolism) |
| Medications that may increase mood cycling |
| Tricyclic antidepressants |
| Selective serotonin reuptake inhibitors |
| Serotonin and norepinephrine reuptake inhibitors |
| Aminophylline |
| Corticosteroids |
| Sympathomimetic amines, such as pseudoephedrine |
DSM-IV criteria for mania—which were developed from data on adults with bipolar disorders—do not take into account developmental differences between bipolar adults and bipolar children and adolescents.
Diagnostic characteristics of the pediatric bipolar disorder subtypes are compared in Table 2. Generally:
- Pediatric patients with bipolar I disorder have multiple daily mood swings, a “mixed” type of episode with short periods of euphoria and longer periods of irritability, and comorbidities such as ADHD, oppositional defiant disorder, or conduct disorder.3,11,12
- Bipolar II disorder presents more typically in adolescence and is usually noticed clinically as a major depressive episode. Past episodes of hypomania may have been missed unless a careful history was taken.
- Cyclothymia is difficult to diagnose because the hypomania and depressive symptoms are not as severe as in bipolar types I or II. Prospective mood charting can help the clinician diagnose cyclothymia (see “Related Resources”).
- Bipolar disorder NOS represents the largest group of patients with bipolar symptoms. This diagnosis is made when bipolar symptoms are present but not of sufficient severity or duration to warrant a diagnosis of bipolar I, II or cyclothymia. Bipolar NOS also can be diagnosed when a bipolar disorder is secondary to a general medical condition, such as fetal alcohol syndrome or alcohol-related neurodevelopmental disorder.
Differential diagnosis. Medications and medical disorders may exacerbate or mimic pediatric bipolar symptoms (Table 3), so it is important to assess these potential confounds before initiating treatment. Psychiatric comorbidities also frequently complicate the presentation of pediatric bipolar disorder and its response to treatment (Table 4). ADHD is the most common comorbidity, with rates as high as 98% in bipolar children.3,13
Outcomes
Long-term outcomes of children and adolescents with bipolar disorders have not been well studied. In the only prospective follow-up investigation of adolescent inpatients with mania, Strober et al found that most of 54 patients (96%) recovered from an index affective episode, but nearly one-half (44%) experienced one or more relapses within 5 years.14 The rate of recovery varied according to the index episode’s polarity. Recovery was faster in patients with pure mania or mixed states, and multiple relapses occurred more frequently in those with mixed or cycling episodes. Twenty percent of the patients attempted suicide.
Recently, Geller et al reported the results of the first large, prospective, follow-up study of children with bipolar disorder.15 In 89 outpatients (mean age 11) with bipolar I disorder, comprehensive assessments at baseline and at 6, 12, 18, and 24 months showed that 65% recovered from mania but 55% relapsed after recovery. Mean time to recovery was 36 weeks, and relapse occurred after a mean of 28.6 weeks. Children living with their intact biological families were twice as likely to recover as those in other living arrangements.
The poor outcomes of these bipolar children highlight the need for earlier recognition and more effective treatments.
Treating acute mania
Many psychotropic medications used to treat adults with bipolar disorders are also used for children and adolescents. To date, only two double-blind, placebo-controlled studies13,16 and one uncontrolled maintenance treatment study17 have examined treatment of acute mania in pediatric bipolar disorder.
Lithium is the most studied medication for pediatric bipolar disorder and the only FDA-approved medication for treating acute mania and bipolar disorder in patients ages 12 to 18. Approximately 40 to 50% of children and adolescents with bipolar disorder respond to lithium monotherapy.18,19
In general, lithium should be titrated to 30 mg/kg/d in two or three divided doses; this typically produces a serum level of 0.8 to 1.2 mEq/L. Common side effects in children and adolescents include nausea, polyuria, polydipsia, tremor, acne, and weight gain. Lithium levels and thyroid function should be monitored, as in adult patients.
Only one prospective, placebo-controlled study has examined lithium use in children and adolescents with bipolar disorders. Twenty-five adolescents with comorbid bipolar and substance use disorders were treated with lithium or placebo for 6 weeks. Positive urine toxicology screens decreased significantly, and global assessment of functioning improved in 46% of those receiving lithium vs. 8% of those receiving placebo.13 This study demonstrated lithium’s efficacy in treating bipolar adolescents with comorbid substance abuse but did not measure its effect on mood.
Risk factors for poor lithium response in children and adolescents with bipolar disorder include prepubertal onset and comorbid ADHD.20
Divalproex. No placebo-controlled studies of antiepileptics in pediatric bipolar disorder have been published. Open-label studies of divalproex have reported response rates of 53 to 82% in manic adolescents.18, 21-23 Several case reports and series have described successful use of carbamazepine as monotherapy and adjunctive treatment in children and adolescents with bipolar disorder.24,25
Table 4
RATES OF COMMON COMORBIDITIES IN PEDIATRIC BIPOLAR DISORDERS
| Disorder | Children (prepubertal) | Adolescents |
|---|---|---|
| ADHD | 70 to 90% | 30 to 60% |
| Anxiety disorders | 20 to 30% | 30 to 40% |
| Conduct disorders | 20 to 30% | 30 to 50% |
| Oppositional defiant disorder | 60 to 80% | 20 to 30% |
| Substance abuse | 10% | 40 to 80% |
| Learning disabilities | 30 to 40% | 30 to 40% |
One 6-week, random-assignment, prospective study compared lithium, divalproex, and carbamazepine in treating 42 acutely manic or hypomanic patients ages 8 to 18.18 In this open study, all three mood stabilizers demonstrated efficacy in treating a mixed or manic episode in youths with bipolar I or II disorder. Response rates—based on a 50% improvement in Young Mania Rating Scale baseline scores—were divalproex 53%, lithium 38%, and carbamazepine 38%.
