Bipolar Disorder

Description

Alternative Names

Medications

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

• Lithium is effective in 60% to 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 has a beneficial effect on psychosocial functioning.
• One study indicated that lithium reduced the risk for suicide regardless of its effects on stabilizing mood.
• One small study suggested that lithium 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 bipolar patients have a faster biologic clock.)
• Despite previous concerns, lithium remains effective 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. Physicians may take different approaches to administering the drug:

• Some physicians 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 physician uses this information combined with a chart called a nomogram to calculate the doses most likely to be therapeutic on a regular basis.

In either case, lithium levels should be monitored regularly. Side effects and toxicity 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 three months during maintenance therapy.

Toxic Effects. Minor toxic reactions include the following:

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

More severe reactions, which occur at higher blood levels, are the following:

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

Very high blood levels of lithium can be fatal.

If toxicity 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 toxic response, long-term use of lithium is not without problems. Some patients may experience the following:

• An unpleasant taste in the mouth.
• Hair loss.
• Weight gain. In one study, 16% of patients gained weight. It is a frequent reason for noncompliance and for relapse.
• Skin eruptions that can resemble acne. (It can worsen psoriasis in patients who also have this condition.)
• Thyroid problems. Up to 20% of patients who take lithium develop symptomatic hypothyroidism, and another 20% to 30% develop hypothyroidism without symptoms.
• An increased risk for diabetes.
• A blunted sexual drive.
• Dulled emotions and mental acuity.
• Memory loss.
• Lack of motor coordination.
• An increased risk for diabetes associated with kidney impairment.
• Reduced sensitivity to light. In some cases, this may slightly affect color recognition. 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 the following:

• 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 the following:

• Antipsychotics.
• Anticonvulsants.
• Calcium-channel blockers.

It should be noted that the risks associated with these drugs are very low, but caution is needed.

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

• Seasonal change. For instance, one study of men with bipolar disorder suggested that 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 physician 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 half believed that lithium had improved their output.

It should be strongly noted that this important drug saves lives. And, physicians 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 Anti-Seizure Drugs

Anti-seizure drugs, also called anti-epileptics or anticonvulsants, affect the neurotransmitter gamma aminobutyric acid (GABA), which helps prevent nerve cells from over-firing. They have become alternative treatments for patients who need a mood-stabilizing agent, but who do not fare well with lithium. They may also be used in combination with lithium.

Standard Anti-Seizure Agents.

• Valproate (Depakote), also called valproic acid or divalproex, is now commonly a first option for many bipolar disorder patients. Valproate is more effective than lithium for patients with a history of many manic episodes. In fact, in one study, lithium had no significant effect for these patients. Valproate also helps migraine headaches, a common problem among bipolar patients.
• Carbamazepine (Epitol, Tegretol) is a standard alternative anti-seizure agent used for mood stabilizing.

Either one may be an alternative for patients (especially substance abusers) who do not tolerate or respond to lithium. Both valproate and carbamazepine are comparable to lithium in long-term effectiveness. Evidence is mixed on the whether they pose a higher risk for breakthrough depression, with one 2001 study suggesting that valproate, in higher doses, may actually have anti-depressant properties.

Newer Anti-Seizure Agents. Newer anti-seizure agents under investigation for bipolar include lamotrigine (Lamictal), levetiracetam (Keppra), topiramate (Topamax), and zonisamide (Zonegran). Lamotrigine is the most studied of these agents and is proving to be particularly effective for depressive episodes and rapid cycling. Topiramate is also proving to be a useful agent in combination with mood stabilizers. It may have a particular advantage over others, in that it does not cause weight gain. It is not clear if any of these agents have any effect on acute mania.

General Side Effects. The side effects given here are associated with valproate. Other anti-seizure agents have similar effects and some specific ones of their own. Most are usually minor, occurring early in therapy, and then subsiding. Those of valproate include the following:

• Gastrointestinal problems (nausea, vomiting, heartburn). (In some studies, such side effects occurred initially in half the patients taking valproate.)
• Headaches.
• Visual disturbances.
• Ringing in the ear.
• Hair loss.
• Weight gain (a significant problem with valproate). In one study 23% of valproate-treated patients gained weight. (Other anti-seizure agents, such as topiramate, may actually be helpful for reducing treatment-related weight gain.)
• Agitation.
• Odd movements.
• In women, menstrual irregularities and a higher risk for polycystic ovary syndrome (PCO). (These side effects also appear in women using other anti-epileptic drugs, but the risk for those taking valproate may be higher.)
• Significant for birth defects when taken by pregnant women. (Valproate is, however, the preferred drug for women taking oral contraceptives.)
• Cognitive impairment and symptoms of Parkinson's disease. (One study of patients taking valproate for epilepsy for longer than a year reported these side effects in some patients. They resolved when valproate therapy was discontinued.)

