Feeling Good: The New Mood Therapy (80 page)

You can see in Table 20–12 that valproic acid can also cause tremor. As with lithium, this effect can sometimes be helped by reducing the dose or by adding one of the beta-blocking drugs (see the discussion of lithium tremor above). Other uncommon side effects include a loss of coordination and weight gain.

Valproic acid can cause a rash in 5 percent of patients, much like the two other mood stabilizers listed in Table 20–12. Some patients have also reported hair loss, and if this develops you should discontinue the drug (after discussing this with your doctor, or course) because it can take several months for the hair to grow back. The hair loss is thought to be due to the fact that valproic acid can interfere with the metabolism of zinc and selenium. Vitamin supplements containing these two metals can be taken to try to prevent this. Dr. Alan Schatzberg and his colleagues recommend the vitamin supplement Centrum Silver for this purpose.
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As many as 20 percent of women have reported menstrual irregularities while on valproic acid. This may be due to the fact that valproic acid can cause blood levels of the relevant hormones to fall, resulting in impaired ovulation. Paradoxically, valproic acid can also cause certain oral contraceptives to fail, so in theory you could become pregnant. Make sure you discuss this possibility with your doctor if you are taking oral contraceptives.

Valproic acid, like a number of other anticonvulsants, may lead to birth defects and should usually not be taken during pregnancy. The deformities include a cleft lip, clotting
abnormalities, spina bifida, and others. During the latter phases of pregnancy (the third trimester) valproic acid can cause liver toxicity for the developing baby, especially when blood levels are greater than 60 mcg per ml. Make sure you inform your doctor if you think there is any chance you could become pregnant while taking this drug.

Special precautions are indicated for women under twenty who receive long-term treatment with valproic acid. Some studies have suggested that they may be more likely to develop polycystic ovaries and increased levels of male sex hormones, but the actual incidence of this complication is not known.
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Drug Interactions for Valproic Acid
. Valproic acid does not seem to have as many drug interactions as lithium or carbamazepine. Because valproic acid can cause sleepiness, it can enhance the effects of other sedative drugs such as alcohol, major and minor tranquilizers, barbiturates, or sleeping pills. These combinations could be hazardous, especially when driving or operating dangerous machinery. In addition, valproic acid can cause substantial increases in blood levels of barbiturates, causing extreme sedation or intoxication. Valproic acid may also cause levels of diazepam (Valium) to rise. The resulting depression of the central nervous system can be serious, and so great caution must be exercised if these drugs are combined with valproic acid.

As noted above, valproic acid can interfere with bleeding and clotting, and so caution needs to be exercised if it is combined with other drugs that interfere with bleeding or clotting, such as warfarin (Coumadin) or aspirin. In addition, valproic acid can lead to increased blood levels of warfarin. This can also enhance the tendency to bleed.

Some caution should be exercised when valproic acid is combined with a tricyclic antidepressant (especially nortriptyline and amitriptyline) because the blood levels of the antidepressant may increase. Your doctor may want to order
a blood test to check the level of the antidepressant so the dose can be adjusted if necessary.

Several types of drugs can cause levels of valproic acid to increase. These include:

If you are taking any of these drugs with valproic acid, your doctor may need to reduce your dose of valproic acid.

Some anticonvulsants, such as carbamazepine (Tegretol), ethosuximide (Zarontin), phenytoin (Dilantin) and possibly phenobarbital (Donnatal) can cause blood levels of valproic acid to fall, and so doses of valproic acid may need to be increased. At the same time, valproic acid can cause the levels of carbamazepine, phenytoin, phenobarbital, and primidone (Mysoline) to increase, and so the doses of these drugs may need to be reduced when they are combined with valproic acid. Patients with difficult cases of bipolar illness may be treated with more than one mood stabilizer, and some careful attention to these complex drug interactions will be needed.

Finally, the antibiotic rifampin (Rifadin) can cause blood levels of valproic acid to fall. This antibiotic is used in the treatment of tuberculosis, and it is also used as a two-to-four-day
preventative treatment for individuals who have been exposed to patients with certain types of meningitis.

Carbamazepine (Tegretol) was introduced in the 1960s as a treatment for a certain type of epilepsy that originates in the temporal lobes of the brain. In the 1970s, Japanese investigators discovered that carbamazepine was helpful in treating manic-depressive patients who did not respond to lithium. Although the FDA has not yet officially approved carbamazepine for the treatment of mania and depression, it appears to be helpful for 50 percent of bipolar (manic-depressive) patients who have failed to respond to lithium. Carbamazepine can be combined with lithium or with one of the major tranquilizers (also known as neuroleptics) in order to enhance the effects of these drugs in the treatment of mania.

