Pharmacotherapy for Bipolar Disorder

US Pharm. 2007;32(11):26-32.

Bipolar disorder, also commonly referred to as manic depression, is a diagnosis of brain dysfunction characterized by severe alterations in mood and energy with a diminished capacity for daily functioning. It is thought to affect approximately 1% of the general population, a lifetime prevalence rate that appears consistent across many cultures. No significant differences in risk for developing the disorder have been detected based on race, ethnicity, or gender. Its key feature involves the emergence of multiple and distinct mood episodes of varying types over time. It is considered a chronic disorder with a variable course and is associated with significant morbidity and mortality; the mean rate of suicide completion approximates 10%.¹

Diagnosis and Symptoms

The four different types of mood episodes associated with bipolar disorder, based on the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision ( DSM-IV-TR), are defined as manic, major depressive, hypomanic, or mixed. A manic episode is probably the type most commonly associated with bipolar disorder. The formal diagnosis requires the presence of elevated--either expansive or irritable--mood for a period of at least one week, accompanied by at least three of the following (four if the mood is only irritable): inflated self-esteem, decreased need for sleep, racing thoughts or flight of ideas, pressured speech, distractibility, increased psychomotor activity, or increased involvement in activities that are pleasurable but have a high risk for negative consequences. Significant impairment of functioning or need for hospitalization should also be present.¹

The criteria for a major depressive episode are identical to that required to make the diagnosis of unipolar major depressive disorder. There should be at least a two-week period of either a clearly depressed mood or the loss of interest or pleasure in usual activities. In addition, other symptoms may include decreased appetite, insomnia or hypersomnia, psychomotor retardation or agitation, feelings of guilt or worthlessness, decreased energy, impaired concentration, and suicidal thoughts. As with manic episodes, major depressive episodes impart considerable disability.¹

The other episode subtypes also fall into a manic spectrum. A mixed episode is defined as a period of at least one week in which both manic and major depressive episodes have emerged nearly every day. A hypomanic episode is similar to mania, but the intensity of symptoms is not as severe and there is no marked impairment in social or occupational functioning. Another clinical phenomenon that may occur in about 10% to 20% of bipolar disorder cases is that of "rapid cycling," defined as four or more mood episodes of any type within a one-year period.¹

Four major subtypes of bipolar disorder are defined by DSM-IV-TR.¹ Bipolar I disorder is characterized by one or more manic or mixed episodes along with major depressive episodes. Bipolar II disorder is defined by a clinical course of recurrent major depressive episodes, accompanied by at least one hypomanic episode without any history of mania or mixed episodes. Cyclothymic disorder consists of chronic fluctuations between subsyndromal depressive and hypomanic episodes. Bipolar Disorder Not Otherwise Specified is used to denote changing mood states that do not meet formal DSM-IV-TR diagnostic criteria for any specific bipolar disorder.

Because most patients with bipolar disorder will present with more depressive episodes than manic ones, ² it is important to obtain a careful longitudinal history of episodes. This will help distinguish the presence of unipolar major depressive disorder from that of bipolar disorder, which requires some evidence of episodes in the manic spectrum. It is also critical to fully characterize the clinical presentation of the patient; i.e., whether symptoms are currently active and causing distress or are stable and in relative remission. Emerging research indicates that knowledge of such details can be particularly useful to clinicians in managing bipolar disorder.

Pharmacotherapy Goals
The selection of appropriate pharmacotherapy depends on both the history and presentation of treatable symptoms. As medication options have increased in number, various treatment guidelines have been developed from clinical studies and expert consensus to facilitate evidence-based medication management. Recent sources for these include the Texas Implementation of Medication Algorithms (TIMA) initiative,³ the Expert Consensus Guideline Series (ECS),⁴ and the American Psychiatric Association (APA).⁵

The specific goals of drug treatment in bipolar disorder will change depending on the stage of the illness. In the acute phase, reduction of active target symptoms and overall mood stabilization are the focus. Once these occur, medications are continued to prevent future mood episodes and to enhance the chances of improved psychosocial functioning. The actual choice of a mood stabilizer is determined by knowledge of established efficacy and a reasonable risk-benefit evaluation regarding the likelihood of adherence and the extent of side effects. Patient preference should also be taken into consideration. It is important to realize that pharmacotherapy alone will not provide the best treatment outcomes. Ideally, all pharmacotherapy is accompanied by psychotherapy or other nonpharmacologic interventions if optimal outcomes are to be achieved, and this is supported by a significant body of literature.⁵ In addition, there may be clinical presentations of bipolar disorder that do not completely respond to a single agent, and combinations of mood stabilizers are commonly required to bring symptoms into remission.

