Bipolar Disorders in Children and Adolescents

Naomi A. Schapiro, RN, MS, CPNP

Disclosures

J Pediatr Health Care. 2005;19(3):131-141. 

In This Article

Pharmacologic Treatment

Pharmacotherapy is the mainstay of treatment for children, as well as adults, with BPD (Weckerly, 2002). As with many psychiatric disorders, treatment for children has been extrapolated from successful trials of medications in adults. The only placebo-controlled trials in juvenile BPD have demonstrated the efficacy of lithium in adolescents with comorbid substance abuse, and the efficacy of quetiapine as adjunctive to valproate (Bhangoo, Lowe, Myers, Treland, Curran, et al., 2003). Lithium carbonate, the medication in longest use for bipolar disorder, and valproic acid, originally used for seizure disorder, are relatively equal in effectiveness as short-term monotherapy (Kusum-akar et al., 2002), each showing significant reductions in mania and improvement in global functioning for half the children who take them in randomized clinical trials (Kowatch, Sethuraman, Hume, Kromelis, & Weinberg, 2003). Kowatch and colleagues found carbamazepine, another antiepileptic drug, to be slightly less effective as a single medication. However, up to half of children treated with mood stabilizers do not respond to their initial therapy, requiring either a switch to another mood stabilizer, use of two mood stabilizers, or an added antipsychotic medication, and even children who do respond initially may need to be switched during the first 6 months of treatment (Kowatch et al.; see Table 2 , Common Mood Stabilizers).

Despite the lack of controlled trials showing efficacy in children, community samples show that children are taking a variety of mood stabilizers, antipsychotics, and selective serotonin reuptake inhibitors (Bhangoo et al., 2003). In a telephone survey of interested families followed by community psychiatrists, children with bipolar disorder were taking a mean of 3.4 medications, with the number of different medications ranging from 0 to over 5. Ninety-eight percent of the children had had a trial of a mood stabilizer/antiepileptic drug, with the most common being valproic acid, lithium, and gabapentin. Seventy-seven percent of the children had taken an antipsychotic drug, most commonly risperidone, olanzapine, and quetiapine (Bhangoo et al.).

Despite lithium carbonate's long track record and proven efficacy, adolescents may not tolerate this medication as well as valproic acid or others (Kusumakar et al., 2002). Lithium has a low margin of safety and can be lethal in overdose, making its use problematic in uncooperative children or chaotic families where compliance and monitoring are issues (Kusumakar et al.). Lithium can cause weight gain and nausea or diarrhea, sedation, tremor, hypothyroidism, and polyuria. Lithium is primarily eliminated by the kidney, and blood levels must be monitored every 3 to 4 days during induction of the medication (Taketomo, Hodding, & Kraus, 2003).

Valproic acid also causes significant weight gain and may have an association with polycystic ovary syndrome in young women who are taking it (Kusumakar et al., 2002). Valproic acid is eliminated by the liver, and there are rare reports of liver toxicity, primarily in very young children taking multiple medications. Valproic acid can cause transient thrombocytopenia, and thus periodic blood counts are indicated (Taketomo et al., 2003). In addition to weight gain and sedation, carbamazepine can cause blood dyscrasias and severe hypersensitivity (Taketomo et al.).

Atypical or second-generation antipsychotics, such as olanzapine, risperidone, and quetiapine, show lower rates of extra pyramidal side effects and tardive dyskinesia than do traditional antipsychotics, such as thorazine or haloperidol (Findling & McNamara, 2004). Atypical antipsychotics have shown promise in the treatment of adults with bipolar disorder (Mitchell & Malhi, 2002). As noted by Bhangoo and colleagues (2003), the majority of surveyed children with BPD have been prescribed an antipsychotic drug, despite the lack of controlled trials in children and adolescents. However, open trials of risperidone and olanzapine and one double-blind study of quetiapine added to valproic acid have shown efficacy in decreasing manic symptoms and improving sleep patterns (Findling & McNamara).