In general, divalproex is started at 20 mg/kg/d, which typically produces a serum level of 80 to 120 μg/ml. Common side effects in children include weight gain, nausea, sedation, and tremor.
A possible association between divalproex and polycystic ovary syndrome (PCOS) has been reported in women with epilepsy.26 The mechanism for PCOS has been hypothesized to be obesity secondary to divalproex, resulting in elevated insulin and androgen levels. Recently, Rasgon et al27 reported that epilepsy—and not the anticonvulsants used to treat it—may increase the risk of PCOS. In contrast, O’Donovan et al reported higher rates of menstrual irregularities and PCOS in women with bipolar disorder who were taking divalproex than in those who were not taking divalproex and in healthy controls.28
Until we learn more about this association, clinicians should monitor bipolar female adolescents treated with divalproex for any signs of PCOS, which include menstrual abnormalities, hirsutism, and acne.
Carbamazepine is used widely for seizure management but less commonly than divalproex in pediatric bipolar disorder. This anticonvulsant must be titrated slowly and requires frequent monitoring of blood levels, which can be a problem in children with needle phobia.
Carbamazepine is usually titrated to 15 mg/kg/d to produce a serum level of 7 to 10 μg/ml. Its most common side effects are sedation, rash, nausea, and hyponatremia. Aplastic anemia and severe dermatologic reactions, such as Stevens-Johnson syndrome, occur uncommonly.28
Atypical antipsychotics. Recent case series and open-label reports suggest that atypical antipsychotics such as clozapine,29 risperidone,30 olanzapine,31-33 and quetiapine16 are effective in treating pediatric bipolar disorder. However, clinically significant weight gain may be associated with the use of olanzapine and risperidone.34 Ziprasidone may increase QTc prolongation, and safety data are limited in children and adolescents. Therefore, ziprasidone should be used with caution in pediatric bipolar disorder, and ECGs should be monitored.
In the only double-blind, placebo-controlled study of an atypical antipsychotic in pediatric bipolar disorder, manic symptoms were more greatly reduced in 15 adolescents given quetiapine plus divalproex than in 15 patients who received divalproex alone. Quetiapine was titrated to 450 mg/d across 7 days and was well-tolerated. The findings suggest that a mood stabilizer plus an atypical antipsychotic may be more effective than a mood stabilizer alone for treating adolescent mania.16
Long-term treatment
In addition to treating acute affective episodes, lithium may also help prevent recurrent affective episodes in younger patients. In the only maintenance treatment study for pediatric bipolar disorder, Strober et al prospectively evaluated 37 adolescents whose bipolar disorder had been stabilized with lithium during hospitalization.17 After 18 months of follow-up, 35% of patients had discontinued lithium, and their relapse rate was 92% (compared with 38% in patients who were lithium-compliant.
It is reasonable to maintain a child or adolescent who has had a single manic episode on mood-stabilizing treatment for several years and then—if the patient is euthymic and asymptomatic—to slowly taper the mood stabilizer(s) over several months. If mood symptoms recur, the agent(s) should be reintroduced.
If a child with bipolar disorder does not respond or only partially responds to a mood stabilizer, it may be necessary to add a second mood stabilizer or an atypical antipsychotic. A bipolar child or adolescent with psychotic symptoms should be maintained on an antipsychotic (typical or atypical) for at least 1 month, even if the psychosis has resolved.35
Treatment of comorbid ADHD. Most children with bipolar disorder have comorbid ADHD, and mood stabilization is necessary prior to starting stimulant medications.36 In bipolar patients, sustained-release psychostimulants may reduce rebound symptoms more effectively than immediate-release formulations. Typical dosages for a child with bipolar disorder and ADHD would be Concerta, 36 mg/d, or Adderall XR, 10 to 20 mg/d.
Psychosocial interventions
Most psychotherapeutic interventions have not been systematically studied in pediatric bipolar disorder but may be beneficial. In a recent study, Fristad et al reported the efficacy of multifamily psychoeducational group therapy for treating bipolar children and adolescents and their families.37
Other useful psychosocial tactics include:
- Minimize periods of overstimulation (for example, these patients do not do well at shopping malls).
- Maintain good sleep hygiene.
- Address medication nonadherence immediately.
- Discuss the risk of substance abuse with the patient.
- Encourage mood charting by the patient and or parent.
- Mood charts appropriate for pediatric patients.
- Child and Adolescent Bipolar Foundation. www.cabf.org
- Findling RF, Kowatch RA, Post RM. Pediatric bipolar disorders: a handbook for clinicians. London, Martin Dunitz Press, 2002.
