Review of Anti-Seizure Drugs For Bipolar Disorder

The editors of the highly respected Medical Letter on Drugs and Therapeutics, for doctors and pharmacists, reviewed evidence from controlled clinical trials of anti-seizure drugs for psychiatric disorders in the December 11, 2000 issue. Controlled clinical trials are the “gold standard” for testing the effectiveness of drugs. Anti-seizure drugs are widely used in treating bipolar disorder (also known as “manic-depressive illness”), and we will focus here primarily on their use for this disorder.

Patients diagnosed with bipolar disorder have mood swings that alternate between periods of extreme highs (mania) to severe lows (depression). These swings are out of proportion to, or totally independent of, everyday events, and affect thoughts, feelings, physical health, behavior and normal functioning.

No single pattern of symptoms fits every sufferer, but there are four distinct types of mood episodes that can occur in the course of the illness:

1. Mania (manic episode) often begins with a pleasurable sense of heightened energy, creativity and social ease—feelings that without proper medical treatment can quickly escalate into a full-blown manic episode. At this point, people typically lack self-awareness, deny that anything is wrong, and angrily blame those who point out a problem.

2. Hypomania (hypomanic episode) is a milder form of mania with less severe symptoms and less overall impairment. For example, the individual may have an elevated mood, feel better than usual, and be more productive. During these episodes patients often feel good—so good, in fact, that they may stop taking their medication.

3. Depression (major depressive episode) takes away one’s capacity to experience pleasure and causes profound sadness and irritability, changes in sleep patterns, a decrease in appetite, inability to concentrate, low self-esteem, and thoughts of suicide. Severe episodes also may include hallucinations or delusions.

4. Mixed episode is perhaps the most disabling since an individual can experience both mania and depression simultaneously or at different times throughout the day.

The two most important types of drugs to control symptoms of bipolar disorder are antidepressants and mood stabilizers. When certain anti-seizure drugs are used to manage the symptoms of bipolar disorder, they are termed mood stabilizers.

Lithium (ESKALITH, LITHOBID, LITHONATE) is the standard primary treatment for bipolar disorder, but it can cause severe toxicity, requiring monitoring of blood levels, and is not effective in some patients. Mood stabilizers are the mainstay of long term preventive treatment for both mania and depression and are used to improve symptoms during acute manic, hypomanic and mixed episodes. The mood stabilizers reviewed in Medical Letter are divalproex (DEPAKOTE), carbamazepine (TEGRETOL), lamotrigine (LAMICTAL), gabapentin (NEURONTIN), and topiramate (TOPAMAX).

Divalproex (DEPAKOTE)

The enteric-coated form of divalproex is the only drug approved by the Food and Drug Administration (FDA) for treatment of bipolar disorder, specifically for manic episodes associated with this condition.

According to Medical Letter, the response to this drug was 48 percent, compared to 49 percent with lithium and 25 percent with a placebo (dummy drug) in a 21-day study of 179 patients hospitalized for acute mania. Smaller studies have confirmed that about half of patients with acute mania respond to divalproex, whether or not they had previously responded to lithium. One 12-month study involving 372 patients found no difference in the time before symptoms recurred whether divalproex, lithium or placebo was administered.

The professional product labeling (“package insert”) for divalproex carries the strongest warning the FDA can require, a “black box” warning, informing doctors and pharmacists about potentially fatal toxicity to the liver and pancreas associated with use of this drug. In the September 2000 issue of Worst Pills, Best Pills News we covered the strengthening of divalproex’s black box warning regarding potentially fatal toxicity to the pancreas.

Carbamazepine (TEGRETOL)

This drug is FDA-approved for specific types of seizure disorders and the severe bursts of facial pain seen with the condition known as trigeminal neuralgia.

Medical Letter found that carbamazepine may be useful in patients who do not respond to, or cannot tolerate, lithium or divalproex. Carbamazepine has been less effective than lithium for maintenance treatment of bipolar disorder, but a combination of carbamazepine and lithium may be more effective than either drug alone.

Carbamazepine’s package insert carries a black box warning concerning bone marrow toxicity that can lead to a loss in production of blood cells.

Lamotrigine (LAMICTAL)

Lamotrigine is approved by the FDA, along with other drugs, for the treatment of seizure disorders.

A clinical trial in 192 patients found lamotrigine more effective than a placebo for bipolar depression. Medical Letter termed lamotrigine about as effective as lithium for the treatment of acute mania and marginally more effective than a placebo when used alone in patients who cycle rapidly between mania and depression.

Like divalproex and carbamazepine, lamotrigine carries a black box warning in its package insert. This one concerns serious rashes than can require hospitalization and discontinuation of treatment that have been reported with the use of lamotrigine. These rashes have included the life-threatening Stevens-Johnson syndrome and toxic epidermal necrolysis. We reported on the requirement for lamotrigine’s black box warning in the May 1997 issue of Worst Pills, Best Pills News.

Dispensing errors have occurred when the anti-fungal drug terbinafine (LAMISIL) was erroneously dispensed by pharmacists instead of LAMICTAL (see the August 2000 issue of Worst Pills, Best Pills News).

Gabapentin (NEURONTIN)

Gabapentin is FDA-approved for seizure disorders along with other anti-seizure drugs. It was found to be less effective than lamotrigine and no more effective than placebo in a small controlled trial in patients with refractory mood disorders.

The most common adverse effects of gabapentin are dizziness, somnolence (drowsiness) and other symptoms and signs of central nervous system (CNS) depression. Patients are warned not to drive a car or operate complex machinery until they have gained sufficient experience with the drug to gauge whether or not it affects mental or motor performance adversely.

Topiramate (TOPAMAX)

This drug is FDA-approved for seizure disorders in conjunction with other anti-seizure medications.

Controlled clinical trials have not been conducted using topiramate in the treatment of bipolar disorder, though uncontrolled case reports do appear in the literature suggesting that topiramate may be useful in managing this illness.

Adverse effects most often associated with topiramate have been related to the CNS. In adults, the most significant adverse effects fall into two general categories: (1) psychomotor slowing, difficulty with concentration, and speech or language problems (in particular, difficulty finding words); and (2) somnolence or fatigue. Additional nonspecific CNS effects occasionally observed with topiramate therapy include dizziness or imbalance, confusion, memory problems, and exacerbation of mood disturbances such as irritability and depression.

Medical Letter observed that, except for divalproex in the treatment of acute mania (an FDA-approved use), the effectiveness of anti-seizure medications for the treatment of psychiatric illness, including bipolar disorder, has not been well established by controlled clinical trials. Still, the mood stabilizing effects of these drugs may be useful.

Most of the prescribing of anti-seizure drugs for bipolar disorder and other psychiatric illness is termed “off-label” as these uses have not been approved by the FDA. Only FDA-approved uses can appear on a drug’s package insert, which is why non-approved use is said to be off-label. A study published in a medical journal, even a well-known one, is no substitute for the FDA’s drug approval process. Medical journal editors must accept the veracity of data submitted for publication, but the FDA has the responsibility of ensuring that data used by agency scientists and outside advisory committees in approving new drugs or new uses for old ones are valid. To complicate matters now, intense competition in the pharmaceutical marketplace has blurred the once-sharp boundaries between medical journal articles and promotional hype by drug companies.

What You Can Do

If you are being treated for a psychiatric disorder, or a member of your family is, and the use of an anti-seizure drug is being considered as a mood stabilizer, you should discuss the risks and potential benefits of these drugs with your doctor if they are going to be prescribed for an off-label use.