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USE OF NEUROLEPTICS IN PRIMARY CARE FOR THE MANAGEMENT OF BIPOLAR DISORDER

OVERVIEW

Primary care physicians face several challenges in treating patients with bipolar disorder. This article is intended to help primary care physicians keep current with advances in psychopharmacology and to improve their ability to treat patients with serious psychiatric disorders.

The complex and chronic nature of bipolar disorder makes it challenging to treat. Because bipolar disorder may present with depressive, hypomanic, or manic episodes, the term bipolar spectrum disorders (BSD) better characterizes this syndrome. These diverse presentations contribute to the difficulty that clinicians face in correctly diagnosing this condition. In particular, clinicians frequently fail to detect hypomania, the defining feature of bipolar II disorder. Anxiety disorders, substance abuse, and personality disorders are frequently comorbid conditions with BSD and may disguise BSD (Grant, 2005). Primary care physicians often misdiagnose or fail to diagnose BSD among patients who screen positively for BSD (Frye, 2005). BSD is more common than was previously thought and may affect up to 30% of primary care patients presenting with anxiety or depressive symptoms (Piver, 2002).

The depressive episodes of patients with BSD typically last 3 times longer than the manic episodes. Because approximately 80% of patients with BSD present with depressive episodes, clinicians tend to misdiagnose these patients with unipolar depression. Although the pharmacological treatment of choice for unipolar depression is an antidepressant, antidepressants can result in significant morbidity and mortality in patients with BSD. For the misdiagnosed patient, the consequences of failing to diagnose BSD may include loss of employment, excessive use of health care resources, impaired relationships, and impaired quality of life. In fact, the total annual cost to society for BSD is estimated to be $45 billion (Sajatovic, 2005). In comparison to patients with major depression and schizophrenia, patients with BSD have equally high or even higher levels of impairments and disabilities (Pini, 2005).

For all of these reasons, primary care physicians should have a practical knowledge of the acute and long-term management of bipolar disorder. Familiarity with common adverse effects and potential drug-drug interactions that may occur with BSD medications is especially important (Berk, 2005).

IMPROVING DIAGNOSTIC ACCURACY OF BSD

The proper use of screening instruments, semi-structured interviews, and collateral history may improve the accurate diagnosis of BSD. Brief screening instruments offer several advantages. They are standardized, well-validated, easily administered and scored, and offer a baseline to measure treatment progress. Indeed, screening for BSD in psychiatric patients may improve the diagnostic accuracy of BSD and may result in appropriate treatment (Hirschfeld, 2005). However, primary care physicians should not diagnose BSD solely based upon the results of the self-administered screening instruments. Instead, the diagnosis should be based upon a comprehensive history, mental status examination, and, when available, collateral history (Phelps, 2006).

The most commonly used screening instrument for BSD is the Mood Disorder Questionnaire (MDQ). The MDQ is a 13-item, yes-no test that most patients can easily complete on their own within 5 minutes (Hirschfeld, 2000). Its sensitivity and specificity for detecting BSD are 0.58 and 0.93, respectively. The MDQ is available at http://www.psycheducation.org/PCP/handouts/mdq.doc.

TREATMENT GOALS FOR BSD

Depending upon the severity of BSD, patients may require hospitalization, day treatment, or intensive outpatient care. This is particularly the case when patients are dangerous to themselves or others or are unable to provide for basic necessities. When in doubt, obtain a psychiatric consultation opinion and err on the side of patient safety. Initial treatment goals include mood stabilization and the selection of one or more medications efficacious in managing comorbid anxiety disorders (Keck, 2006).

According to Glick et al (2001), guidelines for treatment strategies should include the following:

• Treatment strategies should be long-term and should emphasize treatment compliance.
• Treatment choice should be empirical.
• Combinations of medications may be helpful.
• A combination of psychosocial and pharmacologic treatments may be more useful than either alone.
• The patient’s family or significant others must be involved, as should be a consumer organization.

Because of the high morbidity and mortality of BSD, an important goal of the pharmacologic treatment of acute bipolar mania is rapid symptom improvement. Lithium is commonly used to treat BSD, as are several anticonvulsants and antipsychotics. Second-generation antipsychotics are being prescribed more often, as they are associated with lower rates of extrapyramidal symptoms (EPS) (Keck, 2005).

Informed consent

Informed consent is not a written document but, rather, an interactive process with the patient. Items to discuss include indications and benefits, adverse effects and risks, limitations of treatment, likely response without treatment, and alternative treatments. This process can bring to light patient expectations, particularly unrealistic ones, such as immediate response or cure. The World Wide Web, direct-to-consumer advertising, and others’ anecdotal experiences are common sources of such unrealistic expectations (Menaster, 2002).