- Geller B, DelBello MP (eds). Child and early adolescent bipolar disorder: theory, assessment, and treatment. New York: Guilford Publications, 2002.
Drug brand names
- Clozapine • Clozaril
- Divalproex sodium • Depakote
- Olanzapine • Zyprexa
- Risperidone • Risperdal
- Quetiapine • Seroquel
- Ziprasidone • Geodon
Disclosure
Dr. Kowatch receives grant support from, serves as a consultant to, or is on the speakers bureau of Novartis Pharmaceuticals Corp., Abbott Laboratories, Solvay Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, GlaxoSmithKline, and AstraZeneca Pharmaceuticals.
Dr. DelBello receives grant support from, serves as a consultant to, or is on the speakers bureau of Abbott Laboratories, AstraZeneca Pharmaceuticals, Eli Lilly and Co., Ortho-McNeil Pharmaceutical, Shire Pharmaceutical Group, Janssen Pharmaceutica, Pfizer Inc., and GlaxoSmithKline.
Children and adolescents with bipolar disorder are often referred to psychiatrists because of disruptive behaviors at home and in school. They exhibit poor academic performance, disturbed interpersonal relationships, increased rates of substance abuse, legal difficulties, multiple hospitalizations, and high rates of suicide attempts and completions.1,2 Many have comorbid psychiatric problems—particularly attention-deficit/hyperactivity disorder (ADHD).
Although few studies have examined this complex diagnosis, we do know that bipolar disorder presents differently in children and adolescents than in adults. Prodromal symptoms can appear early—before kindergarten in some children. Early recognition therefore is key to effectively treating these sick and often complicated patients.
How often a clinician encounters a child or adolescent with bipolar disorder depends largely on the practice setting (Box).1,3,4 Wherever you practice, however, you can recognize and treat pediatric bipolar disorder if you keep in mind that its presentation and disease progression differ from the adult type.
Pediatric versus adult symptoms
Prodromal symptoms—such as episodes of depressed mood or hopelessness and excessive mood lability—have been detected in youths who later were diagnosed with bipolar disorder. More than one-half of 494 adult members of the Depression and Bipolar Support Alliance have reported that they first exhibited signs of bipolar illness before age 19, with distribution by age as follows:
- 5% before age 5
- 12% at ages 5 to 9
- 14% at ages 10 to 14
- 28% at ages 15 to 19.5
Pediatric bipolar disorder is seen much more commonly in specialized psychiatric settings than in general practice.
Overall prevalence. A large, well-designed population study of mood disorders in adolescents reported a lifetime prevalence of 1% for bipolar spectrum disorders, including bipolar I, bipolar II, and cyclothymia.1 Most adolescents in the bipolar group (84%) reported a distinct period of elevated, expansive, or irritable mood that best fit DSM-IV criteria for bipolar disorder not otherwise specified (NOS). These adolescents—who represented an overall prevalence of 5.7%—had extremely high rates of psychosocial impairment and use of mental health services, similar to those with bipolar I disorder.
In specialized settings. Bipolar disorder is seen much more frequently in specialized settings, such as a pediatric psychopharmacology clinic, than in general psychiatric practice. For example:
- Among 262 children referred consecutively to a specialty pediatric psychopharmacology clinic, 16% met DSM-III-R criteria for mania.3
- In a special education class, 8 of 12 students met DSM-III-R criteria for a bipolar disorder.4
- In child and adolescent psychiatry inpatient units, it is not uncommon to find 30 to 40% of patients with a bipolar disorder.
Table 1
COMMON PRESENTING SYMPTOMS OF PEDIATRIC BIPOLAR DISORDER
| Episodes of depressed mood/hopelessness |
| Excessive mood lability |
| Periods of increased or decreased energy |
| Episodes of decreased need for sleep |
| Anger dyscontrol |
| Markedly irritable moods |
| Frequent argumentativeness |
| Bold/intrusive/demanding behaviors |
In a similar study,6 58 adult patients with bipolar I disorder reported an average interval of 9 to 12 years between the emergence of bipolar symptoms and the onset of a major affective disorder.
Common initial symptoms of pediatric bipolar disorder are listed in Table 1. Most of these symptoms occur in discrete episodes and represent a change from the child’s normal functioning.
Many children and adolescents are labeled “bipolar” without careful consideration of this disorder’s diagnostic complexities and subtypes. Bipolarity in young patients can be difficult to establish because of:
- variability of symptom expression, depending on the illness’ context and phase
- effects of development on symptom expression
- mood and behavioral effects of psychotropic medications the patient is taking.