Acute Mania or Mixed Episodes

There are many pharmacologic options for treating acute manic episodes. If the presenting episode is particularly severe, short-term adjunctive treatment with a benzodiazepine may be used as the mood stabilizer is initiated. As with antidepressants, the full effects of mood-stabilizing agents may not be realized until after several weeks of continuous therapy. The primary therapeutic goal would be the remission of symptoms, including rapid control of any agitation, aggression, or impulsivity that may be present. Antipsychotics have also been used effectively to treat concomitant symptoms of mania and psychosis.⁵

Acute Bipolar Depression
As with unipolar major depression, the most important goal of treatment is remission of the observed signs and symptoms consistent with the episode, with eventual return to normal levels of psychosocial functioning.⁵ A risk associated with the use of antidepressant monotherapy in bipolar depression is if the patient suddenly switches from a depressive to a manic or hypomanic state. Many clinicians would temper this risk by using a mood stabilizer as adjunctive therapy. Other options that do not involve the use of antidepressants alone include lithium, lamotrigine, olanzapine-fluoxetine, and quetiapine.^4,5 

Maintenance Treatment
Once acute symptoms have subsided, the focus shifts to the prevention of relapse, resolution of any residual symptoms, reduction of episode frequency, minimization of suicide risk, and optimization of overall functioning.⁵ To date, there is limited empirical evidence available to inform the clinician attempting to make the best choices of long-term pharmacotherapy. However, much current research has been devoted to this topic, and new data should be forthcoming.

Pharmacotherapy Options for Bipolar Disorder

Lithium

Acute Mania or Mixed Episodes: Lithium has a long history of evidence to support its role as first-line therapy in the treatment of acute mania. Early placebo-controlled studies have suggested that the overall response rate of acute symptoms to lithium is about 78% and that up to two weeks of continuous therapy may be needed to optimize effectiveness.⁶ Because of lithium's narrow therapeutic index, the monitoring of steady-state serum concentrations is part of general clinical practice, with a targeted range of 0.6 to 1.2 mEq/L.

Acute Bipolar Depression: A review of multiple studies revealed that about 60% to 80% of patients with bipolar disorder in the depressive phase responded to lithium monotherapy. ⁷ In general, the time frame for a depressive episode to resolve is longer than that for a manic one (i.e., at least six to eight weeks). If the clinical situation warrants a shorter onset of response, other interventions adjunctive to lithium (adding an antidepressant, psychotherapy, or a second mood stabilizer) may be initiated. Lithium is considered to be one of the first-line agents for this episode subtype, although it may take six to eight weeks of continuous treatment to control or eliminate symptoms of depression. ⁸

Maintenance: Open-label studies and clinical experience have established the efficacy of lithium in reducing the frequency, duration, and severity of both manic and depressive episodes, although more recent data suggest greater efficacy in preventing mania.⁹ The likelihood of sustained effects is enhanced if a patient has a history of good functioning between episodes and a positive family history of bipolar disorder with known lithium response. A significant reduction in mortality may be achieved with long-term lithium, which has been shown to reduce suicide risk by eight to 10-fold.¹⁰

Valproic Acid
Acute Mania or Mixed Episodes: A growing body of controlled clinical studies has supported the use of valproic acid or its derivatives to treat acute mania since divalproex sodium was first approved for this use in 1995. Some reports have suggested that valproate may be more effective than lithium in certain subtypes of the disorder (e.g., when rapid cycling or mixed episodes are present).^5,11 While definitive therapeutic serum concentrations have not been established for valproic acid in bipolar disorder, based on a seminal trial,¹² most clinicians would target a range of 50 to 125 mcg/mL.

