Drugs for bipolar disorder

Drugs for bipolar disorder

Characteristics of Bipolar Disorder

Types of Mood Episodes Seen in BPD

Patterns of Mood Episodes

Treatment of Bipolar Disorder

Nondrug Therapy

Mood-Stabilizing Drugs

Antiepileptic Drugs

Antipsychotic Drugs

Box–1. Omega-3 Fatty Acids for Bipolar Disorder: A Fish Story with a Happy Ending

SPECIAL INTEREST TOPIC

OMEGA-3 FATTY ACIDS FOR BIPOLAR DISORDER: A FISH STORY WITH A HAPPY ENDING

In 1999, researchers from Harvard University made an exciting discovery: Fish oil can stabilize mood in people with bipolar disorder. Their results were so striking, in fact, that the experiment was stopped after 4 months so that control patients could switch to the fish-oil regimen. All subjects in the study had diagnosed bipolar disorder. Some took 9.6 gm of fish oil daily, and some took olive oil as a control. All continued on their usual medications. Among the group that ate fish oil, 11 of 15 improved after 4 months—and only 2 suffered eventual relapse. Among the group that ate olive oil, only 6 of 20 improved after 4 months—and 11 experienced relapse. Patients taking the fish oil had longer periods of remission, and, when symptoms did appear, they were less severe. Several patients were able to discontinue their medications and remain symptom free on fish oil alone. Side effects of the fish oil were minor—nausea, belching, fishy taste, loose stools—and easily controlled. At this time, the long-term benefits or detriments of fish oil are unknown. This study is of special interest in that it suggests that dietary therapy for a major illness can be as effective as drugs.

How does fish oil work? No one knows. Fish oil is composed of omega-3 fatty acids BOX 33–1 *—specifically, eicosapentaenoic acid and docosahexaenoic acid. In humans, the highest concentrations of omega-3s are found in the eyes and brain, where they are present in cell membranes. It may be that eating fish oil increases the concentration of omega-3s in neuronal membranes, and thereby slows nerve signaling, which in turn may stabilize mood. There is some evidence that omega-6 fatty acids—the kind found in vegetable oils, margarine, and mayonnaise—may negate the beneficial effects of omega-3s. Accordingly, patients taking fish oil for bipolar disorder should probably decrease intake of omega-6s.

^*Omega-3 fatty acids are long-chain polyunsaturated fats that have a double bond located three carbons from the methyl terminus of the chain.

Our topic for this chapter is bipolar disorder (BPD), formerly known as manic-depressive illness. The disease afflicts an estimated 3.7% of the adult population—more than 6.7 million Americans. The mainstays of therapy are lithium and divalproex sodium (valproate), drugs that can stabilize mood. Many patients also receive an antipsychotic agent, and some may require an antidepressant. Bipolar disorder is a chronic condition that requires treatment lifelong.

Characteristics of bipolar disorder

Bipolar disorder is a severe biologic illness characterized by recurrent fluctuations in mood. Typically, patients experience alternating episodes in which mood is abnormally elevated or abnormally depressed—separated by periods in which mood is relatively normal. Symptoms usually begin in adolescence or early adulthood, but can occur before adolescence or as late as the fifth decade of life. In the absence of treatment, episodes of mania or depression generally persist for several months. As time passes, manic and depressive episodes tend to recur more frequently. Although the precise etiology of BPD is unknown, it is clear that symptoms are caused by altered brain physiology—not by a character flaw or an unstable personality.

Types of mood episodes seen in BPD

Patients with BPD may experience four types of mood episodes. These are described below.

Pure manic episode (euphoric mania).

Manic episodes are characterized by persistently heightened, expansive, or irritable mood—typically associated with hyperactivity, excessive enthusiasm, and flight of ideas. Manic individuals display overactivity at work and at play and have a reduced need for sleep. Mania produces excessive sociability and talkativeness. Extreme self-confidence, grandiose ideas, and delusions of self-importance are common. Manic individuals often indulge in high-risk activities (eg, questionable business deals, reckless driving, gambling, sexual indiscretions), giving no forethought to the consequences. In severe cases, symptoms may resemble those of paranoid schizophrenia (hallucinations, delusions, bizarre behavior).

Detailed criteria for a manic episode are set forth in the Diagnostic and Statistical Manual of Mental Disorders (DSM). The criteria now in use, published in the fourth edition of the DSM (DSM-IV), were released in 1994. Revised criteria will appear in fifth edition of the DSM (DSM-5), scheduled for release in 2013. The proposed DSM-5 criteria, which are nearly identical to those in DSM-IV, are summarized in Table 33–1.

TABLE 33–1

Proposed DSM-5 Criteria for a Manic Episode

A A distinct period of abnormally and persistently elevated, expansive, or irritable mood and abnormally and persistently increased activity or energy, lasting at least 1 week and present most of the day, nearly every day (or any duration if hospitalization is necessary).

