Bipolar Disorder

Description

Alternative Names

Treatment

Bipolar disorder is a recurrent disease. However, its course is unpredictable. The major goals of treatment, then, are the following:

• To treat and reduce the severity of acute episodes of mania or depression when they occur.
• To reduce the frequency of episodes.
• To avoid cycling from one phase to another.
• To help the patient function as effectively as possible between episodes.

First, the physician will try to determine conditions that might have precipitated the attack and identify any accompanying medical or emotional problems that might interfere with or complicate treatment.

Challenges of Bipolar Treatment

The treatments for bipolar disorder, while very effective, pose some specific challenges for the patient:

• Because the mood variations in bipolar disorder are not predictable, it is sometimes difficult to tell if a patient is responding to treatment or naturally emerging from a bipolar phase.
• A patient with bipolar disorder is not always reliable in reporting the state of the illness to the physician.
• The patient is likely to need more than one medication during the course of the disease. This increases the risk for distressing side effects. Noncompliance is common.
• Patients often have more than one disorder and need different drugs for each disorder. Such agents may interact with drugs used to treat bipolar disorder or increase side effects. For example, children with bipolar disorder have a higher risk for attention deficit-hyperactivity disorder, which is treated with stimulants that can complicate treatment.
• Family members who have not been educated about the disorder may undermine the treatment.
• Treatment strategies for children and the elderly have not been intensively studied and have not been clearly defined.
• Treatments may be costly.

Specific Drugs and Other Treatments Used in Bipolar Disorder

The following are the treatment options for most patients with bipolar disorder, depending on the bipolar disorder phase or episode. Patients should understand that, even with aggressive therapy, either mania or depression recurs in almost three-quarters of patients.

Drugs Used in Bipolar Disorder. Mood stabilizing drugs are the mainstay for patients with bipolar disorder. They are defined as drugs that are effective for acute episodes of mania and depression and that can be used for maintenance. The currently available first-line mood stabilizers are lithium and valproate. Both drugs stimulate the release of the neurotransmitter glutamate, although they appear to work through different mechanisms. Other drugs may also be used.

• Lithium. Lithium has been used for years for bipolar disorder. It remains the best drug for people with pure mania characterized by euphoria and pure depression. And, although imperfect, it is also an effective long-term drug for many patients with other bipolar subtypes.
• Antiseizure Agents. Valproate is an anti-seizure agent that is effective for many patients with mania, rapid-cycling, and mixed states, as well as for patients who are also substance abusers. Carbamazepine (Tegretol, Carbatrol) is usually the second anti-seizure medication of choice. Lamotrigine (Lamictal), a newer antiseizure drug, is proving to be an effective mood-stabilizer and, in fact, is more effective for depressive episodes than is lithium. It may be particularly helpful for patients with rapid cycling and bipolar II disorder, in whom depression remains problematic after taking other mood stabilizers. Other anti-seizure agents used or investigated for bipolar include, gabapentin (Neurontin), zonisamide (Zonegran) and topiramate (Topamax). To date, it is not clear if these newer agents are useful for the treatment of acute mania.
• Atypical Antipsychotics. Agents known as atypical antipsychotics also have mood stabilizing properties. Clozapine (Clozaril) was the first atypical antipsychotic. Newer agents include risperidone (Risperdal), olanzapine (Zyprexa), quetiapine (Seroquel), ziprasidone (Zeldox), and others.

Such agents may be used in combination with each other. Additional drugs, such as conventional antipsychotics, antidepressants, antianxiety drugs, or experimental agents are used as necessary.

Electroconvulsive Therapy. Electroconvulsive therapy is a very effective treatment that may be administered in certain patients for acute episodes or for maintenance.

Non-Medical Treatments. In addition to medical treatments, psychologic therapies and sleep management are also extremely critical components of bipolar disorder treatment to reduce symptoms and to help the patient manage and even prevent relapse.

The Systematic Treatment Enhancement Program for Bipolar Disorder (STEP-BD), an ongoing trial supported by the National Institute of Mental Health, will be the largest treatment study ever conducted for bipolar disorder. With plans to enroll approximately 5,000 patients, STEP-BD aims to evaluate all the best-practice treatment options used for bipolar disorder, including mood-stabilizing medications, antidepressants, atypical antipsychotics, monoamine oxidase inhibitors. It will also evaluate psychosocial interventions, including cognitive behavioral therapy, family-focused therapy, interpersonal and social rhythm therapy, and psychoeducation. Results of STEP-BD may clarify the best treatments for bipolar disorder.

Treatment Guidelines for Acute Manic Episodes

Step 1. Determine the Need for Hospitalization and Eliminate Triggers. The first step in treating an acute manic episode is to rule out any life-threatening conditions and eliminate any triggers, such as antidepressants or other mood elevators.

Patients often require hospitalization at the onset of acute mania. The need for hospitalization depends on a number of factors, including the following:

• Whether the patient is at risk for suicide or for harming others.
• The availability of social and emotional support at home.