Acute Bipolar Depression: In contrast to the literature that has confirmed the use of valproate in acute mania, there are no analogous controlled clinical trials investigating its efficacy in treating acute bipolar depression. The lack of supportive evidence for this indication has led to the relative exclusion of valproate from current practice guidelines for bipolar depression, except in combination with other mood stabilizers and antidepressants in treatment-resistant patients.³

Maintenance: A randomized, placebo-controlled trial compared the effects of lithium, valproate, and placebo in prolonging the time to recurrence of any mood episode over a 52-week study period.⁹ No significant differences were found among the three treatment arms, an outcme that diverges from the known maintenance efficacy of lithium, rendering this trial a "failed study." However, valproate was found to be superior to lithium on the secondary outcome measure of time to recurrence of mania in the study. Other definitive trials using valproate in long-term therapy are lacking.

Carbamazepine

Acute Mania or Mixed Episodes: Carbamazepine has been used for several years off-label for treating acute manic episodes, but only its beaded extended-release formulation has been approved for this indication and for mixed episodes. Historically, it has also been used as an alternative for rapid-cycling patients who evinced minimal responses to lithium. Its known hematologic side-effect profile and propensity for significant drug interactions make it potentially challenging to use. The results from clinical trials with designs of varying credibility generally support the use of carbamazepine for acute mania. In some studies, it was demonstrated to be as effective as valproate and lithium.¹³

Acute Bipolar Depression: Archival double-blind, placebo-controlled studies enrolling depressed patients diagnosed with different subtypes of bipolar disorder demonstrated a good or partial response to carbamazepine.^14,15 More robust responses were found in another trial in which carbamazepine therapy was augmented with lithium.¹⁶

Maintenance: Evidence for the use of long-term carbamazepine in the prevention of mood episodes is limited. One six-month open-label study using the beaded extended-release formulation demonstrated prophylactic activity in patients with recently manic or mixed episodes.¹⁷

Second-Generation or Atypical Antipsychotics

Acute Mania or Mixed Episodes: Much of the recent drug trial research in bipolar disorder has focused on this class of medications, and the collective results of several studies suggest that there may be an antimanic "class effect."¹⁸ Randomized, double-blind, placebo-controlled or comparator studies¹⁹ have established the efficacy of risperidone, quetiapine, ziprasidone, and aripiprazole in the treatment of acute manic or mixed episodes, with some suggesting that the adjunctive use of second-generation antipsychotics (SGAs) with mood stabilizers may be helpful. A complete understanding of the risks associated with long-term use of SGAs is not fully known. However, the growing evidence for emerging metabolic syndrome with this class of drugs has prompted specific guidelines for scheduled laboratory and physical examination assessments in continuing SGA treatment to prevent relapse of psychiatric symptoms.^20,21

Acute Bipolar Depression: Two SGAs that are associated with apparent efficacy in treating acute depressive episodes are quetiapine and olanzapine. In a series of multicenter trials,²² quetiapine monotherapy at dosages of 300 and 600 mg/day was found to be superior to placebo when depressive symptoms in patients with bipolar disorder were assessed. In another study that compared the effects of olanzapine, fluoxetine, and a combination product of olanzapine-fluoxetine in treating bipolar depressive symptoms, olanzapine monotherapy elicited a response that was not as robust as the response associated with the combination.²³ 

Maintenance: The literature supporting the use of SGAs in preventing recurrence of bipolar disorder symptoms is small but growing. Published studies to date have focused on olanzapine and aripiprazole. Olanzapine has been investigated for its efficacy against placebo and comparator drugs. Olanzapine was found to be superior to placebo²⁴ and comparable to lithium²⁵ and divalproex²⁶ in the time to relapse into mania or depression. Aripiprazole has also demonstrated efficacy in delaying the time to relapse compared with placebo.²⁷

Other Drugs and Combinations

Lamotrigine: Per APA and TIMA guidelines^4,5 and controlled trials,^28,29 the niche for this anticonvulsant agent as monotherapy in bipolar disorder appears to be for both treatment of acute depressive episodes and maintenance treatment in patients without a history of frequent or recent episodes of mania. Lamotrigine has received specific approval by the FDA for use in delaying the time to recurrence of mood episodes. Since its effects on resolving manic spectrum symptoms have not been found to be as robust as for treating depressive ones, lamotrigine has often been used successfully in combination with other mood stabilizers to prevent relapse.³⁰ As lamotrigine has been associated with serious rashes, including Stevens-Johnson syndrome, careful monitoring for dermatologic changes is essential.³⁷

Oxcarbazepine: A chemical analog of carbamazepine, oxcarbazepine has positive but limited evidence for its use in the treatment of bipolar disorder. A series of two-week trials in patients with acute mania showed that oxcarbazepine was more effective than placebo and similar in efficacy to lithium or haloperidol. ³¹ A larger 10-week trial demonstrated equal efficacy between valproate and oxcarbazepine.³² Overall, compared to the literature for carbamazepine, there are fewer well-controlled studies of oxcarbazepine in patients with bipolar disorder.