B During the period of mood disturbance and increased energy or activity, three (or more) of the following symptoms (four if the mood is only irritable) are present to a significant degree, and represent a noticeable change from usual behavior:

1. Inflated self-esteem or grandiosity

2. Decreased need for sleep (eg, feels rested after only 3 hours of sleep)

3. More talkative than usual or pressure to keep talking

4. Flight of ideas or subjective experience that thoughts are racing

5. Distractibility (ie, attention too easily drawn to unimportant or irrelevant external stimuli), as reported or observed

6. Increase in goal-directed activity (either socially, at work or school, or sexually) or psychomotor agitation

7. Excessive involvement in activities that have a high potential for painful consequences (eg, engaging in unrestrained buying sprees, sexual indiscretions, or foolish business investments)

C The mood disturbance is sufficiently severe to cause marked impairment in occupational functioning or in usual social activities or relationships with others, or to necessitate hospitalization to prevent harm to self or others, or there are psychotic features.

D The episode is not due to the direct physiologic effects of a substance (eg, a drug of abuse, a medication, or other treatment).

Note: A full manic episode emerging during antidepressant treatment (medication, ECT, etc.) and persisting beyond the physiologic effect of that treatment is sufficient evidence for a manic episode diagnosis. However, caution is indicated so that one or two symptoms (particularly increased irritability, edginess, or agitation following antidepressant use) are not taken as sufficient for diagnosis of a manic episode.

Modified from the proposed criteria for a manic episode, to be published in Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition. Washington, DC: American Psychiatric Association. Expected publication date: May 2013. Copyright © American Psychiatric Association. The proposed criteria are from the DSM-5 web site—www.DSM5.org—accessed on November 20, 2010.

Hypomanic episode (hypomania).

Hypomania can be viewed as a mild form of mania. As in mania, mood is persistently elevated, expansive, or irritable. However, symptoms are not severe enough to cause marked impairment in social or occupational functioning, or to require hospitalization. Psychotic symptoms are absent.

Major depressive episode (depression).

A major depressive episode is characterized by depressed mood and loss of pleasure or interest in all or nearly all of one’s usual activities and pastimes. Associated symptoms include disruption of sleeping and eating patterns; difficulty concentrating; feelings of guilt, worthlessness, and helplessness; and thoughts of death and suicide. The characteristics of major depression are discussed further in Chapter 32.

Mixed episode.

In a true mixed episode, patients experience symptoms of mania and depression simultaneously. Patients may be agitated and irritable (as in mania), but may also feel worthless and depressed. The combination of high energy and depression puts them at significant risk of suicide.

Patterns of mood episodes

Among people with BPD, mood episodes can occur in a variety of patterns. Contrary to popular belief, not all patients alternate repeatedly between mania and depression. Some experience repeated episodes of mania, and some experience repeated episodes of depression (with an occasional episode of mania). Mood may be normal between episodes of mania and depression, or it may be slightly elevated (hypomania) or slightly depressed (dysphoria).

Mood episodes can vary greatly with respect to how often they occur and how long they last. A single episode may last for days, weeks, months, or more than a year. In the absence of treatment, episodes of mania or hypomania typically last a few months, whereas episodes of major depression typically last at least 6 months. On average, people with BPD experience only 4 episodes during the first 10 years of their illness. However, some people cycle much more rapidly, experiencing many episodes every year.

On the basis of mood episode type and frequency, BPD can be subdivided into two major categories:

• Bipolar I Disorder—Patients experience manic or mixed episodes, and usually depressive episodes too.

• Bipolar II Disorder—Patients experience hypomanic or depressive episodes, but not manic or mixed episodes.

Etiology

Theories regarding the etiology of BPD continue to evolve. In the past, there was general agreement that BPD was due primarily to an imbalance in neurotransmitters. Today, researchers suspect the real cause may be disruption of neuronal growth and survival. Why? First, neuroimaging studies have shown an association between prolonged mood disorders and atrophy of specific brain regions—especially the subgenual prefrontal cortex, an area involved in emotionality. Second, mood-stabilizing drugs can prevent or reverse neuronal atrophy in patients with BPD, apparently by influencing signaling pathways that regulate neuronal growth and survival.

Treatment of bipolar disorder

Drug therapy

Types of drugs employed

Bipolar disorder is treated with three major groups of drugs: mood stabilizers, antipsychotics, and antidepressants. In addition, benzodiazepines are frequently used for sedation.

Mood stabilizers.

Mood stabilizers are drugs that (1) relieve symptoms during manic and depressive episodes, (2) prevent recurrence of manic and depressive episodes, and (3) do not worsen symptoms of mania or depression, or accelerate the rate of cycling. The principal mood stabilizers are lithium and two drugs originally developed for epilepsy: divalproex sodium (valproate) and carbamazepine. These drugs are the mainstays of treatment. The pharmacology of lithium and the antiepileptic drugs is discussed below.