TREATMENT OF MANIC EPISODES

For several decades, lithium has been the mainstay treatment for BSD. Numerous studies have found that long-term maintenance therapy with lithium reduces the frequency and intensity of manic and depressive episodes and decreases suicidality. Generic forms are available, keeping costs lower. However, the combination of patient denial regarding the need for medication and the adverse effects of lithium, such as weight gain, frequently results in medication noncompliance after only a few weeks of treatment. Even when patients are compliant with lithium therapy, they may still fail to achieve remission and may remain severely impaired. Both acutely and prophylactically, lithium is more effective in treating mania or hypomania than it is in treating depression.

Several anticonvulsants have been used to treat the manic episodes of BSD, including divalproex, carbamazepine, oxcarbazepine, topiramate, and lamotrigine. Among these medications, only lamotrigine has been demonstrated to be effective in one adequately powered study in acute bipolar I depression. Conventional antidepressants have been associated with emergent mania and cycle acceleration.

Atypical antipsychotics

The newer neuroleptics are called atypical antipsychotics and include olanzapine, risperidone, quetiapine, ziprasidone, and aripiprazole. While not yet categorized as such, the atypical antipsychotics may act as mood stabilizers and improve manic symptoms without inducing depression or manic episodes (Sachs, 2003). In numerous, large, and controlled trials, the atypical antipsychotics have demonstrated efficacy in the treatment of BSD. Specifically, olanzapine, risperidone, and quetiapine are effective in treating manic episodes either as monotherapy or in combination with mood stabilizers, such as lithium and divalproex. Moreover, patients tolerate the atypical antipsychotics better than conventional antipsychotics, such as chlorpromazine and haloperidol. The US Food and Drug Administration (FDA) has approved the atypical antipsychotics risperidone, olanzapine, and quetiapine for treatment of mania associated with bipolar disorder.

Despite these benefits, primary care physicians may be reluctant to prescribe atypical antipsychotics. The term “atypical antipsychotics” itself can be daunting for someone who is a candidate for this treatment. However, “atypical” merely refers to the fact that these antipsychotics affect serotonin and dopamine receptors. Patients and even some primary care physicians may be influenced by the stigma of taking medication for mental health disorders. Extrapyramidal symptoms (EPS) are relatively infrequent; studies have found that EPS associated with atypical antipsychotics occur in a range of only 0-15%. Even so, other adverse effects, such as weight gain, EPS, tardive dyskinesia (TD), and hyperglycemia also contribute to hesitancy in the use of atypical antipsychotics.

Other considerations and indications

In a data review of studies of the newer medications for BSD, Marken and Pies (2006) discovered that, despite the efficacy of medications, poor adherence to BSD regimens, comorbidities, and the need for combination therapy all pose serious challenges to effective treatment.

In particular, atypical antipsychotics may cause more weight gain and metabolic complications when compared to conventional antipsychotics (Marken, 2006). Nevertheless, atypical antipsychotics have become the first-line treatment option for schizophrenia and bipolar disorders. Most atypical antipsychotics have proven efficacy for treating manic episodes. Some are also effective in treating bipolar depression and BSD (Seemuller, 2005). In addition, studies show that some BSD medications may also be effective in treating certain anxiety disorders. Valproate can treat panic disorder; lamotrigine, risperidone, and olanzapine are effective in posttraumatic stress disorder. The atypical antipsychotics risperidone, olanzapine, and quetiapine are efficacious adjuncts in treatment-resistant obsessive-compulsive disorder (OCD) and are effective treatments for panic disorder. In particular, one case report found low-dose quetiapine (50 mg/d) rapidly effective in treating agoraphobia and OCD (Menaster, 2005).

Gianfrancesco and Pesa (2005) conducted a retrospective study based on administrative data from US health plans to determine the average costs per patient per month (PPPM) for the different atypical antipsychotics. They found that costs were similar for the 3 drugs, but that an equivalent daily dose of olanzapine may be more costly than risperidone or quetiapine (Gianfresco and Pesa, 2005).

Quetiapine as monotherapy and adjunct therapy

DelBello et al (2006) compared quetiapine and divalproex as monotherapy in 50 adolescents with BSD who presented with manic or mixed episodes. This study found that quetiapine (400-600 mg/d) had a more rapid onset of action and greater remission rate. The rates of adverse effects were not significantly different (DelBello, 2006).