Very serious side effects are rare but include the following:

• Liver damage.
• Convulsions.
• Coma.
• Pancreatitis in adults and children.

Atypical Antipsychotics

Atypical antipsychotics are standard agents for schizophrenia. They are now proving to be beneficial in combination with mood stabilizers for treating mania. These drugs include clozapine (Clozaril) (the first atypical antipsychotic), olanzapine (Zyprexa), risperidone (Risperdal), quetiapine (Seroquel), zotepine (Zoleptil), and ziprasidone (Geodon). Other atypical agents under investigation include aripiprazole (Abilitat) and iloperidone (Zomaril).

• In January 2004, the U.S. Food & Drug Administration approved quetiapine for the treatment of bipolar mania.
• Several studies published in 2004 confirmed that risperidone is effective in treating acute mania, either alone or in combination with lithium or valproate.
• A 2004 study showed that combination therapy with olanzapine plus lithium or valproate, compared to lithium or valproate alone, significantly prolongs the time that patients are free from manic or depressive symptoms.

Clozapine is useful for rapid cycling, psychosis, and mania, although it has significant side effects and is not usually a first choice among these agents. Olanzapine and risperidone are better tolerated than clozapine and are effective for mania, both in acute and long-term use. Olanzapine was approved in 2000 for acute manic episodes. Others are also showing promise.

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. (In some cases, drugs may also cause restlessness and insomnia, however.)
• Constipation.
• Rapid heart beat.
• Difficulty urinating.
• Skin rash.
• Increased body temperature because of reduced sweating. (On the other hand, some may also cause profuse sweating.)
• Mental effects (confusion, short-term memory problems, disorientation, and impaired attention).

Atypicals also have some rare but serious adverse effects, including the following:

• Seizures. (5% risk per year with clozapine. Others pose less of a risk.)
• An increase in weight, a higher cholesterol level, and a greater risk for diabetes, with a subsequent risk for heart disease. Not all atypicals pose the same risks.
• A higher risk of heat stroke.
• Lack of motor coordination and involuntary movements (called extrapyramidal side effects).
• An increase in risk for cataracts and worsening of any existing glaucoma.
• An increase in prolactin levels. Prolactin is a hormone that can cause fluid secretions from breasts in women or impotence in men. Of concern, is a higher risk for breast cancer in women with increased prolactin levels.
• Heart problems, including arrhythmias (associated with a few reports of sudden death 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, a potentially life-threatening reduction in certain white blood cells. This complication occurs in about 1% of people taking clozapine, most often within three months of treatment and peaking in the third month. If it hasn't appeared within six months, it most likely will not develop. 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 can trigger mania in 12% to 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 ones may be beneficial in certain circumstances, in any case. 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.

Bupropion. The antidepressant bupropion (Wellbutrin) is a unique drug that 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 being 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 the following:

• Nausea and gastrointestinal problems. These effects usually wear off over time.
• Agitation, insomnia, mild tremor, and impulsivity occur in 10% to 20% of people who take SSRIs.
• Dry mouth is common and can increase the risk for cavities and mouth sores.
• Headache.
• Some weight loss during the first few weeks of treatment may occur, but over time patients on maintenance treatment typically return to their pretreatment weight.
• Sexual dysfunction.

Monoamine Oxidase Inhibitors (MAOIs). Drugs known as monoamine oxidase inhibitors (MAOIs), particularly tranylcypromine (Parnate) are recommended for depression that does not respond to the newer antidepressants or SSRIs. MAOIs interact with certain foods to cause severe hypertension. 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 hypertension or toxic reactions can occur. It is very important, therefore, that the patient discusses with the physician any other medications being taken.

Venlafaxine. Venlafaxine (Effexor), another unique antidepressant, may also be used in severe cases of depression that do not respond to other treatments.

Calcium-Channel Blockers

Calcium-channel blockers are agents commonly used for angina and high blood pressure. They also have nerve-protecting properties. Several studies have reported that at least one of these agents--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 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 be beneficial for ultra-rapid cycling. Nimodipine has been shown to reduce hypomania and it is particularly effective when added to carbamazepine.

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