Pediatric bipolar patients often present with a mixed or “dysphoric” picture characterized by frequent short periods of intense mood lability and irritability rather than classic euphoric mania.3,7 Clinicians who evaluate children with pediatric bipolar disorders often try to fit them into the DSM-IV “rapid cycling” subtype. This subtype does not fit bipolar children very well, however, because they often lack clear episodes of mania. Rather, researchers are reporting that bipolar children cycle far more frequently than the four episodes/year in DSM-IV’s diagnostic criteria:
- Continuous, daily cycling from mania or hypomania to euthymia or depression was seen in 81% of a well-defined group of pediatric bipolar patients.7,8
- A high rate of rapid cycling and onset of a first manic episode at mean age 7 was reported in 90 children and adolescents (mean age 11) with bipolar I disorder.9
The picture that emerges from independent research groups is that multiple daily mood swings and irritability are much more common than euphoria in prepubertal children with bipolar disorder.8,10
Making the diagnosis
DSM-IV’s diagnostic classification system for bipolar disorders is complex, involving:
- five types of episodes (manic, hypomanic, mixed, depressed, unspecified)
- four severity levels (mild, moderate, severe without psychosis, severe with psychosis)
- and three course specifiers (with or without inter-episode recovery, seasonal pattern, rapid cycling).
Table 2
PEDIATRIC BIPOLAR DISORDER SUBTYPES: DIAGNOSTIC CHARACTERISTICS AND ASSOCIATED FEATURES
| DSM-IV subtype | Minimum duration of manic symptoms | Depression symptoms | Cardinal features |
|---|---|---|---|
| Bipolar I | Pure mixed or manic 1 week (or hospitalization needed) | Major depressive disorder presentation of bipolar may be the first disorder, particularly in adolescents | Multiple daily mood swings with severe irritability (mood lability) Short periods of euphoria Decreased need for sleep Hypersexuality Grandiosity Racing thoughts Pressured speech |
| Bipolar II | Hypomania 4 days | One or more prior episodes of major depressive disorder required, each with a duration of 2 weeks | Noticeable manic symptoms that do not cause significant dysfunction or lead to hospitalization |
| Cyclothymia | Hypomania cycling with depressive symptoms 1 year | Hypomania cycling with depressive symptoms, without manic, mixed, or major depressive episodes (1 year, with symptom-free intervals <2 months) | Chronic, low-level mood cycling |
| Bipolar NOS | < 4 days of bipolar symptoms | Rapid alternation (within days) between manic depressive symptoms without full manic, mixed, or major depressive episodes | May include hypomanic and episodes (but <4 days) without intercurrent depression May also be diagnosed when clinician determines bipolar disorder is present but cannot determine whether it is primary, due to a general medical condition, or substance-induced, such as severe mood lability secondary to fetal alcohol syndrome or alcohol-related neurodevelopmental disorder |
| NOS: not otherwise specified | |||
Table 3
COMPLICATING FACTORS IN PEDIATRIC BIPOLAR DISORDER
| Medical conditions that may mimic bipolar mania |
| Temporal lobe epilepsy |
| Hyperthyroidism |
| Closed or open head injury |
| Multiple sclerosis |
| Systemic lupus erythematosus |
| Alcohol-related neurodevelopmental disorder |
| Wilson’s disease (rare progressive disease caused by defective copper metabolism) |
| Medications that may increase mood cycling |
| Tricyclic antidepressants |
| Selective serotonin reuptake inhibitors |
| Serotonin and norepinephrine reuptake inhibitors |
| Aminophylline |
| Corticosteroids |
| Sympathomimetic amines, such as pseudoephedrine |
DSM-IV criteria for mania—which were developed from data on adults with bipolar disorders—do not take into account developmental differences between bipolar adults and bipolar children and adolescents.
Diagnostic characteristics of the pediatric bipolar disorder subtypes are compared in Table 2. Generally:
- Pediatric patients with bipolar I disorder have multiple daily mood swings, a “mixed” type of episode with short periods of euphoria and longer periods of irritability, and comorbidities such as ADHD, oppositional defiant disorder, or conduct disorder.3,11,12
- Bipolar II disorder presents more typically in adolescence and is usually noticed clinically as a major depressive episode. Past episodes of hypomania may have been missed unless a careful history was taken.
- Cyclothymia is difficult to diagnose because the hypomania and depressive symptoms are not as severe as in bipolar types I or II. Prospective mood charting can help the clinician diagnose cyclothymia (see “Related Resources”).
- Bipolar disorder NOS represents the largest group of patients with bipolar symptoms. This diagnosis is made when bipolar symptoms are present but not of sufficient severity or duration to warrant a diagnosis of bipolar I, II or cyclothymia. Bipolar NOS also can be diagnosed when a bipolar disorder is secondary to a general medical condition, such as fetal alcohol syndrome or alcohol-related neurodevelopmental disorder.
Differential diagnosis. Medications and medical disorders may exacerbate or mimic pediatric bipolar symptoms (Table 3), so it is important to assess these potential confounds before initiating treatment. Psychiatric comorbidities also frequently complicate the presentation of pediatric bipolar disorder and its response to treatment (Table 4). ADHD is the most common comorbidity, with rates as high as 98% in bipolar children.3,13
Outcomes
Long-term outcomes of children and adolescents with bipolar disorders have not been well studied. In the only prospective follow-up investigation of adolescent inpatients with mania, Strober et al found that most of 54 patients (96%) recovered from an index affective episode, but nearly one-half (44%) experienced one or more relapses within 5 years.14 The rate of recovery varied according to the index episode’s polarity. Recovery was faster in patients with pure mania or mixed states, and multiple relapses occurred more frequently in those with mixed or cycling episodes. Twenty percent of the patients attempted suicide.
