Bipolar Disorder: Increasing the Effectiveness and Decreasing the Side Effects of Treatment

Bipolar disorder is the sixth leading cause of medical disability worldwide for persons aged 15 to 44 years.¹ People with bipolar disorder work 14 years less than the average population,² and unemployment often exceeds 60%, even among patients with a college education.^3,4 The social consequences are also high. More than 65% of patients have difficulty in maintaining long-term relationships and 60% have troubled relationships with their children.³ Bipolar disorder is further associated with an extreme danger to oneself. Up to 50% of patients with bipolar disorder will attempt suicide and as many as 20% will complete suicide.⁵ Given these serious consequences, it is important to implement a treatment plan that treats bipolar episodes rapidly and effectively.

After the resolution of an acute episode, maintenance therapy can be used to reduce future relapses. Without treatment, more than 90% of patients will experience subsequent manic or depressive episodes.⁶ Even with treatment, relapse rates range from 40% to 60%.^7,8 Each additional mood episode worsens a patient’s long-term prognosis and increases the risk of future relapses. Therefore, it is crucial that a prophylactic treatment plan be implemented.^9,10

While effective treatments for acute mania and bipolar prophylaxis are available, they are not without risk. Many medication regimens are associated with significant adverse effects. As a result, side effect mitigation has become an important part of the treatment plan.

This article examines the latest research on treating acute manic episodes and reducing the risk of future episodes, including optimal dosing and titration schedules. It also discusses common medication side effects and mitigation strategies.

Treatment of acute manic episodes

The treatment of acute mania initially centered on mood stabilizers and typical antipsychotics including lithium(Drug information on lithium), valproate(Drug information on valproate)/divalproex, carbamazepine(Drug information on carbamazepine), and chlorpromazine(Drug information on chlorpromazine). More recently, second-generation antipsychotics (SGAs) have been found to reduce the duration of manic episodes while minimizing extrapyramidal symptoms (EPS) often associated with typical antipsychotics. Trials studying the efficacy of pharmacologic agents in acute mania have used several approaches. These include the analysis of individual medications versus placebo, active comparator trials, and combination therapy studies. Each type of trial provides clinically relevant information that can be used to improve the treatment of acute mania.

Monotherapy versus placebo

In studies of individual medications versus placebo, 9 agents have shown efficacy and received an FDA indication for the treatment of acute mania. Once efficacy has been established, it is important to evaluate the time to onset of symptom reduction given the high rates of morbidity and mortality associated with mania. Among FDA-approved agents, onset varies from 3 to 21 days.¹¹ Medication dosing and rate of titration can significantly affect clinical response and may increase the risk of side effects.^12,13

Early studies demonstrated the benefits of lithium, valproate/divalproex, carbamazepine, and chlorpromazine in the treatment of acute mania. Later trials found that SGAs are also efficacious in reducing the duration of manic episodes. It has been hypothesized that SGAs decrease dopamine(Drug information on dopamine) transmission through blockade or partial agonism of dopamine D₂ receptors. This may explain their antimanic effect, since mania is reportedly associated with dopaminergic hyperactivity.¹⁴

TABLE 1

Treatment of mania with second-generation antipsychotics

All 5 SGAs (olanzapine, risperidone(Drug information on risperidone), quetiapine, ziprasidone, and aripiprazole(Drug information on aripiprazole)) have been examined in at least 2 placebo-controlled, double-blind trials for the treatment of acute mania. The primary measure of efficacy in the majority of studies was the change from baseline to end point based on the Young Mania Rating Scale (YMRS). Ziprasidone(Drug information on ziprasidone) studies evaluated changes based on Mania Rating Scale scores of the Schedule for Affective Disorders and Schizophrenia (MRS-SADS). Most studies lasted 3 weeks, with the exception of olanzapine(Drug information on olanzapine) (4 weeks) and quetiapine(Drug information on quetiapine) (12 weeks). Given the similarity of these trials, it is possible to directly compare important parameters including starting dose relative to onset of action, response rates, completion rates, use of concomitant medications, and statistically significant differences in side effects. The design and results of these studies are summarized in Table 1.