A randomized, double-blind, placebo-controlled study of 302 patients with bipolar I disorder (manic episode) compared quetiapine (up to 800 mg/d), haloperidol (up to 8 mg/d), and placebo (McIntyre, 2005). By day 21, patients taking quetiapine showed improvement; by day 84, this improvement became statistically significant (McIntyre, 2005). In an international, multicenter, double-blind, parallel-group, 12-week study, Bowden et al (2005) compared quetiapine, lithium, and placebo as monotherapy for the treatment of mania associated with BSD. The results of this study are available here and demonstrated that quetiapine was superior to placebo in patients with bipolar mania (Bowden, 2005).

In a combined analysis of 2 placebo-controlled studies, Vieta et al (2005) confirmed the results of the original studies: in the treatment of mania, quetiapine as monotherapy is fast-acting, well-tolerated, and effective across various mood symptoms. The full methodology of this analysis is available here.

Pae et al (2005) used several rating scales to study the effectiveness and tolerability of quetiapine as an adjunct to other mood stabilizers in bipolar mania. Their results are available here. They suggest that quetiapine is effective in this role in the long-term treatment of bipolar mania.

According to a retrospective chart review taken by Sokolski and Denson (2003), quetiapine is an efficacious adjunctive therapy for bipolar patients whose response to lithium or valproate treatment is incomplete. The details of this chart review are available here.

TREATMENT OF DEPRESSIVE EPISODES

In addition to their efficacy in the manic phase of BSD, the atypical agents olanzapine, risperidone, and quetiapine are also efficacious during the depressive phase. Post and Calabrese (2004) reported that all 3 of these atypical antipsychotics demonstrated improvements in depressive symptoms in patients with various BSDs.

Although conventional antidepressants (eg, selective serotonin reuptake inhibitors [SSRIs], bupropion, serotonin-norepinephrine reuptake inhibitors [SNRIs]) may relieve depressive symptoms of BSD when used in combination with mood stabilizers, they are not recommended as monotherapy for bipolar depression (Yatham, 2005). Even as combination therapy, they may instigate a switch from the depressive to the manic episode and must, therefore, be used with caution (Yatham, 2005).

After a review of current literature, Yatham et al (2005) note an important point of commonality among the antidepressant treatments and the atypical antipsychotics olanzapine and quetiapine. To treat depression, SSRIs, SNRIs, and electroconvulsive therapy downregulate 5-HT(2A) receptors. Olanzapine and quetiapine also downregulate 5-HT(2A) receptors. This similarity may explain the antidepressant efficacy of these atypical antipsychotics. The additional mood-stabilizing benefits of atypical antipsychotics over more conventional antidepressant treatments may stem from their antagonisms of dopamine (Yatham, 2005).

EXTENDED USE OF QUETIAPINE IN ADOLESCENTS

Data on extended use of quetiapine in adolescents are limited. In one open-label extension trial, quetiapine was demonstrated as well-tolerated and effective in treating certain psychotic disorders in adolescents (McConville, 2003). To view details of the trial, please click here.

ENHANCED TREATMENT COMPLIANCE

Adverse effects of atypical antipsychotics

The adverse effects of atypical antipsychotics include extrapyramidal symptoms, tardive dyskinesia, weight gain, sedation, and sexual dysfunction. The adverse effects contribute to medication noncompliance and may adversely impact the overall course of illness.

In particular, weight gain is a significant issue. The weight gain experienced by patients treated with atypical antipsychotics is not only detrimental to patient compliance, but it also can adversely affect cardiovascular health. These medications are associated with the development of type II diabetes mellitus (Sussman, 2003). Long-term studies found that clozapine and olanzapine were associated with the greatest degree of weight gain, followed by risperidone. Further data suggest that patients receiving quetiapine as long-term treatment experience minimal weight gain and are not at greater risk of developing type II diabetes as a result of such treatment (Sussman, 2003).

In many cases, the advantages of prescribing atypical antipsychotics for schizophrenic and bipolar disorders outweigh the disadvantages. However, physicians recommending these treatments for their patients must be aware of the risk of weight gain and its associated comorbidities (Sussman, 2003).

Denial or anger from patient

A patient’s belief that he or she does not require (or no longer requires) medication is also a large risk factor for noncompliance. The physician must understand the individual patient’s situation and formulate a diagnosis and treatment plan.

Patients may also exhibit anger toward the treatment because of unmet expectations. The physician must understand the origin of a patient’s anger and validate his or her feelings. These patients need empathy and assistance formulating constructive ways to cope with their anger (Menaster, 2004).

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