Pharamacologic Treatment of ADHD in Children With BPD

Given the high comorbidity of BPD with ADHD and the usual appearance of symptoms consistent with BPD after the diagnosis of ADHD, there has been some controversy regarding the use of stimulants in children with mood disorders, particularly concerns about worsening of mania with stimulants (Bhangoo et al., 2003) and lack of efficacy (Kusumakar et al., 2002). Carlson, Loney, Salisbury, Kramer, and Arthur (2000), reporting on a longitudinal study of boys with ADHD considered to be at risk for BPD, found that boys who eventually were diagnosed with BPD did not respond to methylphenidate differently than did boys without a BPD diagnosis, either in dosage, change of medication, associated symptoms, or a precipitation of manic or hypomanic symptoms. However, other studies, including case reports, indicate that use of methylphenidate is associated with new or increased manic symptoms (State, Altshuler, & Frye, 2002). Because some children spontaneously switch from depressed or euthymic to manic states, it is difficult to attribute causality in any particular child (State et al.).

Pharmacologic Treatment of Depression in Children With BPD

Some children initially present as depressed, rather than manic, or have a mixed picture (such as BPD II) with both depressed and hypomanic symptoms that are not initially assessed as being clinically significant (Cicero, El-Mallakh, Holman, & Robertson, 2003). These children may be diagnosed as having unipolar depression and started on selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine or sertraline. In reviewing the research on SSRIs and mania, Cicero and colleagues noted that numerous adult studies associate SSRI treatment with shifts to mania and a more rapid rate of switching than would be expected without medication. In a retrospective chart review, they found that prior SSRI use was associated with a younger age of diagnosis of BPD. A recent review, through a database, of the medication histories of 7 million privately insured persons ages 5 to 29 years found that 5.4% converted into their first known manic episode during antidepressant therapy (Martin, Young, Leckman, Mukonoweshuro, Rosenheck, et al., 2004), and that 10- to 14-year-olds seemed to be most vulnerable to this conversion.

Even when BPD I or II is the recognized diagnosis, lithium, valproic acid, and carbamazepine have limited effect in treating depressive symptoms and an SSRI may be prescribed along with a mood stabilizer, although evidence for or against the effectiveness of this combination has not yet been accumulated (Kusu-makar et al., 2002). In their study of community treatment of BPD, Bhangoo and associates (2003) found that 52% of the children in their study experienced activating adverse effects from SSRIs, although they were not able to control for concurrent mood stabilizer use.

The Role of the Primary Care PNP in Prescribing Medications to Children With BPD

The challenges of providing primary care to children with BPD include monitoring multiple medications and avoiding adverse drug-drug interactions, as exemplified in the case of Marina. Like many children in the community, Marina is taking three medications in a combination that has not yet been validated by the research literature: an antipsychotic (quetiapine), a mood stabilizer/AED (topiramate) and an SSRI (sertraline) (Bhangoo et al., 2003). Table 3 shows potential drug-drug interactions for Marina's medications, and Box 3 provides Web resources for more information on drug interactions. For a youth who is allergic to amoxicillin, macrolides are a reasonable choice for sinusitis, but erythromycin and clarithromycin may interact with quetiapine to prolong the QTc interval (Taketomo et al., 2003). There are several choices among the cephalosporin antibiotics, such as cefuroxime axetil, cefpodoxime, cefdinir, and loracarbef, which do not interact with any of Marina's medications, but there is some risk of cross-reactivity to cephal-osporins in a child who is allergic to amoxicillin (Taketomo et al.).

Topiramate, like most antiepil-eptic drugs, results in increased clearance and decreased serum concentrations of estrogen, rendering low-dose oral contraceptives ineffective (Hatcher, Nelson, Zieman, Darney, Creinin, et al., 2003; Taketomo et al., 2003) Because hypersexuality and increased impulsivity are both common in manic persons (DelBello & Grcevich, 2004) and because most mood stabilizers have teratogenic risks (Kusumakar et al., 2002), it is particularly important for Marina's PNP to ensure that she is using a hormonal contraceptive that is effective in combination with her medication. Hatcher and colleagues offer three alternatives: (a) a high-dose combined oral contraceptive with 50 μg of estrogen; (b) a 35 μg pill, either given continuously without pill-free intervals or two cycles without a pill-free interval; or (c) depot medroxyprogesterone injections every 12 weeks.

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