Step 2. Control Symptoms of Acute Manic with a Mood Stabilizer. Physicians must often try different agents to control a manic episode, usually adding them one at a time to the regimen if the current drugs are not effective. It may take several weeks for a mood stabilizer to be effective and other agents may be needed.

The following is an example of a stepped approach recommended by some experts:

• Initiating a mood-stabilizing drug is the critical first step. Either valproate or lithium is the standard first agent for most manic episodes. Lithium is effective in 60% to 80% of all hypomanic and manic episodes. Valproate is not usually preferred, however, for patients with multiple manic episodes, mixed episodes, and rapid cycling. Carbamazepine, another anti-seizure, agent is a good alternative. Combinations of these mood stabilizers may be used if the patient does not respond to a single agent.
• If the patient does not respond fully within a week, atypical antipsychotics may be added to one or more mood stabilizers. Atypicals include olanzapine (Zyprexa), risperidone (Risperdal) and quetiapine (Seroquel). Olanzapine, in fact, has been approved as sole therapy for manic episodes. It has not been studied for very long, however and may have more side effects (importantly weight gain) than does valproate. Clozapine (Clozaril), the oldest atypical agent, is also effective but it is not generally used because of its potential for severe side effects and the need for weekly monitoring of white blood cell counts.
• Finally, the physician may consider adding newer anti-seizure agents, such as lamotrigine, topiramate, or gabapentin.

Step 3. Addition of Other Treatments. Other treatments may be added to speed recovery, treat any psychosis, and achieve remission. They include any of the following:

• Standard antipsychotic drugs (also called neuroleptics), such as haloperidol (Haldol). These agents may be used for acute mania. They can cause severe side effects, however, particularly those known as extrapyramidal effects, which disrupt motor control. They are not generally used on a long-term basis for those with bipolar disorder.
• Benzodiazepines, such as clonazepam (Klonopin) or lorazepam (Ativan), are anti-anxiety agents that may be particularly beneficial agents to add if the patient is experiencing severe mania.
• Electroconvulsive therapy. This treatment helps patients who do not respond to medication and may even be life-saving in elderly patients with severe late-onset mania.

Step 4. Terminate Some Drug Treatments. Drugs may be stopped under the following circumstances:

• When side effects are intolerable.
• When the patient does not respond to the maximum dose.
• When the patient improves and recovery is sustained. In such cases, the neuroleptic or benzodiazepine is slowly withdrawn and only the mood-stabilizing drug is continued.

Step 5. Continuation of Mood Stabilizers. Mood stabilizers are typically continued for about eight weeks, unless the patient shows signs of shifting to another mood state. If the patient remains stable at that time, the physician may decide to continue maintenance treatment or to gradually withdraw medications.

Treatment Guidelines for Depressive Episodes

Depressive episodes pose a particular challenge. They are a significant cause of suffering and yet the use of standard antidepressants poses a significant risk for triggering mania. Their effectiveness is also questionable. In fact, depressive episodes are so difficult to treat that some experts advise patients who do not respond to mood stabilizers to simply expect to endure the depressive episode for about two to three months.

First Choice: Mood Stabilizers. Mood stabilizers are first-line treatment for depressive episodes. (About half of all patients with bipolar disorder and depressive episodes will respond to this treatment.) Lithium and valproate are the standard mood stabilizers. One study suggested that increasing the dosage of valproate may help avoid the need for antidepressants. Of note, evidence suggests that lamotrigine, one of the anti-seizure agents, may be an especially beneficial as a mood stabilizer for depressive episodes.

Subsequent Choices: Antidepressants. If improvement does not occur within two to four weeks, then an antidepressant may be added.

The first choices are bupropion (Wellbutrin) or one of the selective serotonin reuptake inhibitors (SSRIs), such as paroxetine (Paxil) or sertraline (Zoloft). These agents are similar in effectiveness and also for risks for switch-back to a manic state (12% to 28%). Patients might try other antidepressants if mood does not improve. Such antidepressants are typically either a monoamine oxidase inhibitor (MAOI), such as tranylcypromine (Parnate), or a newer antidepressant called venlafaxine (Effexor).

It should be noted that a number of studies have found no additional benefits from antidepressants. A 2002 study found no difference in the duration of depression among patients regardless of whether or not they were taking the medications. One 2002 study suggested, however, that patients taking antidepressants for depressive episodes that followed an episode-free state might expect good results. In such cases response rates were 63%. On the other hand, only 28% of patients whose depression had followed a manic or hypomanic episode responded to antidepressants. In addition, their chances of switching back into a manic state were greater, whether or not they were taking an antidepressant or a mood stabilizer.

Any patient on antidepressants who develops symptoms of hypomania should stop taking them, since this is often a sign of impending mania. All antidepressants should be tapered after the mood has been stabilized for a month. Of some concern was a study reporting a paradoxical response in which manic symptoms developed in some patients when they discontinued antidepressant therapy, even though they were also receiving mood stabilizers.

