Posted by SLS on October 27, 2004, at 15:45:17
In reply to To Medicate or Not? Pros and Cons, posted by momof1bpkid on October 26, 2004, at 11:46:35
Diagnostic Complexities and Treatment Issues in Childhood Bipolar Disorder
Melissa P. DelBello, MD
Medscape Psychiatry & Mental Health 9(2), 2004. © 2004 MedscapePosted 10/19/2004
Introduction
Bipolar disorder in children was previously thought to be an uncommon occurrence. It is becoming increasingly recognized that bipolar disorder commonly presents in childhood and early adolescence. However, the diagnostic process is complex in youth. The developmentally specific and variable presentation that characterizes pediatric bipolar disorder leads to diagnostic confusion, yet the impact of bipolar disorder on the psychosocial and psychological development of children and adolescents is significant. Early diagnosis and treatment of bipolar disorder may decrease the symptoms and possibly alter the course of illness. Treatment options for bipolar disorder are expanding rapidly, and the clinician is now better able to treat the disorder while minimizing side effects.
Prevalence
In a community sample of 1507 adolescents, the rate of bipolar disorders was found to be approximately 1%.[1] A subset of these individuals was resurveyed at age 24 years and the prevalence was found to be 2%. In a survey by the National Depressive and Manic Depressive Association, 59% of individuals with bipolar disorder reported the onset of symptoms during childhood or adolescence.[2] Individuals with early onset were more likely to report a positive family history of mood disorders, more depressive or mixed symptoms, and more frequent recurrences. Increased social difficulties were also associated with childhood- and adolescent-onset bipolar disorder, but these difficulties were lessened by treatment.
Diagnostic Challenges
Childhood manifestations of bipolar disorder often overlap with other syndromes.[3] Comorbidity is common in early onset bipolar disorder. In a study comparing children aged 12 years or younger with bipolar disorder (N = 43), attention-deficit/hyperactivity disorder (ADHD) patients without bipolar disorder (N = 164), and non-ADHD controls (N = 84), 98% of those with bipolar disorder also met criteria for ADHD.[4] The ADHD children with bipolar disorder had a higher incidence of major depression, psychosis, multiple anxiety disorders, conduct disorder, and oppositional defiant disorder than the ADHD children without bipolar disorder. In a study of 90 youths with bipolar I disorder, aged 5 to 17 years, 75% met criteria for disruptive behavior disorder.[5]Bipolar disorder is one of the most heritable of the psychiatric disorders, and studying symptoms in offspring aids our understanding of the evolution of the disorder.[6] In a review of 17 studies of children of bipolar parents, the rate of mood disorders in the offspring varied from 5% to 67% compared with the 0% to 38% rate in the offspring of healthy volunteers.[7] The rate of nonmood psychopathology was also higher in the bipolar parent offspring at 5% to 52% compared with the 0% to 25% rate in controls. The degree of relatedness to a bipolar proband has been shown to correlate with symptoms during childhood.
In addition to inheritance patterns, there may be a genetic contribution to treatment response. In a study comparing the offspring of lithium responders (N = 34) with lithium nonresponders (N = 21), the children of lithium responders tended to have good premorbid functioning with a classical episodic course.[8] However, the children of lithium nonresponders exhibited poorer premorbid functioning, a chronic course, and increased comorbidity.
Need for Early Intervention
The consequences of untreated bipolar disorder in children are very significant. Children with bipolar disorder have more academic problems, difficulties in relationships with family and peers, legal difficulties, substance abuse, and increased suicide rates.[9-11] Early identification and treatment of the syndrome with psychosocial and psychopharmacologic interventions is advisable to normalize the developmental processes.Psychopharmacologic Treatment
There is a dearth of controlled clinical trials in children and adolescents with bipolar disorder. The clinician must therefore rely on data from adult clinical trials, although appropriate interventions in children may differ from those in adults with bipolar disorder. Mood stabilizers have generally formed the mainstay of treatment in children and adolescents; however, the atypical antipsychotics may be more effective as first-line treatment options. As in adults, mood stabilization is often difficult to achieve in bipolar youth, and polypharmacy is commonly used. One survey found that children and adolescents with bipolar disorder were treated with a mean of 3.40 ± 1.48 medications and had previous trials of 6.32 ± 3.67 trials of psychotropic medications.[12] Ninety-eight percent had been treated with a mood stabilizer, and the most commonly used agents were valproate in 79% and lithium in 51%.Lithium. Lithium, the oldest mood stabilizer, has the most extensive database in adults. However, there are few controlled studies in children. In a double-blind, placebo-controlled study of lithium in adolescents with concurrent substance abuse disorder, lithium was found to be efficacious in the treatment of bipolar symptomatology as well as in decreasing substance abuse.[13] In a recent placebo-controlled trial of lithium discontinuation in children and adolescents with acute mania, individuals who had responded to an open trial of lithium lasting for at least 4 weeks were assigned to a 2-week continuation phase of lithium or placebo.[14] There was a slightly lower exacerbation rate in the lithium-treated individuals compared with those on placebo (52.6% vs 61.9%); however, the difference was not statistically significant. Lithium has a narrow therapeutic window, and blood monitoring is essential. This may increase resistance to treatment in both children and adolescents. Side effects, including acne and tremor, may be particularly troublesome in an adolescent population since cosmetic issues are often of paramount concern in this age group.