Recently, Geller et al reported the results of the first large, prospective, follow-up study of children with bipolar disorder.15 In 89 outpatients (mean age 11) with bipolar I disorder, comprehensive assessments at baseline and at 6, 12, 18, and 24 months showed that 65% recovered from mania but 55% relapsed after recovery. Mean time to recovery was 36 weeks, and relapse occurred after a mean of 28.6 weeks. Children living with their intact biological families were twice as likely to recover as those in other living arrangements.
The poor outcomes of these bipolar children highlight the need for earlier recognition and more effective treatments.
Treating acute mania
Many psychotropic medications used to treat adults with bipolar disorders are also used for children and adolescents. To date, only two double-blind, placebo-controlled studies13,16 and one uncontrolled maintenance treatment study17 have examined treatment of acute mania in pediatric bipolar disorder.
Lithium is the most studied medication for pediatric bipolar disorder and the only FDA-approved medication for treating acute mania and bipolar disorder in patients ages 12 to 18. Approximately 40 to 50% of children and adolescents with bipolar disorder respond to lithium monotherapy.18,19
In general, lithium should be titrated to 30 mg/kg/d in two or three divided doses; this typically produces a serum level of 0.8 to 1.2 mEq/L. Common side effects in children and adolescents include nausea, polyuria, polydipsia, tremor, acne, and weight gain. Lithium levels and thyroid function should be monitored, as in adult patients.
Only one prospective, placebo-controlled study has examined lithium use in children and adolescents with bipolar disorders. Twenty-five adolescents with comorbid bipolar and substance use disorders were treated with lithium or placebo for 6 weeks. Positive urine toxicology screens decreased significantly, and global assessment of functioning improved in 46% of those receiving lithium vs. 8% of those receiving placebo.13 This study demonstrated lithium’s efficacy in treating bipolar adolescents with comorbid substance abuse but did not measure its effect on mood.
Risk factors for poor lithium response in children and adolescents with bipolar disorder include prepubertal onset and comorbid ADHD.20
Divalproex. No placebo-controlled studies of antiepileptics in pediatric bipolar disorder have been published. Open-label studies of divalproex have reported response rates of 53 to 82% in manic adolescents.18, 21-23 Several case reports and series have described successful use of carbamazepine as monotherapy and adjunctive treatment in children and adolescents with bipolar disorder.24,25
Table 4
RATES OF COMMON COMORBIDITIES IN PEDIATRIC BIPOLAR DISORDERS
| Disorder | Children (prepubertal) | Adolescents |
|---|---|---|
| ADHD | 70 to 90% | 30 to 60% |
| Anxiety disorders | 20 to 30% | 30 to 40% |
| Conduct disorders | 20 to 30% | 30 to 50% |
| Oppositional defiant disorder | 60 to 80% | 20 to 30% |
| Substance abuse | 10% | 40 to 80% |
| Learning disabilities | 30 to 40% | 30 to 40% |
One 6-week, random-assignment, prospective study compared lithium, divalproex, and carbamazepine in treating 42 acutely manic or hypomanic patients ages 8 to 18.18 In this open study, all three mood stabilizers demonstrated efficacy in treating a mixed or manic episode in youths with bipolar I or II disorder. Response rates—based on a 50% improvement in Young Mania Rating Scale baseline scores—were divalproex 53%, lithium 38%, and carbamazepine 38%.
In general, divalproex is started at 20 mg/kg/d, which typically produces a serum level of 80 to 120 μg/ml. Common side effects in children include weight gain, nausea, sedation, and tremor.
A possible association between divalproex and polycystic ovary syndrome (PCOS) has been reported in women with epilepsy.26 The mechanism for PCOS has been hypothesized to be obesity secondary to divalproex, resulting in elevated insulin and androgen levels. Recently, Rasgon et al27 reported that epilepsy—and not the anticonvulsants used to treat it—may increase the risk of PCOS. In contrast, O’Donovan et al reported higher rates of menstrual irregularities and PCOS in women with bipolar disorder who were taking divalproex than in those who were not taking divalproex and in healthy controls.28
Until we learn more about this association, clinicians should monitor bipolar female adolescents treated with divalproex for any signs of PCOS, which include menstrual abnormalities, hirsutism, and acne.
Carbamazepine is used widely for seizure management but less commonly than divalproex in pediatric bipolar disorder. This anticonvulsant must be titrated slowly and requires frequent monitoring of blood levels, which can be a problem in children with needle phobia.
Carbamazepine is usually titrated to 15 mg/kg/d to produce a serum level of 7 to 10 μg/ml. Its most common side effects are sedation, rash, nausea, and hyponatremia. Aplastic anemia and severe dermatologic reactions, such as Stevens-Johnson syndrome, occur uncommonly.28
Atypical antipsychotics. Recent case series and open-label reports suggest that atypical antipsychotics such as clozapine,29 risperidone,30 olanzapine,31-33 and quetiapine16 are effective in treating pediatric bipolar disorder. However, clinically significant weight gain may be associated with the use of olanzapine and risperidone.34 Ziprasidone may increase QTc prolongation, and safety data are limited in children and adolescents. Therefore, ziprasidone should be used with caution in pediatric bipolar disorder, and ECGs should be monitored.
