Lithium has been shown through placebo-controlled trials to significantly reduce episodes of new manic and/or depressive episodes in adults. However, approximately 42% to 64% of patients do not respond to lithium (Solomon et al., 1995). To obtain maximum benefit and prevention of relapses, it appears that the blood level of lithium needs to be titrated to and maintained at a blood level range of 0.8 to 1.2 mmol/L (Gelenberg et al., 1989). At this higher blood level the patient may experience an increase in side effects, such as tremor, diarrhea, weight gain, increased urinary frequency, and gastrointestinal distress. Long-term treatment with lithium may lead to hypothyroidism, renal compromise, and cardiovascular side effects. Patients who are diagnosed with mixed states, rapid cycling, and mania due to medical disorders may be less responsive to lithium treatment (Bowden et al., 1997).

Divaloproex and carbamazepine are anticonvulsants used to treat acute symptoms of bipolar disorder as well as for long-term maintenance treatment. Bowden and colleagues (1994) published a double-blind, randomized, parallel-group trial in which patients hospitalized with acute mania (N = 179) were randomly assigned to 3 weeks of treatment with lithium, divaloproex, or placebo. Both lithium and divaloproex significantly reduced patients' symptoms of mania compared to placebo. Bowden and colleagues (2000) completed a double-blind, randomized maintenance treatment trial of lithium vs. divaloproex vs. placebo for patients diagnosed with bipolar I. The study's primary end point was the time to develop any mood episode and there was no difference found between the three groups. However, divaloproex was shown to significantly reduce the number of patients who dropped from the study because of relapse and it also showed a significantly improved outcome of secondary mood measurements.

Lamotrigine has been shown to be an effective treatment for bipolar I depression (Hirschfeld et al., 2002) and for long-term treatment of in patients with bipolar II disorder and rapid cycling (Bowden et al., 1999). Treatment with lamotrigine is associated with a 5% incidence of a skin rash. Most of these rashes appear in the first 8 weeks of treatment and resolve with cessation of drug treatment. However, these skin rashes can evolve to a more serious form of a skin reaction such as Stevens-Johnson syndrome (Wong, Kennedy, & Lee, 1999). At this time, there are limited data to support the use of gabapentin or topiramate as mood stabilizers.

Olanzapine is presently the most studied atypical antipsychotic medication for the treatment of bipolar disorder and was approved by the FDA

for treatment of acute mania (Tohen et al., 1999). The most concerning side effect with this medication is weight gain. Segal, Berk, and Brook (1998) showed in a randomized study that risperidone, compared to lithium and haloperidol, produces similar improvement in manic symptoms. It has also been shown in combination as an add-on therapy with a mood stabilizer to have superior efficacy to that of monotherapy, as found in a study using quetiapine (Sachs, Grossman, Ghaemi, Okamoto, & Bowden, 2002).

There are conflicting views on the use of antidepressants for the treatment of bipolar depression. However, there is agreement that antidepressants should only be used in combination with a mood stabilizer for the treatment of bipolar depression (Thase, Bhargave, & Sachs, 2003). For patients who are suffering from a severe depressive episode it is recommended that lithium or lamotrigine be used as first-line therapy. If the patient is nonresponsive, then a combination is recommended, such as the addition of lamotrigine, bupropion, or paroxetine. Another option would be to add an SSRI, venlafaxine, or an MAOI. It appears that SSRIs have a lower risk of inducing mania than that with TCAs (Moller & Nasarallah, 2003). For bipolar depression, there are limited data available that compare the treatment outcome of treating only with a mood stabilizer versus the combination of a mood stabilizer with an antidepressant.

Several agents have been examined within the context of acute prospective monotherapy treatment trials (Table 2.4). More research has been done to examine the use of lithium for the treatment of mania than any other compound. Although several open-label studies have been conducted, at present there has only been one published, methodologically rigorous study that has examined the acute efficacy of lithium in the treatment of mania in young people (Kowatch & DelBello, 2003). In that study, 25 adolescents with bipolar-spectrum disorders with secondary substance abuse dependence were randomized to receive either lithium monotherapy or placebo for 6 weeks. The average age of the subjects was 16 years. The authors found that subjects treated with lithium had superior global functioning and fewer positive urine drug assays than those who were treated with placebo (Geller et al., 1998).

A review of the available treatment studies suggest that lithium carbonate may often be useful in ameliorating symptoms of bipolar disorder in young people and is generally well tolerated. The available data also suggest that approximately half of patients treated with this agent will respond to acute treatment with lithium (Chang & Ketter, 2001; Kowatch et al., 2000). The implication of this observation is that a substantial number of patients will not experience a meaningful response to lithium treatment alone. Moreover, many patients treated with lithium monotherapy who benefit from substantial symptom reduction will not experience syn

dromal remission when treated with lithium alone.

At present, there are no published placebo-controlled studies that have examined the efficacy of divalproex sodium (Depakote) in the treatment of pediatric mania. There are several open trials that have examined the acute effectiveness of divalproex sodium (Depakote) in young patients with mania or mixed states. In the largest of these trials, 40 youths between the ages of 7 and 19 who were suffering from either a manic, hypomanic, or mixed episode were treated with open-label divalproex sodium for up to 8 weeks (Wagner, 2002; Wagner et al., 2002). Overall, the authors reported that divalproex sodium was an effective and reasonably well-tolerated intervention in the study subjects. Approximately 60% of the subjects were considered to be treatment responders.

