Medications

Lithium (Carbolith, Duralith, Lithobid, Lithizine, Eskalith, Lithane) is one of the standard mood stabilizing drugs for bipolar disorder. Lithium is extremely helpful for most patients and it significantly reduces the rate of hospitalizations in bipolar disorder. Some studies report the following advantages of lithium:

• Lithium is effective in 60 - 80% of all hypomanic and manic episodes. (Valproate may be better in patients with multiple manic episodes, mixed episodes, and rapid cycling.)
• It helps to prevent relapses.
• It helps psychosocial functioning.
• It may help reduce the risk for suicide regardless of its effects on stabilizing mood.
• It may act directly on the nerve clusters affecting the circadian rhythm and slow down the cycle of this "biologic clock." (There is some evidence that patients with bipolar disorder have a faster biologic clock.)
• It works well for most patients even if they have discontinued taking it and wish to restart treatment.

Administration of Lithium. Lithium may take weeks to become totally effective, so patients should not expect an immediate response during an acute episode. Doctors may take different approaches to administering the drug:

• Some doctors initially administer lithium in two low doses and gradually increase the dosage over time until an effective (therapeutic) level is achieved.
• Another approach is to administer a higher dose initially and measure blood levels of the drug after 24 hours. The doctor uses this information combined with a chart called a nomogram to calculate the doses most likely to be therapeutic.

In either case, lithium levels should be monitored regularly. Side effects can occur at therapeutic levels or at those only slightly higher than desired. Blood tests that measure drug levels should be conducted frequently during acute attacks and about every 3 months during maintenance therapy.

Side Effects.

Minor side effects include:

• Trembling hands
• Nausea
• Increased urine output
• Blurred vision
• Some loss of coordination

More severe reactions, which occur at higher blood levels, include:

• Vomiting
• Convulsions
• Uncontrolled jerky movements in arms and legs
• Stupor
• Coma

Very high blood levels of lithium can be fatal.

If overdose occurs, drugs should be stopped immediately and one or more of the following steps taken, depending on the severity:

• Patients are given fluids and drugs to increase excretion of lithium salts.
• Gastric lavage, a procedure that rinses the stomach, may be used to treat very recent overdoses.
• Hemodialysis, a procedure that filters lithium out of the blood, may also be performed in severe cases.

Long-Term Side Effects. Even for patients who do not experience a severe response, long-term use of lithium is not without problems. In one study, 16% of patients gained weight. Weight gain is one of the main reasons why some patients want to stop taking the drug. Other side effects include:

• An unpleasant taste in the mouth
• Hair loss
• Skin eruptions that can resemble acne and make psoriasis worse
• Low thyroid function
• An increased risk for diabetes
• A blunted sexual drive
• Dulled emotions and lack of mental clarity
• Memory loss
• Lack of motor coordination
• Reduced sensitivity to light. I

In some cases, light sensitivity may slightly affect a person's ability to recognize colors. More seriously, it can cause problems with night driving. This effect occurs regardless of how long a person has been on the drug. Experts recommend that patients wear sunglasses outside and avoid extensive exposure to bright light.

Drug Interactions. Because lithium is eliminated from the body by the kidneys, any drugs or dietary factors that slow the kidneys' actions may increase lithium blood levels and should be used with great caution. Such drugs include:

• Nonsteroidal anti-inflammatory drugs (NSAIDs)
• Thiazide diuretics
• ACE inhibitors

There have been reports of interactions between lithium and certain drugs commonly used in combination, including:

• Antipsychotics
• Anticonvulsants
• Calcium-channel blockers

The risks associated with these drug interactions are very low, but caution is needed.

Other Factors that Affect Lithium Levels. In addition to drugs, other factors may affect lithium levels:

• Seasonal change --  lithium levels may be higher in summer
• Menstrual cycle -- lithium levels may drop during the premenstrual phase
• Weight loss
• Changes in salt intake
• Dehydration
• Diarrhea

Patients should be sure to contact their doctor if they have any suspicious symptoms or illnesses.

Noncompliance. Noncompliance is common. One study of lithium users found that patients took their medication only 34% of the time. Another reported that nearly a third of patients eventually went off the drug.

Side effects are certainly one reason for noncompliance. Some patients regret the loss of their manic episodes and the exhilaration and creativity that sometimes accompany them. In one small study of artists with bipolar disorder, however, only 25% felt their work had declined, while another 25% found no change in their creative output, and 50% believed that lithium had improved their output.

