Treatment of Bipolar Disorder: The Evolving Role of Atypical Antipsychotics

Management of bipolar disorder (BPD) may require multiple medications, including lithium, anticonvulsants, and antipsychotics (both conventional and atypical). Updated treatment guidelines reflect an expanded role for atypical antipsychotics (AAPs) in BPD treatment. Five AAPs—olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole—are approved by the US Food and Drug Administration (FDA) as monotherapy for first-line treatment of acute manic and (except for quetiapine) mixed episodes. Two AAPs—olanzapine (in fixed-dose combination with fluoxetine) and quetiapine— are also FDA approved for bipolar depression. For long-term maintenance therapy, one option is to continue effective, well-tolerated acute phase treatment; however, only olanzapine and aripiprazole are FDA approved for maintenance, based on evidence from randomized, placebo-controlled clinical trials.

Although head-to-head comparisons are scarce, meta-analysis data suggest that olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have similar antimanic efficacy; therefore, AAP selection for this indication should be guided by other considerations such as safety, tolerability, and cost. Safety and tolerability issues to consider when selecting an AAP include metabolic dysfunction (weight gain, type 2 diabetes, and dyslipidemia); hyperprolactinemia; extrapyramidal symptoms; QTc prolongation; and pharmacokinetic drug interactions.

(Am J Manag Care. 2007;13:S178-S188)

Treatment of bipolar disorder (BPD) is challenging in part because of the diversity of presenting symptoms. These may include full Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV) episodes of mania, depression, and mixed states (in which patients meet criteria for both mania and depression simultaneously); any of these may be accompanied by psychotic symptoms. Patients may also present with milder periods of hypomania or subthreshold depression, or with symptoms of comorbidities such as anxiety disorders, substance abuse disorders, attention-deficit/hyperactivity disorder,1 eating disorders,² and impulse control disorders,3 all of which are quite common among bipolar individuals.

To manage these manifestations, an array of medications from multiple classes is available. Currently,¹¹ drugs are approved by the US Food and Drug Administration (FDA) for use in some aspect of BPD (Table),^4-16 while others are widely used off-label based on varying degrees of evidence. Furthermore, agents approved for one phase of BPD are used off-label in other phases (eg, a drug approved for acute mania may be continued as maintenance therapy).

Commonly prescribed treatments in BPD include lithium; anticonvulsants such as divalproex, carbamazepine, or lamotrigine; and antipsychotics, both conventional and atypical. Adjunctive agents include benzodiazepines (in acute mania) and antidepressants (in depressive episodes).

Nonpharmacologic approaches also have a role in BPD treatment. Psychosocial interventions that address illness management (eg, treatment adherence, lifestyle change, early recognition of prodromal symptoms) and interpersonal difficulties are an important adjunct to pharmacotherapy.¹⁷ These interventions may include psychoeducation; cognitive behavioral or other psychotherapy; group therapy; family therapy; and support groups.^17,18 Electroconvulsive therapy is an option in life-threatening manic, mixed, or depressive episodes; for treatment-resistant illness; or as an alternative to medication (eg, during pregnancy).¹⁷

Because of the protean nature of BPD and the many treatment options, clinical decision-making can be complex. To assist the clinician,various groups have developed guidelines. In the United States, these include:

- the 2002 American Psychiatric Association (APA) practice guideline,¹⁷ which is to be updated in the coming year- the 2004 update of the Expert Consensus Guideline Series¹⁹

All of the published guidelines note that effective decision-making requires accurate monitoring of the patient's symptoms and clinical state. Rather than relying on memory and general impressions, systematic measurement provides greater precision in monitoring treatment response, helps avoid errors of omission, and facilitates informed patient participation.¹

TMAP is an example of a measurement-based care model. The TMAP algorithms were developed as part of a comprehensive program that includes systematic assessment of symptoms and drug adverse effects (AEs) at each clinic visit to guide treatment adjustments.²¹ The clinician-administered Brief Bipolar Disorder Symptom Scale (BDSS) was developed for clinical use and evaluated as part of the TMAP program.^22,23

Another measurement-based model is the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).¹ Measurement tools provided by this program–including a clinicianadministered Clinical Monitoring Form, a Clinical Self Report Form that patients can fill out in the waiting room at each visit, and a Mood Chart for tracking data between visits–are available online at www.manicdepressive.org.

