Adolescent Mania and Bipolar Disorder

Scott A. West, MD

Disclosures

Medscape Psychiatry & Mental Health eJournal. 1997;2(5) 

In This Article

Pharmacologic Management

Pharmacotherapy for early-onset bipolar disorder is one of the least studied areas of child and adolescent psychopharmacology. Although there are numerous well-controlled trials evaluating the safety and efficacy of various antidepressants in patients with unipolar depression, data for patients with bipolar disorder are very limited. Several factors contribute to this dearth of information, including the relatively poor understanding of the presentation of this illness in younger populations, issues of informed consent and assent, and FDA regulations regarding trials in minors. Therefore, the vast majority of available data are derived from case reports, case series, and small open-label trials, many of which include patients with various diagnoses, making it difficult to interpret the results in any meaningful way. Thus, not unlike other areas in child and adolescent psychopharmacology, double-blind placebo-controlled trials are needed to rigorously assess the safety and efficacy of mood stabilizers and other ancillary medications in a well-defined bipolar population. Because mood stabilizers are the mainstay of pharmacotherapy in bipolar disorders, data on these agents for adolescents are summarized in Table I.

Lithium, which has received the most attention in the literature, appears to be beneficial in approximately 50% of adolescents. These data were recently summarized by Alessi and colleagues,[15] who found that of the available literature on lithium, studies specifically addressing bipolar disorder included 18 of 22 (82%) case reports, 16 of 26 (62%) case series, and 2 of 9 (22%) controlled trials--taken together, these reports represent less than 0.5% of the total lithium literature and include a very small number of patients.

Although systematic evaluations of the safety and tolerability of lithium in adolescents are lacking, anecdotal reports suggest that lithium is difficult for many patients to tolerate. Adolescents seem particularly sensitive to dermatologic problems (eg, acne, psoriasis); weight gain; tremor; and cognitive impairment. These adverse effects may be very difficult to overcome, and any of them can also affect treatment compliance. Additionally, potentially detrimental effects of lithium on thyroid and renal function may be of special concern during periods of physical growth and maturation. These concerns, as well as the apparent lack of efficacy in a substantial number of bipolar adolescents, have resulted in the search for alternative mood stabilizers.

Lithium is typically initiated at 30mg/kg/day, given in divided doses, which usually provides an adequate serum concentration. However, the dose should be titrated according to clinical response and tolerability, because there is no correlation between serum concentration and response. Due to the narrow therapeutic window, serum concentrations should be monitored regularly and patients and families educated about signs of toxicity. Relatively high daily doses are often required due to the high renal clearance in this age group, which may also influence the total number of required daily doses.

More recent research has focused on the use of valproate, an anticonvulsant shown to be effective in adults with bipolar disorder. As with lithium, data on adolescents are very limited and are based largely on case series and small open-label trials. Kastner and colleagues[16] published the first report suggesting that valproate may be effective in acutely manic adolescents. In a larger case series including 15 patients, Papatheodorou and associates[17] reported valproate to be effective and well tolerated in acutely manic patients with and without comorbidity. Of note, one patient showed a decrease in peripheral thyroxine and cortisol concentrations, which normalized with dose reduction. In an open trial of hospitalized patients with acute mania, both mixed and pure, West and colleagues[18] found valproate to be at least moderately effective in 9 of 11 patients, with adverse effects limited to sedation, which occurred in 2 patients. This small series was followed up by an oral-loading study that included 5 consecutively admitted adolescents with mixed mania.[19] Valproate (specifically divalproex sodium) was given as a single bedtime dose of 20mg/kg on the first day and adjusted thereafter as clinically indicated. Three of 5 patients improved substantially, and adverse effects consisted mainly of mild to moderate sedation, with the loading dose being very well tolerated overall. Taken together, these data suggest that valproate may be an effective and well-tolerated mood stabilizer in adolescents, although these data need to be confirmed by double-blind placebo-controlled trials.

Valproate is available as several different preparations, including divalproex sodium and valproic acid. Divalproex is generally much better tolerated, resulting in reduced potential for adverse effects, most notably gastrointestinal distress. Common side effects include nausea, gastrointestinal discomfort, and sedation, which are typically transient and occur much less frequently with the use of the divalproex formulation. Transient elevation in serum transaminases may also occur but is not indicative of future hepatic problems. Concerns of hepatic toxicity have been raised, but to date, this has almost exclusively involved children younger than 3 years with severe neurological problems who are receiving multiple anticonvulsants.[20]

Valproate is typically gradually titrated upward from an initial dose of 250mg 2 to 3 times per day. In more acute situations, or if sleep is problematic, a single dose at bedtime may be helpful and may also improve compliance, since the number of daily doses is limited. Like lithium, there is no correlation between plasma concentration and response, although the therapeutic range for bipolar disorder is defined as 50 to 125mg/L.

There are essentially no data on the use of carbamazepine in the treatment of adolescents with bipolar disorder. This is in sharp contrast to adults, in whom carbamazepine has been extensively studied and found to be very effective in many patients. Available studies in children and adolescents have assessed carbamazepine in various behavioral disorders (diagnostically heterogeneous groups), and it is therefore possible that they included some patients with bipolar disorder. However, there have been no studies evaluating the efficacy of carbamazepine in well-defined adolescents with bipolar disorder. Furthermore, there are several reports of carbamazepine-induced mania in juveniles who have been treated for various behavioral problems, so it seems prudent to monitor adolescents for manic induction when using carbamazepine.[21]

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