Medications Used in the Management of Bipolar Spectrum Disorders

By Kevin M. Furmaga, Pharm.D., BCPP

INTRODUCTION

The first recognized medication treatment for bipolar symptoms emerged in 1949 with the discovery that lithium carbonate could be used safely to control mania. Since 1972, this simple mineral has been the gold standard to which all other antimanic agents are compared. Psychiatry has witnessed a recent expansion in the number of medications available to manage the complex and varied symptoms that can occur during an episode of bipolar mania or bipolar depression. However, no single drug effectively controls all symptoms or stabilizes all phases of this chronic illness. Successful treatment of bipolar disorder usually requires that two or more medications be prescribed at the same time. Close symptom monitoring with frequent adjustment in the type and dose of medications may be necessary to achieve long-term mood stability. This article will help familiarize you with the medications available to manage bipolar symptoms and review steps persons with this illness can take to meet the therapeutic challenge.

MEDICATIONS

The goal of drug therapy is to eliminate target symptoms and to prevent future symptom episodes from occurring. The challenge of preventing recurrent mania and depression episodes usually requires lifelong treatment using medication combinations. Psychiatric medications are classified according to the broad group of mood, thought, or behavioral symptoms they treat. For example, antidepressants are prescribed to treat depression, antipsychotics treat psychosis, and anxiolytics are used to rapidly reduce symptoms of anxiety. Antimanic agents or mood stabilizers target mania and serve as the foundation for the medication management of bipolar disorders. In addition to treating mania, effective drug therapy for bipolar disorders must also target and prevent depression, anxiety, and not infrequently, psychotic symptoms. For this reason, a strategy involving combinations of medications from different classes of psychiatric drugs is employed.

THE FOUNDATION OF DRUG THERAPY FOR BIPOLAR SPECTRUM DISORDERS

ANTIMANIC AGENTS (MOOD STABILIZERS)

Antimanic medications are essential for the treatment of bipolar disorder. Not only do they treat manic symptoms, they can reduce the risk of recurrent manic episodes, enhance antidepressant effects, and increase the safety of antidepressant treatment by preventing antidepressant-induced mania. FDA-approved and off-label medications for the treatment of mania can be divided into three groups: 1) Lithium Salts, 2) Anticonvulsants, and 3) New-Generation Antipsychotics.

Lithium Salts

Lithium carbonate and lithium citrate are salts of lithium that come in a variety of immediate-release and extended-release oral products. These first-line medications are prescribed for the treatment of active mania symptoms and useful either alone or in combination with an antidepressant for treating both bipolar and unipolar depression. Lithium salts are also effective for preventing episodes of both mania and depression. Therapeutic drug monitoring is standard when lithium salts are prescribed. This involves routine monitoring of lithium blood levels and blood tests to check kidney function, thyroid function, and blood electrolyte balance.

Mood-stabilizing anticonvulsants

Some medications originally used to treat epilepsy are also used in the management of bipolar disorder.

This applies to valproic acid and carbamazepine, medications that not only treat seizures, but are FDA-approved for treating mania and mixed episodes of mania and depression. The most commonly prescribed formulation of valproic acid is the prodrug, divalproex sodium. Marketed under the brand names Depakote® and Depakote ER®, divalproex is converted to valproic acid. There are a number of brand name formulations of carbamazepine (see table on page 12), with Equetro® being approved for treating mania and mixed episodes of mania and depression. Regardless of the formulation used, the different brands of valproic acid or carbamazepine are equally effective as long as therapeutic blood levels are reached. Monitoring of blood levels, blood tests for liver function, and blood cell counts are routinely used to optimize the safe use and effectiveness of valproic acid and carbamazepine.

Lamotragine (Lamictal®) is FDAapproved for use in patients with bipolar disorder to prevent recurrent episodes of depression. Unlike some antidepressants, lamotragine does not trigger episodes of mania. Its usefulness in treating active symptoms of depression is limited by the safety requirement that the dosage be increased slowly (6 – 8 weeks to reach a therapeutic dose). Rapid increases in dosage can lead to a serious allergic reaction called Stevens-Johnson Syndrome.