Olanzapine-Fluoxetine: This combination product shares the distinction with quetiapine of being one of the few agents with an FDA indication for the acute treatment of depressive episodes in bipolar disorder. In a double-blind, placebo-controlled study that included a parallel arm testing olanzapine monotherapy, olanzapine-fluoxetine was found to be superior to both placebo and olanzapine alone in effectively reducing the core mood symptoms of depression.²³

Benzodiazepines: Short-term use of longer-acting benzodiazepines--e.g., clonazepam and lorazepam--is appropriate in the management of acute mania, significant agitation or anxiety, or severe insomnia during a mood episode. These agents are often used as adjunctive therapy to mood stabilizers but are generally discontinued as these acute symptoms subside.^5,33

Antidepressants: Prior to the discovery that SGAs demonstrate efficacy against bipolar depression, both tricyclic and SSRI antidepressants were used to treat the debilitating target symptoms associated with this condition. Such use had been a choice made with caution, since antidepressant monotherapy had been linked to a risk of "switching" into mania in individuals with undiagnosed bipolar disorder. Current guidelines recommend the concurrent use of antidepressant and mood stabilizer pharmacotherapy if agents from those therapeutic classes are chosen.^3-5

Third-Generation Anticonvulsants: Earlier reports of the therapeutic efficacy of gabapentin in treating acute mania through open-label trials have been countered by more recent controlled, double-blind studies that have shown no difference between gabapentin and placebo.^29,34 The lack of well-designed controlled trials involving the use of topiramate in the management of acute bipolar mania or depression indicates that its role has yet to be defined, although open-label trials have suggested some efficacy as adjunctive treatment with other mood stabilizers. ³⁵

Dosing information for the most commonly used medications in the treatment of bipolar disorder is listed in Table 1.

The Role of the Pharmacist

Pharmacists have a key role in the drug therapy management of bipolar disorder. In addition to the usual counseling of patients about the common side effects and potential drug interactions associated with their prescribed medications, education regarding the nature of the disease state and expected medication responses can be extremely helpful to patients and their supportive caregivers. Many of the agents now used in treating bipolar disorder were originally approved for other indications. Patients may need to be reassured that a drug that they perceive as being used to treat primarily seizures or psychosis can be also appropriate for their mood symptoms. Pharmacists can direct patients to community resources; e.g., the National Alliance for the Mentally Ill, consumer links on the National Institute of Mental Health (NIMH) Web site, or community or Internet-based support groups for individuals with bipolar disorder. In order to optimize medication response, other useful advice may include maintaining regular patterns of sleep and daily activities, avoiding alcohol or street drugs, and engaging in relaxation or stress-reduction techniques.

A recent major NIMH-sponsored research initiative exploring various interventions in more naturalistic settings has been the Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD).³⁶ Unlike controlled trials, this study enrolled subjects with a more heterogeneous spectrum of symptoms typically found in clinical settings where patients with bipolar disorder are managed. The intent was to identify best practices in "real world" pharmacotherapy, with particular interest in areas for which clinical drug trials are relatively lacking (i.e., bipolar depression and relapse prevention). While the core study has been completed, the entire analysis of the data has not yet been fully reported or published. Pharmacists may access an updated bibliography of studies at www.stepbd.org/referencelist.html.

Summary

Advances in the medication management of bipolar disorder beyond the traditional mood stabilizers include use of the second-generation or atypical antipsychotics, lamotrigine, and combination therapies for acute manic and mixed episodes. Bipolar depression may require specific treatment modalities that differ from those used for unipolar major depressive disorder. Optimizing long-term pharmacotherapy with the intention of preventing relapse is now a significant focus of research. Overall quality of life improvement is now recognized as a critical therapeutic outcome and may involve nonpharmacologic approaches in concert with medications. Because of pharmacists' knowledge of bipolar disorder and the medications used for treatment, they can serve as an invaluable resource in their role as educators and providers of pharmaceutical care.

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