Antiepileptic Agents. Although both divalproex and carbamazepine have demonstrated efficacy in adults with bipolar disorder, the data in children are much more limited and often based on case reports or retrospective reviews. In an open study comparing the treatment effect sizes of antimanic agents in the treatment of mania or hypomania, the effect sizes were 1.63 for divalproex (53% response rate), 1.06 for lithium (38% response rate), and 1.00 for carbamazepine (38% response rate).[15]
In an open label study of divalproex in youths, the response rate in subjects completing the trial was 61%.[16] Over 50% of the sample dropped out, primarily due to ineffectiveness, intolerance, or nonadherence. In a chart review of youths with bipolar disorder, the response rate was 53%.[17] The discontinuation rate was 40%, primarily due to side effects. The most common side effect was weight gain, which was noted in 27%. Liver enzyme increases necessitated discontinuation in one individual, although this normalized after discontinuation of the medication. Although the role of carbamazepine in adult bipolar disorder has been established, there are only case reports supporting its use in youths with bipolar disorder. The complex metabolic issues, need for blood monitoring, risk of agranulocytosis, and other serious side effects make carbamazepine a difficult agent to use.[18]
Both valproate and carbamazepine should be used with caution in adolescent females, since there is an increased risk of neural tube defects with both agents. The addition of folate may be helpful in preventing these defects; however, the data are inconsistent. Carbamazepine may accelerate the metabolism of oral contraceptives and thereby lower the blood concentrations, increasing the risk of an unplanned pregnancy.[19] Menstrual irregularities as well as polycystic ovarian syndrome have also been associated with valproate.[20]
Many of the newer antiepileptic medications are being evaluated for their effectiveness in children. Topiramate was found to effective in 26 children and adolescents with bipolar I and II disorder based on a retrospective chart review.[21] The rate of response was 73% over the 1- to 30- month follow-up period. Other antiepileptic agents that have some limited data indicating effectiveness include lamotrigine, gabapentin, and oxcarbazepine.[11]
Atypical Antipsychotics. There is emerging evidence from the adult literature that atypical neuroleptics are effective in the treatment of bipolar disorder, whether or not psychotic symptoms are present. In contrast to the typical antipsychotics, the atypicals have unique pharmacologic profiles that result in markedly different side effect profiles. The balance between therapeutic efficacy and side effects must be weighed to optimize treatment interventions.[22]
Olanzapine was the first of the atypical agents shown to be effective in adults with bipolar disorder. This agent also appears to have some efficacy in children. In an 8-week, open-label, prospective study of olanzapine in 23 youths aged 5 to 14 years, the overall response rate was found to be 61%.[23] Weight gain was significant, however, with an increase of 5.0 ± 2.3 kg over the 8-week course of the study.
The atypical agents appear to be helpful as adjunctive agents to mood stabilizing agents such as lithium and valproate. Quetiapine was added to valproate in a double-blind, placebo-controlled trial in adolescents with mania.[24] Patients aged 12 to 18 years were randomized to receive valproate with quetiapine (dose titrated up to 450 mg/day) or placebo. The response rate, as measured on the Young Mania Rating Scale, was significantly greater in the quetiapine adjunctive group (83%) compared with the placebo adjunctive group (53%). These data are similar to the positive adjunctive role demonstrated for quetiapine in adults with mania.[25]
The effectiveness of risperidone in the treatment of 28 youths with bipolar disorder aged 10.4 ± 3.8 years was analyzed retrospectively via chart review.[26] The dose of risperidone was 1.7 ± 1.3 mg and the duration of treatment was 6.1 ± 8.5 months. A total of 82% of the sample manifested improvement in manic and aggressive symptoms, and 69% demonstrated improvement in psychosis scores.
Comparing Side Effect Profiles
Although the atypical agents all have a lower incidence of extrapyramidal symptoms and tardive dyskinesia compared with the typical neuroleptics, there are other side effects that occur frequently. The most significant side effect concern is the increase in obesity, hyperlipidemia, and hyperglycemia. Both olanzapine and clozapine have been shown to have the greatest risk potential in these areas.[27-29]Weight gain on olanzapine was found to be significantly greater than that on quetiapine in a retrospective study of patients younger than 18 years treated for 14 days or more.[30] The weight gain on olanzapine was 3.8 kg and on quetiapine 0.03 kg. In a study of Israeli hospitalized adolescents, both olanzapine and risperidone were associated with weight gain, although the gain with olanzapine was significantly greater compared with the risperidone-treated patients (7.2 ± 6.3 kg vs 3.9 ± 4.8 kg).[31]
Sexual dysfunction may occur with risperidone and may be particularly problematic in adolescence. Since patients may not spontaneously report this side effect or may be unaware of the association with the medication, it is important that the patient be informed about the potential for these sexual problems. In an open-label study in adults with schizophrenia, the incidence of sexual side effects was much greater in patients treated with risperidone (50%) compared with quetiapine (16%).[32] Only 11.7% spontaneously reported sexual difficulties prior to direct questioning. Risperidone resulted in retrograde ejaculation and urinary dysfunction in 2 adolescent patients.[33]
Summary and Conclusions
Bipolar disorder commonly presents in childhood and adolescence and is associated with significant psychosocial difficulties as well as psychological and behavioral impairments. Early intervention may decrease these difficulties. There are many new treatment options available for the clinician, making effective interventions possible. However, there is an obvious lack of controlled clinical trials in children and adolescents, so the child psychiatrist must extrapolate findings from the adult literature until rigorously designed studies are carried out in younger age groups. The clinician must weigh the benefit of intervention against the side effect burden of each agent in order to maximize treatment effects and maintain adherence to pharmacotherapy.
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