Oxcarbazapine (Trileptal®) and topiramate (Topamax®) are anticonvulsants used in bipolar disorder but at this time are not FDA-approved for this indication. Oxcarbazapine is similar to carbamazepine and a few clinical studies support its effectiveness in treating manic symptoms. It does not require therapeutic monitoring like carbamazepine and is overall better tolerated. Current evidence supporting the use of topiramate in bipolar disorder is very limited. It can sometimes prevent weight gain associated with other bipolar medications, which is another reason topiramate is prescribed as part of mood stabilizing regimens. Both Trileptal and Topamax are considered second line bipolar medications and should not be used unless first line medications fail or are not tolerated due to side effects.

New Generation Antipsychotics (NGAs)

Before they received FDA approval for treating manic symptoms, newer antipsychotics were used to treat psychotic illnesses like schizophrenia. Since the drugs in this antipsychotic subgroup also treat manic symptoms, they are sometimes referred to as broad spectrum psychotropics. Psychosis is not uncommon during episodes of bipolar mania or bipolar depression so these agents are particularly helpful for mania when psychotic symptoms are also present. New generation antipsychotics are often combined with mood-stabilizing anticonvulsants or lithium salts to better manage mania or combined with antidepressants to treat depression (and reduce the risk of antidepressant-induced mania). While they have a lower risk of causing the movement side effects (e.g., tremor, rigidity, slowed movements) commonly associated with older antipsychotics, safety concerns with NGAs center on their potential metabolic effects. An increased risk for weight gain, elevation in blood cholesterol and triglycerides, and diabetes requires monitoring in patients treated with this class of antimanic medication.

ANTIDEPRESSANTS

Antidepressants are used to treat bipolar depression, but patients with bipolar disorder should watch for early signs of mania after treatment with an antidepressant is started. Certain antidepressants appear to be more likely to trigger manic episodes than others. Older tricyclic antidepressants (e.g., Elavil®, Pamelor®), the dualacting antidepressants Effexor XR® and Cymbalta®, and Remeron® appear to increase the risk of mania in patients with a bipolar illness. Selective Serotonin Reuptake Inhibitor (SSRI) antidepressants, bupropion products (Wellbutrin®, Wellbutrin SR®, and Wellbutrin XR®) and nefazadone (formerly marketed under the brand name, Serzone) appear to have a lower risk for causing antidepressant-induced mania. To reduce the risk of mania with antidepressant treatment, an antimanic agent is also prescribed. Moodstabilizing lithium salts, anticonvulsants, or antipsychotics are all used for this purpose. The brand name medication, Symbyax®, is a combination of the mood stabilizing antipsychotic, olanzapine (Zyprexa®), and the antidepressant, fluoxetine (Prozac®).

ANXIOLYTICS (ANTI-ANXIETY MEDICATIONS)

Medications from the benzodiazepine class are often prescribed for bipolar treatment to target anxiety, agitation and restlessness, as well as insomnia. They are prescribed on either an “as needed” basis or a regular schedule to help manage symptoms over days or weeks. While medications like Ativan®, Klonopin®, Xanax®, and Valium® work within 30 minutes for selected symptoms, tolerance can develop to their therapeutic effects and they can be habit-forming. Given the high incidence of alcohol and other substance abuse in people with bipolar disorder, this is not a class of medication that can be prescribed safely in everyone with a bipolar diagnosis.

MEETING THE THERAPEUTIC CHALLENGE OF BIPOLAR DISORDER

Available medications can effectively treat individual episodes of depression or mania but the real challenge is prevention of future mood episodes. People with a bipolar illness can achieve long-term mood stability only by working closely with their doctor to address factors that may destabilize their mood such as: 1) Non-adherence with prescribed medications, 2) Not recognizing or not reporting early signs of an evolving mood episode, and 3) Life stressors that are likely to trigger an episode of mania or depression.