In the only double-blind, placebo-controlled study of an atypical antipsychotic in pediatric bipolar disorder, manic symptoms were more greatly reduced in 15 adolescents given quetiapine plus divalproex than in 15 patients who received divalproex alone. Quetiapine was titrated to 450 mg/d across 7 days and was well-tolerated. The findings suggest that a mood stabilizer plus an atypical antipsychotic may be more effective than a mood stabilizer alone for treating adolescent mania.16
Long-term treatment
In addition to treating acute affective episodes, lithium may also help prevent recurrent affective episodes in younger patients. In the only maintenance treatment study for pediatric bipolar disorder, Strober et al prospectively evaluated 37 adolescents whose bipolar disorder had been stabilized with lithium during hospitalization.17 After 18 months of follow-up, 35% of patients had discontinued lithium, and their relapse rate was 92% (compared with 38% in patients who were lithium-compliant.
It is reasonable to maintain a child or adolescent who has had a single manic episode on mood-stabilizing treatment for several years and then—if the patient is euthymic and asymptomatic—to slowly taper the mood stabilizer(s) over several months. If mood symptoms recur, the agent(s) should be reintroduced.
If a child with bipolar disorder does not respond or only partially responds to a mood stabilizer, it may be necessary to add a second mood stabilizer or an atypical antipsychotic. A bipolar child or adolescent with psychotic symptoms should be maintained on an antipsychotic (typical or atypical) for at least 1 month, even if the psychosis has resolved.35
Treatment of comorbid ADHD. Most children with bipolar disorder have comorbid ADHD, and mood stabilization is necessary prior to starting stimulant medications.36 In bipolar patients, sustained-release psychostimulants may reduce rebound symptoms more effectively than immediate-release formulations. Typical dosages for a child with bipolar disorder and ADHD would be Concerta, 36 mg/d, or Adderall XR, 10 to 20 mg/d.
Psychosocial interventions
Most psychotherapeutic interventions have not been systematically studied in pediatric bipolar disorder but may be beneficial. In a recent study, Fristad et al reported the efficacy of multifamily psychoeducational group therapy for treating bipolar children and adolescents and their families.37
Other useful psychosocial tactics include:
- Minimize periods of overstimulation (for example, these patients do not do well at shopping malls).
- Maintain good sleep hygiene.
- Address medication nonadherence immediately.
- Discuss the risk of substance abuse with the patient.
- Encourage mood charting by the patient and or parent.
- Mood charts appropriate for pediatric patients.
- Child and Adolescent Bipolar Foundation. www.cabf.org
- Findling RF, Kowatch RA, Post RM. Pediatric bipolar disorders: a handbook for clinicians. London, Martin Dunitz Press, 2002.
- Geller B, DelBello MP (eds). Child and early adolescent bipolar disorder: theory, assessment, and treatment. New York: Guilford Publications, 2002.
Drug brand names
- Clozapine • Clozaril
- Divalproex sodium • Depakote
- Olanzapine • Zyprexa
- Risperidone • Risperdal
- Quetiapine • Seroquel
- Ziprasidone • Geodon
Disclosure
Dr. Kowatch receives grant support from, serves as a consultant to, or is on the speakers bureau of Novartis Pharmaceuticals Corp., Abbott Laboratories, Solvay Pharmaceuticals, Eli Lilly and Co., Janssen Pharmaceutica, GlaxoSmithKline, and AstraZeneca Pharmaceuticals.
Dr. DelBello receives grant support from, serves as a consultant to, or is on the speakers bureau of Abbott Laboratories, AstraZeneca Pharmaceuticals, Eli Lilly and Co., Ortho-McNeil Pharmaceutical, Shire Pharmaceutical Group, Janssen Pharmaceutica, Pfizer Inc., and GlaxoSmithKline.
1. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 1995;34:454-63.
2. Nottelmann E. National Institute of Mental Health Research Roundtable on Prepubertal Bipolar Disorder. J Am Acad Child Adolesc Psychiatry 2001;40:871-8.
3. 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.
4. Isaac G. Misdiagnosed bipolar disorder in adolescents in a special educational school and treatment program. J Clin Psychiatry 1992;53(4):133-6.
5. Lish JD, Dime-Meenan S, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994;31(4):281-94.
6. Egeland JA, Hostetter AM, Pauls DL, Sussex JN. Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories. J Am Acad Child Adolesc Psychiatry 2000;39(Oct):1245-52.
7. Geller B, Sun K, Zimerman B, Luby J, Frazier J, Williams M. Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 1995;34:259-68.
8. Geller B, Zimerman B, Williams M, et al. Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2000;10:157-64.
9. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3:202-10.
10. Wozniak J, Biederman J. Childhood mania: insights into diagnostic and treatment issues. J Assoc Acad Minor Phys 1997;8(4):78-84.
11. West SA, McElroy SL, Strakowski SM, et al. Attention-deficit/hyperactivity disorder in adolescent mania. Am J Psychiatry 1995;152(2):271-3.
12. Kovacs M, Pollock M. Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J Am Acad Child Adolesc Psychiatry 1995;34(6):715-23.
13. 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.
14. Strober M, Schmidt-Lackner S, Freeman R, Bower S, Lampert C, DeAntonio M. Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 1995;34(6):724-31.
15. Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M, Zimerman B. Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002;159(6):927-33.
16. DelBello M, Schwiers M, Rosenberg H, Strakowski S. Quetiapine as adjunctive treatment for adolescent mania associated with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2002;41(10):1216-23.
17. Strober M, Morrell W, Lampert C, Burroughs J. Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study. Am J Psychiatry 1990;147(4):457-61.
18. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium and carbamazepine in children and adolescents with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2000;39(6):713-20.
19. Youngerman J, Canino IA. Lithium carbonate use in children and adolescents. A survey of the literature. Arch Gen Psychiatry 1978;35(2):216-24.
20. Strober M. Mixed mania associated with tricyclic antidepressant therapy in prepubertal delusional depression: three cases. J Child Adolesc Psychopharmacol 1998;8:181-5.
21. Wagner KD, Weller E, Biederman J, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002;41(10):1224-30.
22. West SA, Keck PE, Jr, McElroy SL, et al. Open trial of valproate in the treatment of adolescent mania. J Child Adolesc Psychopharmacol 1994;4:263-7.
23. Papatheodorou G, Kutcher SP, Katic M, Szalai JP. The efficacy and safety of divalproex sodium in the treatment of acute mania in adolescents and young adults: an open clinical trial. J Clin Psychopharmacol 1995;15(2):110-6.
24. Evans RW, Clay TH, Gualtieri CT. Carbamazepine in pediatric psychiatry. J Am Acad Child Adolesc Psychiatry 1987;26(1):2-8.
25. Puente RM. The use of carbamazepine in the treatment of behavioural disorders in children. In: Birkmayer W (ed). Epileptic seizures - behaviour - pain. Baltimore: University Park Press, 1975;243-52.
26. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329(19):1383-8.
27. Rasgon NL, Altshuler LL, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000;61:173-8.
28. O'Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 2002;63:322-30.
29. Kowatch RA, Suppes T, Gilfillan SK, et al. Clozapine treatment of children and adolescents with bipolar disorder and schizophrenia: a clinical case series. J Child Adolesc Psychopharmacol 1995;5(4):241-53.
30. Frazier J, Meyer M, et al. Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry 1999;38:960-5.
31. Soutullo C, Sorter M, Foster K, et al. Olanzapine in the treatment of adolescent acute mania: a report of seven cases. J Affect Disord. 1999;53:279-83.
32. Khouzam H, El-Gabalawi F. Treatment of bipolar I disorder in an adolescent with olanzapine. J Child Adolesc Psychopharmacol 2000;10:147-51.
33. Chang K, Ketter T. Mood stabilizer augmentation with olanzapine in acutely manic children. J Child Adolesc Psychopharmacol 2000;10:45-9.
34. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 2002;41:337-43.
35. Kafantaris V, Dicker R, et al. Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania. J Child Adolesc Psychopharmacol 2001;11:409-13.
36. 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.
37. Fristad MA, Goldberg-Arnold JS. Working with families of children with early-onset bipolar disorder. In: Geller B, DelBello M (eds). Child and early adolescent bipolar disorder: Theory, assessment, and treatment. New York: Guilford Publications, 2002.
1. Lewinsohn PM, Klein DN, Seeley JR. Bipolar disorders in a community sample of older adolescents: prevalence, phenomenology, comorbidity, and course. J Am Acad Child Adolesc Psychiatry 1995;34:454-63.
2. Nottelmann E. National Institute of Mental Health Research Roundtable on Prepubertal Bipolar Disorder. J Am Acad Child Adolesc Psychiatry 2001;40:871-8.
3. 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.
4. Isaac G. Misdiagnosed bipolar disorder in adolescents in a special educational school and treatment program. J Clin Psychiatry 1992;53(4):133-6.
5. Lish JD, Dime-Meenan S, et al. The National Depressive and Manic-depressive Association (DMDA) survey of bipolar members. J Affect Disord 1994;31(4):281-94.
6. Egeland JA, Hostetter AM, Pauls DL, Sussex JN. Prodromal symptoms before onset of manic-depressive disorder suggested by first hospital admission histories. J Am Acad Child Adolesc Psychiatry 2000;39(Oct):1245-52.
7. Geller B, Sun K, Zimerman B, Luby J, Frazier J, Williams M. Complex and rapid-cycling in bipolar children and adolescents: a preliminary study. J Affect Disord 1995;34:259-68.
8. Geller B, Zimerman B, Williams M, et al. Diagnostic characteristics of 93 cases of a prepubertal and early adolescent bipolar disorder phenotype by gender, puberty and comorbid attention-deficit/hyperactivity disorder. J Child Adolesc Psychopharmacol 2000;10:157-64.
9. Findling RL, Gracious BL, McNamara NK, et al. Rapid, continuous cycling and psychiatric co-morbidity in pediatric bipolar I disorder. Bipolar Disord 2001;3:202-10.
10. Wozniak J, Biederman J. Childhood mania: insights into diagnostic and treatment issues. J Assoc Acad Minor Phys 1997;8(4):78-84.
11. West SA, McElroy SL, Strakowski SM, et al. Attention-deficit/hyperactivity disorder in adolescent mania. Am J Psychiatry 1995;152(2):271-3.
