Bipolar Disorder: Treating Both Ends of the Spectrum

SEPTEMBER 01, 2007
Renee Michelle Striker, PharmD, and Matthew A. Fuller, PharmD, BCPS, BCPP, FASHP

Bipolar spectrum disorder is a range of mental illness that includes a continuum of depression, euthymia, hypomania, and mania. Patients may experience 1 or a mix of these presentations, with or without psychotic features. It is estimated that the incidence of bipolar spectrum disorder is 3.7% to 3.9% in the United States.1,2

Bipolar spectrum disorder comprises 2 main diagnoses, Bipolar I (BDI) and Bipolar II (BDII) disorders. A diagnosis of BDI disorder is made when mania is present for at least 1 week or is severe enough to require hospitalization, whereas BDII disorder is associated with hypomania lasting at least 4 days and not requiring hospitalization.

Both classifications of bipolar disorder may include periods of depression, which are associated with the majority of the morbidity and mortality seen in bipolar disorder.

The distinction between BDI and BDII disorders is the presence of hypomania or mania.

Other symptoms of bipolar mania include inflated self-esteem or grandiosity, decreased need for sleep, rapid speech or increased talkativeness, racing thoughts or experiencing a flight of ideas, distractibility, increased goal-directed activity, and increased activity in risky behaviors (eg, spending sprees, bad investments, risky sexual behavior).3

Currently, treatment guidelines exist only for the management of BDI. Literature regarding the treatment of BDII is not strong enough to support the formation of treatment guidelines. Because the distinction between mania and hypomania can be difficult to assess, in practice patients with BDI and BDII typically are treated in a similar fashion. The treatment of BDI manic episodes will be discussed further.

Medication-approval History

For decades, lithium has been the cornerstone of pharmacotherapy for the treatment of bipolar spectrum disorders. Although it has been used for mood stabilization since the late 1800s, it was not approved for the treatment of bipolar mania until 1970. It remains the gold standard of therapy for bipolar spectrum disorder (both acute and maintenance).

It was not until 1995 that divalproex was approved for the acute treatment of mania. In current practice, divalproex is used for the maintenance treatment of bipolar spectrum disorder, although it carries FDA approval only for the treatment of acute manic episodes.

After the approval of divalproex, many other antiepileptic medications began to see use in the treatment of acute mania and the maintenance of bipolar disorder. Carbamazepine ER (Equetro) was approved for use in bipolar mania in 2004 and lamotrigine for bipolar maintenance in 2003. Oxcarbazepine (Trileptal) also is considered an option for bipolar disorder as an off-label therapy.

Recently, the atypical antipsychotics (olanzapine, risperidone, aripiprazole, quetiapine, and ziprasidone) have gained indications for acute and maintenance treatment of bipolar disorder as well. Quetiapine and olanzapine/fluoxetine currently are the only agents approved for the treatment of bipolar depression.

Treatment Guidelines

Three different sets of guidelines exist for the treatment of BDI. They are from the American Psychiatric Association, the Expert Consensus Guideline Series, and the Texas Implementation of Medication Algorithms (TIMA).4-6 Currently, the TIMA guidelines are the most up-to-date. They were published in 2005, and the other 2 bodies are in the process of updating their guidelines.

For this reason, there are differences in the recommendations, based on the pool of published data available at the time the guidelines were prepared.

In general, first-line agents recommended in the TIMA guidelines include lithium, divalproex, aripiprazole, quetiapine, risperidone, and ziprasidone. Alternate first-line agents are olanzapine and carbamazepine. If one of the first-line agents is unsuccessful, the next option is typically changing to another of the previously mentioned agents and then moving on to a 2-drug combination, changing to oxcarbazepine, adding a typical antipsychotic, or employing electroconvulsive therapy.

Patients who experience psychotic features during a manic episode typically are placed on an antipsychotic agent in addition to a mood stabilizer.

Choosing an Agent

Although the guidelines support the use of many different agents for the firstline treatment of bipolar spectrum disorders, in the practice setting choosing a pharmacologic agent is individualized, based on patient-specific factors.