Despite side effects and other concerns, this important drug saves lives. Doctors are confident that lithium, which has been in use for more than 50 years, can be taken safely, even for life, by most patients.

Valproate and Other Antiseizure Drugs

Antiseizure drugs, also called anti-epileptics or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. These drugs may be an alternative for patients (especially substance abusers) who do not tolerate or respond to lithium. They also may be used in combination with lithium, atypical antipsychotics, or other drugs.

Standard Antiseizure Drugs.

• Valproate (Depakote), also called valproic acid or divalproex, is now a first option for many bipolar disorder patients. Valproate also helps migraine headaches, a common problem among patients.
• Lamotrigine (Lamictal) is approved for maintenance treatment of adults with bipolar I disorder. It also appears to be be better for treating bipolar depression than other mood stabilizers.
• Carbamazepine (Epitol, Tegretol) is a standard alternative antiseizure drug used for mood stabilizing. In 2004, the FDA approved an extended release form of carbamazepine (Equetro). Oxcarbazepine (Trileptal) is another drug that is similar to carbamezepine.

General Side Effects. The side effects given here are associated with valproate. Other antiseizure drugs have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy and then subsiding. Valproate side effects include:

• Gastrointestinal problems such as nausea, vomiting, and heartburn
• Headaches
• Visual disturbances
• Ringing in the ear
• Hair loss
• Weight gain (a significant problem with valproate)
• Agitation
• Odd movements
• Menstrual irregularities and a higher risk for polycystic ovary syndrome (PCOS)
• Birth defects when taken by pregnant women 
• Cognitive impairment and symptoms of Parkinson's disease

Very serious side effects are possible. Stevens-Johnson syndrome (SRS) is a rare, but severe and potentially life-threatening, rash that can develop as a side effect of carbamazepine, lamotrigine, oxcarbazepine and other anticonvulsants. Because this is a very serious condition, these drugs are discontinued at the first sign of rash. Other serious side effects, also rare, may include:

• Liver damage
• Convulsions
• Coma
• Pancreatitis

Atypical Antipsychotics

Atypical antipsychotics are standard drugs for schizophrenia. They are now proving to be beneficial for bipolar disorder when used alone or in combination with the mood stabilizers that treat mania. These drugs include clozapine (Clozaril) (the first atypical antipsychotic), olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), aripiprazole (Abilify) and ziprasidone (Geodon).

• Olanzapine was the first atypical antipsychotic approved for treatment of bipolar disorder. In 2000, the FDA approved it to treat bipolar mania and mixed states. In 2004, the drug became the first atypical antipsychotic approved for bipolar maintenance treatment.
• Symbyax, a drug that combines olanzapine and the antidepressant fluoxetine, was approved in 2003 for treatment of bipolar depression.
• Risperidone, ziprasidone, and ariprazole have been approved for treatment of bipolar mania and mixed states. Quetiapine is approved only for treatment of bipolar mania but is also being investigated for bipolar depression.
• Clozapine has not yet been approved for treatment of bipolar disorder, but has shown promise in investigative studies. However, this drug has more significant side effects than other atypical antipsychotics. It poses a risk of white blood cell reduction (agranulocytosis) and has the highest risk of weight gain of all atypicals.

Side Effects. Although atypical antipsychotics have fewer severe side effects than standard antipsychotics, many patients fail to comply with regimens containing them. Common side effects include the following:

• Nasal congestion or runny nose
• Drooling
• Dizziness
• Headache
• Drowsiness -- however, these drugs may also cause restlessness and insomnia
• Constipation
• Rapid heart beat
• Difficulty urinating
• Skin rash
• Increased body temperature
• Confusion, short-term memory problems, disorientation, and impaired attention
• Weight gain --risk is highest with clozapine and olanzapine

Atypicals also have some rare but serious side effects:

• Diabetes. All atypical antipsychotics can increase the risk of elevated blood sugar (hyperglycemia) and diabetes. The risk is highest for clozapine and olanzapine. All patients treated with atypical antipsychotics should receive a baseline blood sugar level reading and be monitored for any increases in blood sugar levels during drug treatment.
• Seizures. There is a 5% risk per year with clozapine. Others pose less of a risk.
• Heat stroke. People who take atypicals have a higher risk of heat stroke.
• Extrapyramidal effects, which are lack of motor coordination and involuntary movements.
• The risk for cataracts increases. Existing glaucoma may get worse.
• Prolactin levels may be increased. Prolactin is a hormone that can cause fluid secretions from breasts in women or impotence in men. Women with increased prolactin levels have a higher risk for breast cancer.
• Heart problems, including arrhythmias, have been reported with initial usage of the drug. The risk for abnormal heart rhythms appears to be highest with clozapine and olanzapine, moderate with risperidone, and low with quetiapine.
• Agranulocytosis is a potentially life-threatening reduction in certain white blood cells. This complication occurs in about 1% of people taking clozapine, most often after 3 three months of treatment, and peaks in the third month. This complication can be reversed if the drug is withdrawn at once. Older women are at higher risk.