12. Kovacs M, Pollock M. Bipolar disorder and comorbid conduct disorder in childhood and adolescence. J Am Acad Child Adolesc Psychiatry 1995;34(6):715-23.
13. 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.
14. Strober M, Schmidt-Lackner S, Freeman R, Bower S, Lampert C, DeAntonio M. Recovery and relapse in adolescents with bipolar affective illness: a five-year naturalistic, prospective follow-up. J Am Acad Child Adolesc Psychiatry 1995;34(6):724-31.
15. Geller B, Craney JL, Bolhofner K, Nickelsburg MJ, Williams M, Zimerman B. Two-year prospective follow-up of children with a prepubertal and early adolescent bipolar disorder phenotype. Am J Psychiatry 2002;159(6):927-33.
16. DelBello M, Schwiers M, Rosenberg H, Strakowski S. Quetiapine as adjunctive treatment for adolescent mania associated with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2002;41(10):1216-23.
17. Strober M, Morrell W, Lampert C, Burroughs J. Relapse following discontinuation of lithium maintenance therapy in adolescents with bipolar I illness: a naturalistic study. Am J Psychiatry 1990;147(4):457-61.
18. Kowatch RA, Suppes T, Carmody TJ, et al. Effect size of lithium, divalproex sodium and carbamazepine in children and adolescents with bipolar disorder. J Amer Acad Child Adolesc Psychiatry 2000;39(6):713-20.
19. Youngerman J, Canino IA. Lithium carbonate use in children and adolescents. A survey of the literature. Arch Gen Psychiatry 1978;35(2):216-24.
20. Strober M. Mixed mania associated with tricyclic antidepressant therapy in prepubertal delusional depression: three cases. J Child Adolesc Psychopharmacol 1998;8:181-5.
21. Wagner KD, Weller E, Biederman J, et al. An open-label trial of divalproex in children and adolescents with bipolar disorder. J Am Acad Child Adolesc Psychiatry 2002;41(10):1224-30.
22. West SA, Keck PE, Jr, McElroy SL, et al. Open trial of valproate in the treatment of adolescent mania. J Child Adolesc Psychopharmacol 1994;4:263-7.
23. Papatheodorou G, Kutcher SP, Katic M, Szalai JP. The efficacy and safety of divalproex sodium in the treatment of acute mania in adolescents and young adults: an open clinical trial. J Clin Psychopharmacol 1995;15(2):110-6.
24. Evans RW, Clay TH, Gualtieri CT. Carbamazepine in pediatric psychiatry. J Am Acad Child Adolesc Psychiatry 1987;26(1):2-8.
25. Puente RM. The use of carbamazepine in the treatment of behavioural disorders in children. In: Birkmayer W (ed). Epileptic seizures - behaviour - pain. Baltimore: University Park Press, 1975;243-52.
26. Isojarvi JI, Laatikainen TJ, Pakarinen AJ, Juntunen KT, Myllyla VV. Polycystic ovaries and hyperandrogenism in women taking valproate for epilepsy. N Engl J Med 1993;329(19):1383-8.
27. Rasgon NL, Altshuler LL, et al. Medication status and polycystic ovary syndrome in women with bipolar disorder: a preliminary report. J Clin Psychiatry 2000;61:173-8.
28. O'Donovan C, Kusumakar V, Graves GR, Bird DC. Menstrual abnormalities and polycystic ovary syndrome in women taking valproate for bipolar mood disorder. J Clin Psychiatry 2002;63:322-30.
29. Kowatch RA, Suppes T, Gilfillan SK, et al. Clozapine treatment of children and adolescents with bipolar disorder and schizophrenia: a clinical case series. J Child Adolesc Psychopharmacol 1995;5(4):241-53.
30. Frazier J, Meyer M, et al. Risperidone treatment for juvenile bipolar disorder: a retrospective chart review. J Am Acad Child Adolesc Psychiatry 1999;38:960-5.
31. Soutullo C, Sorter M, Foster K, et al. Olanzapine in the treatment of adolescent acute mania: a report of seven cases. J Affect Disord. 1999;53:279-83.
32. Khouzam H, El-Gabalawi F. Treatment of bipolar I disorder in an adolescent with olanzapine. J Child Adolesc Psychopharmacol 2000;10:147-51.
33. Chang K, Ketter T. Mood stabilizer augmentation with olanzapine in acutely manic children. J Child Adolesc Psychopharmacol 2000;10:45-9.
34. Ratzoni G, Gothelf D, Brand-Gothelf A, et al. Weight gain associated with olanzapine and risperidone in adolescent patients: a comparative prospective study. J Am Acad Child Adolesc Psychiatry 2002;41:337-43.
35. Kafantaris V, Dicker R, et al. Adjunctive antipsychotic treatment is necessary for adolescents with psychotic mania. J Child Adolesc Psychopharmacol 2001;11:409-13.
36. 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.
37. Fristad MA, Goldberg-Arnold JS. Working with families of children with early-onset bipolar disorder. In: Geller B, DelBello M (eds). Child and early adolescent bipolar disorder: Theory, assessment, and treatment. New York: Guilford Publications, 2002.