Cognitive-Behavioral Therapy. Cognitive-behavioral therapy (CBT) programs may help patients endure depressive episodes by developing ways to manage negative thoughts and behaviors.

Other Treatments. Electroconvulsive therapy (ECT) is another option for depression that does not respond to less intense approaches. Other drugs sometimes used for depressive episodes include antipsychotic medication for severely depressed and delusional patients. Small studies indicate that a subgroup of patients may respond to thyrotropin-releasing hormone, a substance that regulates thyroid hormones.

Treatment Guidelines for Mixed Episodes and Rapid Cycling

At one time, patients with rapid cycling were treated with a single drug, but now treatment typically involves the use of three or four drugs. There are different approaches:

• Mixed states and rapid cycling tend to be more resistant to lithium, and so valproate in combination with other agents is usually a reasonable choice. One approach, for example, uses valproate first, followed by carbamazepine, and then a combination of carbamazepine and lithium.
• The anti-seizure drug lamotrigine is proving to be especially effective for rapid cyclers, particularly those who have severe depression. Other newer generation anti-seizure agents may also be useful for rapid cyclers.
• Atypical drugs, such as clozapine, may help some patients.
• One biological mechanism involved with rapid cycling is an excessive influx of calcium into brain cells. Cardiovascular drugs called calcium channel blockers, such as nimodipine, may be beneficial for ultra-rapid cycling.
• In some cases, levothyroxine, a synthetic derivative of the thyroid hormone T4 (thyroxine), has helped stabilize rapid-cycling patients. Because of possible problems with long-term use of thyroid hormone, however, other agents should be tried first.
• Electroconvulsive therapy can be useful in emergency situations.

In addition, other measures should be taken:

• Patients should avoid anti-anxiety drugs, alcohol, caffeine, and stimulants.
• Patients should avoid exposure to bright light.
• All efforts should be made to help the patient sleep normally.

Treatment Guidelines for Maintenance

Drugs Used During Maintenance. Relapse occurs in most patients after treatment of acute attacks, and patients who are at high risk for recurring episodes should consider life-long maintenance therapy, generally using mood-stabilizing agents.

• Lithium is a first-line mood stabilizer used in maintenance therapy. The anti-epileptic agent valproate is also a first-ling agent. In general, the two are equal in effectiveness, although valproate may be better for patients who have had multiple manic episodes. There are some differences in side effects but the drop-out rates between the drugs are similar.
• Carbamazepine, another anti-epileptic agent, is a third alternative.
• The atypical antipsychotic drugs clozapine (Clozaril), olanzapine (Zyprexa), and risperidone (Risperdal) are also proving useful for maintenance, particularly in combination with mood stabilizers.

The general recommendations for maintenance therapy with lithium are as follows:

• The earlier lithium is started in the disease process, the more effective it is. Studies are showing that patients on long-term lithium therapy have survival rates comparable to the general population, but those who permanently drop out of therapy have significantly lower survival rates. In one study, patients who stopped taking it increased their risk of suicide in the first year by 20-fold.
• Lithium is still effective for patients who discontinue and then restart treatment later on. In such cases, however, there may be a greater need for drug combinations. In addition, patients who stop and start again may be at higher risk for hospitalization than those who use the drug continuously.
• For those who want to stop, a gradual discontinuation (over 15 to 30 days) may help to delay recurrence. Stopping it quickly poses a high risk for relapse and even for suicide.

Electroconvulsive Therapy. Some studies are finding that maintenance electroconvulsive therapy (ECT) may be helpful for those who do not respond to medications. In one study of patients with bipolar disorder, those who had intractable recurrent episodes were maintained on monthly ECT treatments for more than a year and a half. Without ECT, those patients spent an average of almost half a year in the hospital, suffering at least three episodes annually. After ECT, all the rapid cyclers achieved full or partial remission.

Treatment Guidelines for Children and Adolescents

There are few studies on the optimal treatment of bipolar disorder in children and adolescents. The drugs used for bipolar disorder have considerable side effects, which may be severe in younger people. Parents should consider the potential risks and benefits of treatment for their children.

The drugs that have been most studied for this population are lithium and valproate. Some evidence suggests that larger rather than smaller doses of valproate or lithium may be more effective in children and adolescents with bipolar disorder. However, side effects of these drugs in children may be especially problematic, including severely impaired thinking, acne, and increased urination (caused by lithium) and menstrual irregularities and polycystic ovary syndrome (from valproate).

Atypical antipsychotics, especially olanzapine (Zyprexa) or risperidone (Risperdal), are being investigated in combination with mood stabilizers. They may be helpful for young people with severe aggression. These drugs can cause severe side effects, including significant weight gain.

Electroconvulsive therapy (ECT) may be effective and safe in children and adolescents. The side effects (e.g., amnesia, fractures, and panic) associated with older ECT techniques have been greatly reduced. Given the significant side effects of bipolar drugs, parents should discuss this technique with their physicians.