Prior to the initiation of an agent, it is vital that a detailed medication history be obtained to assess prior medication trials. When possible, it is best to inquire not only about the agent(s) used but also about the dose that was taken and the duration of therapy.

Adherence to therapy also should be assessed, because patients may report that a medication has been ineffective after a short trial with a subtherapeutic dose of medication, or they may discontinue treatment after feeling better.

Patient-specific factors that impact pharmacologic selection include the patient?s medication history, medical and psychiatric comorbidities, concurrent drug therapy, potential medication side effects and drug?drug interactions, and the prescriber?s experience.

The Pharmacist?s Role

In the treatment of bipolar spectrum disorder, pharmacists can be involved in medication management in a variety of ways. Pharmacists working on inpatient units or in outpatient clinics may be involved in obtaining a medication history, patient education, drug selection, and providing drug information to the treatment team. Pharmacists have an opportunity to use their unique training in patient counseling and in obtaining a detailed medication history.

Pharmacists also may be involved in the monitoring of medications. The majority of the medications used to treat bipolar spectrum disorder require continued monitoring for effectiveness and safety.

Agents such as lithium, divalproex, and carbamazepine can be monitored in the blood. Lithium has a well-defined therapeutic range (0.5-1.5 mEq/L), and assessing serum levels of divalproex (50-125 ?/mL) is helpful in evaluating efficacy and toxicity. Although carbamazepine levels often are obtained, these serum levels have not correlated with efficacy for the management of bipolar disorder.

In addition to therapeutic drug levels, agents also require monitoring for side effects such blood dyscrasias, weight gain, and electrolyte abnormalities. In addition, lithium therapy necessitates monitoring of thyroid function, the ability of the kidney to concentrate urine, and glucose regulation. Moreover, a baseline electrocardiogram is recommended for those patients who are older than 40 years or those with preexisting cardiovascular disease (Table 1).

Monitoring Schedule for Lithium (LI), Divalproex (DVP), and Carbamazepine (CBZ)

Therapeutic drug levels are not used in atypical antipsychotic therapy. As a class, these medications require extensive monitoring of potential metabolic side effects. These effects include weight gain, dyslipidemia (primarily increased triglycerides), and glucose dysregulation independent of weight gain. The American Diabetes Association has ranked the ability of the various atypical antipsychotics for their likelihood of producing metabolic side effects and has developed guidelines for monitoring them (Table 2).7

Metabolic Monitoring Schedule for the Atypical Antipsychotics

One of the most valuable roles any pharmacist can play is that of patient educator. Community pharmacists come into contact with patients more frequently than inpatient pharmacists and many outpatient providers and are readily accessible to the public. Pharmacists can educate patients on side effects and required monitoring, and they can reinforce the need for continuing adherence to medications and follow-up with providers.


1. Hirschfeld RM, Calabrese JR, Weissman MM, et al. Screening for bipolar disorder in the community. J Clin Psychiatry. 2003;64:53-59.

2. Kessler RC, Berglund P, Demler O, Jin R, Merikangas KR, Walters EE. Lifetime prevalence and age-of-onset distributions of DSM-IV disorders in the National Comorbidity Survey Replication. Arch Gen Psychiatry. 2005;62:593-602.

3. American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th ed, text rev. Washington, DC: APA; 2000.

4. Suppes T, Dennehy EB, Hirschfeld RM, et al. The Texas implementation of medication algorithms: update to the algorithms for treatment of bipolar I disorder. J Clin Psychiatry. 2005;66:870-886.

5. Keck PE, Perlis RH, Otto MW, Carpenter D, Ross R, Docherty JP. The expert consensus guideline series: treatment of bipolar disorder 2004. Postgrad Med. 2004 Dec; Spec No:1-116.

6. American Psychiatric Association. Practice guidelines for the treatment of patients with bipolar disorder (rev). Am J Psychiatry. 2002;159(4 suppl):1-50.

7. American Diabetes Association, American Psychiatric Association, American Association of Clinical Endocrinologists, North American Association for the Study of Obesity. Consensus Development Conference on Atypical Antipsychotic Drugs and Obesity and Diabetes. J Clin Psychiatry. 2004;65:267-272.