Treatment of Bipolar Disorder
Drug Therapy
Types of Drugs Employed
The American Psychiatric Association (APA) and the Veterans Administration both published treatment guidelines for bipolar disorder in 2010. These guidelines discussed both pharmacologic and nonpharmacologic treatments for BPD. To begin, BPD 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 later.
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 later, the second-generation antipsychotics (e.g., olanzapine, risperidone) are generally preferred to the first-generation agents (e.g., haloperidol).
Antidepressants
Antidepressants may be needed during a depressive episode. However, in patients with BPD, antidepressants are always combined with a mood stabilizer 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, a systematic review published in 2014 indicates that the risk for inducing mania may be much lower than previously thought. These data suggest that use of a selective serotonin reuptake inhibitor (SSRI) may be reasonable for the short-term treatment of bipolar depression. Nonetheless, the current guidelines suggest continuing 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, research is still lacking in patients with BPD. At this time, there are insufficient data 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 SSRIs, such as fluoxetine [Prozac] and sertraline [Zoloft]. One thing we do know is that use of tricyclic antidepressants (TCAs) appears to promote more incidence of mania, and therefore TCAs are not recommended in treatment of BPD. The pharmacology of these drugs is discussed in Chapter 25.
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 (e.g., euphoric mania, mania with psychosis, rapid-cycling BPD). As shown in Table 26.1, 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 26.1
Initial Treatment of First Manic Episode
| Clinical Presentation | Preferred Strategy | Preferred Drugs* | |
| 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 | |
If needed, an antipsychotic agent or a benzodiazepine may be added to the regimen. These adjuvants can help relieve symptoms (e.g., insomnia, anxiety, agitation) until the mood stabilizer takes full effect. For patients with mild mania, a benzodiazepine (e.g., 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 lamotrigine) may be sufficient. If the mood stabilizer is inadequate, an antidepressant can be added, although benefits may be limited. Symbyax, a combination drug containing both olanzapine and fluoxetine, was shown to be beneficial in the short-term treatment of BPD in a small study. 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, to ensure adherence, short-term hospitalization may be required. To achieve this, collaboration with the patient’s family may be needed. Because hospitalization per se won’t guarantee success, lithium administration should be directly observed to ensure that each dose is actually taken.
Nondrug Therapy
Education and Psychotherapy
Ideally, BPD should be treated with a combination of drugs and adjunctive psychotherapy (individual, group, or family); drug therapy alone is not optimal. BPD is a chronic illness that requires supportive therapy and education for the patient and family. Counseling can help patients cope with the sequelae of manic episodes, such as strained relationships, reduced self-confidence, and a sense of shame regarding uncontrolled behavior. Certain life stresses (e.g., moving, job loss, bereavement, childbirth) can precipitate a mood change. Therapy can help reduce the destabilizing effect of these events. Patients should be taught to recognize early symptoms of mood change and encouraged to contact their primary clinician immediately if these develop. Additional measures by which patients can help themselves include the following:
• Maintaining a stable sleep pattern
• Maintaining a regular pattern of activity
• Avoiding alcohol and psychoactive street drugs
• Enlisting the support of family and friends
• Taking steps to reduce stress at work
Electroconvulsive Therapy
Electroconvulsive therapy (ECT) is an effective intervention that can be lifesaving in patients with severe mania or severe depression. However, ECT is not a treatment of first choice. It should be reserved for patients who have not responded adequately to drugs. Candidates for ECT include patients with psychotic depression, severe nonpsychotic depression, severe mania, and rapid-cycling BPD. Details of ECT are discussed in Chapter 25.
Mood-Stabilizing Drugs
As noted, mood stabilizers are drugs that can relieve an acute manic or depressive episode and can prevent symptoms from recurring—all without aggravating mania or depression and without accelerating cycling. The agents used most often are lithium, valproate, and carbamazepine.
Lithium
Lithium [Lithobid, Carbolith 
] can stabilize mood in patients with BPD. Beneficial effects were first described in 1949 by John Cade, an Australian psychiatrist. Because of concerns about toxicity, lithium was not approved for use in the United States until 1970. Lithium has a low therapeutic index. As a result, toxicity can occur at blood levels only slightly greater than therapeutic levels. Accordingly, monitoring lithium levels is mandatory.
Chemistry
Lithium is a simple inorganic ion that carries a single positive charge. In the periodic table of elements, lithium is in the same group as potassium and sodium. Not surprisingly, lithium has properties in common with both elements. Lithium is found naturally in animal tissues but has no known physiologic function.
Therapeutic Uses
BPD
Lithium is a drug of choice for controlling acute manic episodes in patients with BPD and for long-term prophylaxis against recurrence of mania or depression. In manic patients, lithium reduces euphoria, hyperactivity, and other symptoms but does not cause sedation. Antimanic effects begin 5 to 7 days after treatment onset, but full benefits may not develop for 2 to 3 weeks. In the past, lithium was considered the drug of choice for all patients experiencing an acute manic episode, regardless of clinical presentation. Today, however, lithium is reserved primarily for patients with classical (euphoric) mania, and valproate is generally preferred for all other patients (see Table 26.1). However, more recent data show that lithium is superior to valproate at preventing suicide in patients with BPD, and hence use of lithium is likely to increase.
Mechanism of Action
Although lithium has been studied extensively, the precise mechanism by which it stabilizes mood is unknown. In the past, research focused on three aspects of brain neurochemistry: (1) altered distribution of certain ions (calcium, sodium, magnesium) that are critical to neuronal function; (2) altered synthesis and release of norepinephrine, serotonin, and dopamine; and (3) effects on second messengers (e.g., cyclic adenosine monophosphate, phosphatidylinositol), which mediate intracellular responses to neurotransmitters. Unfortunately, this research has failed to provide a definitive explanation of how lithium works. Current neurochemical research suggests that lithium may work by (1) altering glutamate uptake and release, (2) blocking the binding of serotonin to its receptors, or (3) inhibiting glycogen synthase kinase-3 beta.
There has been growing interest in the neurotrophic and neuroprotective actions of lithium. As noted earlier, there is evidence that symptoms of BPD may result from neuronal atrophy in certain brain areas. In animal studies, “therapeutic” doses of lithium doubled the level of neurotrophic Bcl-2 proteins. In addition, lithium has been shown to facilitate regeneration of damaged optic nerves. In patients with BPD taking lithium long term, volume of the subgenual prefrontal cortex is greater than in untreated patients. Furthermore, lithium can increase total gray matter in regions known to atrophy in BPD, including the prefrontal cortex, hippocampus, and caudate nucleus. All of these studies suggest that the benefits of lithium may result at least in part from an ability to protect against neuronal atrophy or promote neuronal growth.
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