On the basis of results of this trial and other published reports, the available data suggest that, similar to lithium, divalproex sodium may be an effective treatment for young patients with mania and related mood states (Wagner, 2002; Wagner et al., 2002). Like lithium, it appears that a substantial number of youths will not respond to monotherapy and only a small number of patients will experience syndromal remission with divalproex sodium monotherapy.

Carbamazepine has historically been given as a treatment to young people with a variety of neuropsychiatric conditions. Most reports describing the use of this drug in young people with neuropsychiatric conditions lack methodological rigor. At present, there is only one prospective study that has examined this agent's utility in young people with bipolar disorder. In that trial, Kowatch and colleagues treated 42 youths with an average age of 11 years, 20 of whom met diagnostic symptom criteria for bipolar 1 disorder and 22 of whom met diagnostic symptom criteria for bipolar II disorder (Kowatch et al., 2000). In order to be enrolled in this trial, the subjects had to have moderate symptoms of mania. Upon enrollment, subjects were randomized to open treatment with carbamazepine, divalproex sodium, or lithium. Of the 41 youths who completed at least 1 week of medication therapy, 13 were treated with carbamazepine. Treatment with carbamazepine was associated with an effect size of 1.00 with an overall response rate of 34 percent. Although these numbers were more modest than those seen with lithium or divalproex sodium, no statistically significant differences in effectiveness were noted between the three different study drugs.

At present there is one prospective open-label trial that has examined the use of olanzapine in youths suffering from a manic, mixed, or hypomanic episode (Frazier et al., 2001). In that trial, the 23 patients (mean age, 10.3 years) were

treated with olanzapine in doses that could range between 2.5 and 20 mg/day. The authors noted that treatment was associated with reductions in symptoms of mania and that the agent was generally well tolerated, with the most common reported adverse events being increased appetite and sedation. The average weight gain over the course of the study was 5 kg.

There are several other agents that have been noted to have possible roles in the treatment of bipolar disorder in adults. These include lamotrigine, gabapentin, omega-3 fatty acids, verapamil, and topiramate. At present, none of these agents have been examined in a methodologically sound prospective treatment study in pediatric patients with bipolar disorder. Therefore, definitive statements about these agents' possible utility cannot be made.

Since a substantial number of patients do not appear to derive optimal clinical response from acute treatment with a single drug, investigators have begun to explore whether treatment with more than one agent may be useful in the acute therapy of young people who present with symptoms of mania. The majority of these studies have explored treatment with an atypical antipsychotic combined with a traditional mood stabilizer.

In a retrospective chart review, Kowatch and colleagues (1995) described five youths with bipolar disorder and mixed presentations between the ages of 8 and 15 years who were treated with clozapine. In four of these five cases, clozapine was an adjunct to other psychotropic agents (most commonly lithium). At clozapine doses ranging from 75 to 150 mg/day, the authors noted that all five patients had a “marked” response to clozapine. The authors also observed that clozapine therapy was generally well tolerated. The authors concluded that clozapine might be an effective treatment for treatment-refractory patients.

The response of 35 adolescent inpatients treated predominantly with lithium plus haloperidol or lithium plus risperidone for up to 4 consecutive weeks has been described (Kafantaris, Coletti, Dicker, Padula, & Kane, 2001). These youths, who were between the ages of 12 and 18, had prominent symptoms of psychosis as well as moderate symptoms of mania at the time of treatment initiation. At the end of the trial, almost all of the subjects had their psychotic symptoms fully resolved, with most subjects experiencing significant amelioration of mood symptoms. The authors then took some of the subjects who responded to combination treatment and discontinued their antipsychotic. The authors found that most patients experienced clinical deterioration during lithium monotherapy. This response suggests that they would have benefited from continued combination treatment.

In a chart review study, Frazier and colleagues (1999) examined the use of risperidone in a group of 28 young people with bipolar-spectrum disorders. All but one patient was being treated with one or more concomitant medications during risperidone administration. These concomitant agents most commonly included mood stabilizers and ADHD medications (stimulants and α2-agonists). At an average total daily dose of 1.7 mg, the authors noted that risperidone appeared to be effective in symptom reduction and that the risperidone appeared to be generally well tolerated.

There is one published study that has rigorously examined quetiapine treatment as an adjunct in young people ages 12 to 18 suffering from bipolar I disorder (DelBello, Schwiers, Rosenberg, & Strakowski, 2002). In that 6-week trial, 30 hospitalized adolescents with mania or mixed presentations were treated with divalproex sodium at an initial dose of 20 mg/kg/day. Half of the subjects were randomized to receive adjunctive quetiapine and half were randomized to receive adjunctive placebo. The quetiapine was titrated to a total daily dose of 450 mg. Results from this trial noted greater reductions in manic symptomatology in the cohort of youths randomized to receive combination therapy. However, sedation was also more common in these youths.

The largest prospective trial that has examined combination pharmacotherapy in pediatric bipolar disorder described the response of 90 outpatients with a mean age of about 11 years who were treated with combination lithium and

divalproex sodium therapy for up to 20 weeks (Findling et al., 2003). In that trial, the authors observed that the response rates were larger than those seen in other prospective trials in this patient population. The authors also found that response rates were higher than those described in adults using a similar combination treatment paradigm. In addition, it was noted that combination treatment was well tolerated. Of particular interest was the observation that residual depressive symptomatology was not manifest after combination lithium plus divalproex treatment in this patient population. This is in direct contrast to adults, in whom depression was often seen as a problematic residual mood state.