Non-Adherence with Prescribed Medications

Having to take several medications everyday for a lifetime can be difficult. The need for longterm medication treatment underscores one of the important limitations of drug therapy: medications manage symptoms but rarely do they cure illness. Whether it’s high blood pressure, diabetes, or bipolar disorder, chronic illnesses are usually going to require lifelong treatment to control and prevent worsening of symptoms.

Adherence to long-term medication regimens is challenging for many with a bipolar illness for other reasons as well. Effective medications target the symptoms of euphoria and elevated energy that characterize mania and that many patients find desirable. This idealized mood state is short-lived with depression symptoms likely to follow. Untreated mood symptoms, even if they don’t appear to lead to problem behaviors, increase the risk of long-term mood instability and a more difficult-to-treat illness. Medication doses cannot be adjusted to allow bipolar patients to continue “a little manic” as some would like. The mood is destined to destabilize.

Another common reason cited for not continuing medications is side effects. Treatment with several medications at the same time increases the likelihood of undesirable side effects. Virtually any medication side effect can be managed but it requires the person alert his or her doctor and discuss options available. In many cases tolerance develops to medication side effects after a few days or weeks, making any major change in therapy unnecessary. Often changes in the dosage or time of day the medication is taken can relieve certain side effects. Some medication side effects are treated with the addition of another medication. With more serious side effects, the suspected medications may be discontinued and replaced with a better tolerated option. People should discuss any medication problem with their doctor; there is usually a way to address most issues. This is particularly true if a medication is helping with bipolar symptoms. Stopping a medication without the knowledge of the prescribing physician can lead to worsening of bipolar symptoms, which may be more difficult to treat.

Recognizing and Reporting Symptoms

People who experience severe manic symptoms have a disturbed sense of reality, lose control of their behavior, and are unable to recognize when they are ill. Most will have some early indicators that an episode of mania or depression is coming. Adjusting the dosage of existing medications or the addition of a new medication will often prevent worsening of symptoms and reduce existing ones. It is much more difficult to treat an episode of mania or depression once the symptoms have fully evolved than to catch mood symptoms at an early stage. For this reason, people with bipolar disorder should be aware of the early signs of their mania and depression, and contact their doctor when they occur. Common early signs include new onset sleeping difficulties, increase in irritability, or worsening anxiety.

Stress Triggers

Medications that control bipolar symptoms do so by improving the function of brain chemicals that regulate mood, thinking, and behavior. However, emotional stress can dysregulate brain chemistry and can trigger mania or depression episodes in people with bipolar disorder. For this reason, long-term stability not only involves adherence with prescribed medications but also is aided by lifestyle changes and counseling (psychotherapy) that help reduce and manage emotional stressors. For most people with bipolar disorder, the combination of medications and stress reduction offers the best approach toward long-term mood stability. Even people with bipolar disorder who faithfully take their medications are at increased risk for mood instability if they do not effectively address stresses in their life.

Life Charting is becoming an important tool to help patients and their doctors monitor mood symptoms, identify medication factors that are therapeutic, and stress factors that may trigger depression or mania. Copies of the Life Chart Manual along with detailed instructions on how to use it are available through National Institute of Mental Health (NIMH) at www.bipolarnews.org. This tool enables people with bipolar disorder to track their daily mood symptoms and follow the effects of medications and life stressors on their symptoms. Over time, the Life Chart is used by patients and their doctors to make adjustments in medications or identify lifestyle changes that will improve mood symptom management and the likelihood of long-term mood stability.

People with bipolar disorder should expect their medications to treat and prevent mood symptoms. Currently available medications can effectively manage bipolar symptoms, making full and productive lives possible. Longterm mood stability is likely when people with bipolar disorder are knowledgeable about the medications they are prescribed, report manic and depression symptoms to their doctor early, and recognize periodic adjustment in dose and change in medication may be necessary.