One major shift in treatment in the past several years has been the increasing application of atypical antipsychotics (AAPs). The remainder of this article focuses on the roles of 5 AAPs–olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole– in the treatment of bipolar mania, bipolar depression, and mixed states. Although clozapine has been used to treat refractory BPD, it is not FDA approved for this purpose and a discussion of its use in BPD is beyond the scope of this article.

AAP Efficacy in Bipolar Disorder

This section briefly summarizes selected AAP safety and tolerability issues.

Weight gain, hyperglycemia, dyslipidemia.

Acute manic or mixed episodes. The 2002 APA guidelines recommend either lithium, divalproex, or an antipsychotic (eg, olanzapine) as first-line therapy. In less severe cases, they may be applied as monotherapy, while in more severe cases, lithium or divalproex may be combined with an antipsychotic.¹⁷

Since the APA guidelines were published, 4 additional AAPs (risperidone, quetiapine, ziprasidone, and aripiprazole) have been approved by the FDA for acute mania or mixed episodes. These expanded options are reflected in the 2005 updated TMAP algorithm. Based on efficacy evidence, the algorithm recommends first-line monotherapy with either

Management of BPD may require multiple medications including lithium, anticonvulsants, and antipsychotics, as well as adjunctive agents. Updated treatment guidelines reflect an expanded role for AAPs in the treatment of BPD.

Based on data from RDBPC trials, 5 AAPs– olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole–are approved by the FDA as monotherapy for first-line treatment of bipolar mania. All except quetiapine are also approved for mixed episodes. The antimanic efficacy of these AAPs is similar to that of other widely used agents such as lithium, divalproex, and haloperidol. Olanzapine, risperidone, and quetiapine have also demonstrated efficacy as add-on therapy with lithium or divalproex.

Of the AAPs, only olanzapine (in fixed-dose combination with fluoxetine) and quetiapine are approved by the FDA for bipolar depression.

Olanzapine and aripiprazole have demonstrated long-term maintenance efficacy in RDBPC trials, and both are FDA approved for that indication. However, open-label evidence suggests that quetiapine and ziprasidone also have maintenance efficacy.

Clozapine is the only AAP not FDA approved for BPD. It is used off-label in treatment-resistant BPD.

Although head-to-head comparisons are scarce, meta-analysis data suggest that olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole have similar efficacy for acute mania. Therefore, AAP selection for this indication should be guided by other considerations such as AE profiles and cost.

Safety and tolerability issues with AAPs(excluding clozapine) include:

- Weight gain, type 2 diabetes, and dyslipidemia. Available evidence suggests that the risk may be highest with olanzapine and lowest with ziprasidone and aripiprazole; however, experience with the latter 2 is limited.

- EPS. AAPs cause fewer acute EPS than conventional antipsychotics; the risk of tardive EPS with AAPs awaits clarification with long-term data.

- Pharmacokinetic drug interactions. Ziprasidone is less likely than other AAPs to have clinically important interactions with CYP inhibitors or inducers.

Acknowledgment: Pamela Mausner, MD, contributed to the writing of this article. Dr Perlis and Dr Mausner each received an honorarium from Pfizer Inc in connection with the development of this manuscript. Editorial support was provided by Ascend Healthcare and funded by Pfizer Inc.

Address correspondence to: Roy H. Perlis, MD, Harvard Medical School, 15 Parkman Street, AC 812, Boston, MA 02114-3117. E-mail: rperlis@partners.org. Pamela Mausner, MD, contributed to the writing of this article. Disclosure: Dr Perlis has received research grants from or served as a consultant to: AstraZeneca, Bristol-Myers Squibb, Eli Lilly and Company, GlaxoSmithKline, and Pfizer.1. Nierenberg AA, Ostacher MJ, Borrelli DJ, et al. The integration of measurement and management for the treatment of bipolar disorder: a STEP-BD model of collaborative care in psychiatry. J Clin Psychiatry. 2006;67(suppl 11):3-7.2. McElroy SL, Kotwal R, Keck PE Jr, Akiskal HS. Comorbidity of bipolar and eating disorders: distinct or related disorders with shared dysregulations? J Affect Disord. 2005;86:107-127.

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