Antidepressants

Antidepressants are sometimes used for depressive episodes in bipolar disorder, but their use is controversial. They trigger mania in 12 - 28% of patients. In addition, a number of studies report no additional benefits from antidepressants. A 2002 study suggested that they may be helpful for patients whose depression occurs after an episode-free period (rather than after a manic or hypomanic episode.) Specific antidepressants may be beneficial in certain circumstances. However, any patient on antidepressants who develops symptoms of hypomania should stop taking these drugs, since hypomania is often a sign of impending mania. All antidepressants should be tapered off after the mood has been stabilized for a month.

Bupropion. The antidepressant bupropion (Wellbutrin) appears to pose a lower risk for triggering mania than do other antidepressants. Side effects include restlessness, agitation, sleeplessness, headache, rashes, stomach problems, and in rare cases, hallucinations and bizarre thinking. Initial weight loss occurs in about 25% of patients. High doses may cause seizures. This side effect is uncommon and tends to occur in patients with eating disorders (anorexia or bulimia) or those with risk factors for seizures.

Selective Serotonin Reuptake Inhibitors. Serotonin reuptake inhibitors (SSRIs), such as fluoxetine (Prozac), citalopram (Celexa), sertraline (Zoloft), and paroxetine (Paxil), are sometimes used to treat bipolar depression, but their benefits have not yet been established. They may be useful in patients whose depression does not respond to lithium; they do not appear to be useful as an add-on treatment to lithium. Side effects include:

• Nausea and gastrointestinal problems, which usually wear off over time
• Agitation, insomnia, mild tremor, and impulsivity
• Dry mouth, which can increase the risk for cavities and mouth sores
• Headache
• Sexual dysfunction

Some weight loss may occur during the first few weeks of treatment, but over time patients on maintenance treatment typically return to their pretreatment weight.

Monoamine Oxidase Inhibitors (MAOIs). Older drugs known as monoamine oxidase inhibitors (MAOIs), particularly tranylcypromine (Parnate) are recommended for depression that does not respond to newer antidepressants. MAOIs can interact with certain foods and cause severe high blood pressure. Such foods have a high tyramine content and include aged cheeses, most red wines, vermouth, dried meats and fish, canned figs, fava beans, and concentrated yeast products. MAOIs can also have severe interactions with certain drugs, including some common over-the-counter cough medications. In such cases, severe high blood pressure or dangerous reactions can occur. It is important that patients discuss with their doctor any other medications they are taking.

Venlafaxine. Venlafaxine (Effexor) may also be used in patients with severe cases of depression who do not respond to other treatments.

Calcium-Channel Blockers

Calcium-channel blockers are drugs commonly used for treating angina and high blood pressure. They also have nerve-protecting properties. Several studies have reported that at least one of these drugs--verapamil (Calan, Isoptin, Verelan)--has anti-manic and possibly mood-stabilizing effects. In a 2002 study, all patients with mania or hypomania reported at least a 50% improvement in their symptoms. In addition, 78% of patients with mixed states reported that mania improved and 39% of patients with depression and no mania or hypomania improved. Other calcium channel blockers, such as nimodipine (Nimotop), may help treat ultra-rapid cycling. Nimodipine has been shown to reduce hypomania and may work particularly well when added to carbamazepine.

These drugs do not cause mental dysfunction, sedation, or weight gain as do other bipolar drugs. They may be safer during pregnancy and breastfeeding. Their side effects can include fluid build-up in the feet, constipation, fatigue, impotence, gingivitis, flushing, and allergic symptoms. Overdose can cause a severe drop in blood pressure. Note: Grapefruit and Seville (sour) oranges boost the effects of calcium-channel blocking drugs. (Regular oranges do not appear to pose any problems.)

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Review Date: 12/13/2005
Reviewed By: Harvey Simon, MD, Associate Professor of Medicine, Harvard Medical School; Physician, Massachusetts General Hospital