Antipsychotics.

In patients with BPD, antipsychotic drugs are given to help control symptoms during severe manic episodes, even if psychotic symptoms are absent. Although antipsychotics can be used alone, they are usually employed in combination with a mood stabilizer. For reasons discussed below, the second-generation antipsychotics (eg, olanzapine, risperidone) are generally preferred to the first-generation agents (eg, haloperidol).

Antidepressants.

Antidepressants may be needed during a depressive episode. However, in patients with BPD, antidepressants are always combined with a mood stabilizer. Why? Because of the long-held belief that, when used alone, antidepressants may elevate mood so much that a hypomanic or manic episode will result. However, data published in 2007 indicate that the risk of inducing mania may be much lower than previously thought. Nonetheless, until the issue is fully resolved, it would seem prudent to continue the traditional practice of using an antidepressant only if a mood stabilizer is being used as well.

Although antidepressants have been studied extensively in patients with major depression, very little research has been done in patients with BPD. As a result, we lack reliable information on which to base drug selection. Even so, experts do have their preferences. Among clinicians with extensive experience in BPD, the following are considered antidepressants of choice: bupropion [Wellbutrin], venlafaxine [Effexor XR], and the selective serotonin reuptake inhibitors (SSRIs), such as fluoxetine [Prozac] and sertraline [Zoloft]. The pharmacology of these drugs is discussed in Chapter 32.

Drug selection

Acute therapy: manic episodes.

Two mood stabilizers—lithium and valproate—are preferred drugs for acute management of manic episodes. The choice between them is based on clinical presentation (eg, euphoric mania, mania with psychosis, rapid-cycling BPD). As shown in Table 33–2, valproate is preferred to lithium in most cases. In fact, the only exception is euphoric mania, for which lithium is the drug of choice. If the patient does not respond adequately to lithium or valproate alone, the drugs may be used together. Responses to mood stabilizers develop slowly, taking 2 or more weeks to become maximal.

TABLE 33–2

Initial Treatment of First Manic Episode

		Preferred Drugs*
Clinical Presentation	Preferred Strategy	Mood Stabilizers	Antipsychotics
Euphoric mania	Mood stabilizer alone	Valproate or lithium
Dysphoric mania or true mixed mania	Mood stabilizer alone	Valproate or lithium
Mania with psychosis	Mood stabilizer plus an antipsychotic	Valproate or lithium	Olanzapine or risperidone
Rapid cycling (currently manic)	Mood stabilizer alone	Valproate

Valproate = divalproex sodium.

^*Drugs of choice, if established, are presented in bold type.

If needed, an antipsychotic agent or a benzodiazepine may be added to the regimen. These adjuvants can help relieve symptoms (eg, insomnia, anxiety, agitation) until the mood stabilizer takes full effect. For patients with mild mania, a benzodiazepine (eg, lorazepam [Ativan]) may be adequate. For patients with severe mania or with symptoms of psychosis, an antipsychotic is preferred; olanzapine or risperidone would be a good choice.

Acute therapy: depressive episodes.

Depressive episodes may be treated with a mood stabilizer alone, or with a mood stabilizer plus an antidepressant—but never with an antidepressant alone (because hypomania or mania might result). If depression is mild, monotherapy with a mood stabilizer (lithium or valproate) may be sufficient. If the mood stabilizer is inadequate, an antidepressant can be added, although benefits may be limited. Preferred antidepressants are bupropion, venlafaxine, or an SSRI.

Long-term preventive treatment.

The purpose of long-term therapy is to prevent recurrence of both mania and depression. As a rule, one or more mood stabilizers are employed. Drug selection is based on what worked acutely. For example, if the patient responded to acute therapy with lithium alone, then lithium alone should be tried long term. Other long-term options include valproate alone, and valproate plus lithium. More recently, antipsychotic agents have been employed for long-term maintenance, either as monotherapy or in combination with a mood stabilizer.

Promoting adherence

Poor patient adherence can frustrate attempts to treat a manic episode. Patients may resist treatment because they fail to see anything wrong with their thinking or behavior. Furthermore, the experience is not necessarily unpleasant. In fact, individuals going through a manic episode may well enjoy it. As a result, in order to ensure adherence, short-term hospitalization may be required. To achieve this, collaboration with the patient’s family may be needed. Since hospitalization per se won’t guarantee success, lithium administration should be directly observed to ensure that each dose is actually taken.

After an acute manic episode has been controlled, long-term prophylactic therapy is indicated, making adherence an ongoing issue. To promote adherence, the patient and family should be educated about the nature of BPD and the importance of taking medication as prescribed. Family members can help ensure adherence by overseeing medication use, and by urging the patient to visit his or her prescriber or a psychiatric clinic if a pattern of nonadherence develops.

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