Carbamazepine can also be helpful for some rapidly cycling manic-depressives. These individuals have more than four manic episodes per year and can sometimes be challenging to treat. Some studies have also suggested that carbamazepine may be helpful for manic-depressive patients who experience anger and paranoia during their “high” phases. Finally, some psychiatrists report that carbamazepine may be helpful in the treatment of patients with borderline personality disorder when severe anxiety, depression and anger coexist with impulsive, self-destructive behavior such as wrist-slashing. However, in one study the therapists but not the patients reported that the carbamazepine was helpful. It is difficult to know how to interpret such findings.

Many of the studies of carbamazepine have been conducted on patients who were also taking other drugs at the same time, such as lithium or a neuroleptic. These drugs can also have effects on mania. Dr. Alan Schatzberg and his colleagues have pointed out that this makes it difficult to tease out the true effects of the carbamazepine.
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The
limited data and patent issues may explain why the drug is not yet approved as a primary treatment for mania—because the safety and effectiveness of the drug in the treatment of mania have not yet been convincingly demonstrated through large, well-controlled studies.

Doses for Carbamazepine
. The beginning dose of carbamazepine is 200 mg twice daily for two days. It may then be raised to 200 mg three times a day for five days. After this, the dose is gradually increased by 200 mg per day every five days up to a total daily maximum of 1,200 mg to 1,600 mg.

Carbamazepine usually takes at least one to two weeks to be effective, as do many psychiatric medications. If it is helpful, your doctor will probably suggest you stay on the drug for a longer period of time to prevent a relapse of the mania.

Blood Testing
. Carbamazepine blood testing is required, just as it is for the two mood stabilizers discussed above (lithium and valproic acid). You will need a blood test every week for the first two months. After that, you will need a blood test every one or two months. The results will guide your doctor in the amount she or he prescribes. The usual effective blood level for carbamazepine is in the range of 6 mg to 12 mcg per ml, but some experts recommend blood levels in the range of 6 mg to 8 mcg per ml for most patients with depression or mania. Like any drug, there are fewer side effects at lower doses, but if the blood level gets too low, the drug will lose its effectiveness.

Levels of other drugs in your blood may fall if you are taking carbamazepine. This is because carbamazepine stimulates certain liver enzymes, and so your liver clears these drugs out of your system faster than usual. One of the drugs that is affected by carbamazepine is carbamazepine! In other words, after you have been on the drug for several weeks, you may find that you need a larger dose to maintain the same blood level. This is because your liver begins to
metabolize the carbamazepine more rapidly, so it leaves your body faster.

Your doctor will probably want to check the blood levels of certain liver enzymes before you start the carbamazepine, and from time to time when you are on it. This is because carbamazepine may cause an elevation of liver enzymes in your blood, indicating possible liver inflammation or damage. Earlier you learned that valproic acid can have similar effects on the liver. Some elevation of liver enzymes occurs in most patients taking carbamazepine, but this is not usually a cause of concern. However, you will still want to watch out for any signs of hepatitis described in the previous section on valproic acid.

Your doctor will also order frequent complete blood counts while you are taking carbamazepine. This is because carbamazepine may cause a drop in your red blood cells, white blood cells, or platelets. These cells are all produced by your bone marrow, and carbamazepine can sometimes make the bone marrow less active. Each type of blood cell serves a different function. The white cells help to fight infections. If you did not have enough white cells, you would be more vulnerable to infections. As noted above, a normal white blood cell count is in the range of 6,000 to 10,000. If your white cell count falls below 3,000, your physician will immediately consult with a hematologist (blood specialist). Roughly 10 percent of patients taking carbamazepine experience a drop in the white blood cell count, and levels below 3,500 are common. You should be reassured to know that a drop in the white blood cell count rarely develops into a serious problem. If carbamazepine is helping you, most doctors will continue prescribing it as long as your white cell counts are above 1,000. However, white cell counts below this level can be extremely dangerous, so your physician will monitor your blood count more frequently if your white cell count starts to drop.

Levels of red blood cells and blood platelets may also fall if you are taking carbamazepine. The red blood cells carry oxygen, and the platelets cause bleeding to stop. If
your red blood cells fell to very low levels, you would experience anemia. You might appear pale and feel fatigued. If your platelets fell to low levels, you might experience an increased tendency to bleed. Dr. Alan Schatzberg and colleagues
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state that these changes in the blood count are expected. They emphasize that good patient education and routine bloodcounts are the best ways to monitor them.
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If you are taking carbamazepine, make sure you let your doctor know immediately if you develop any symptoms suggesting a change in your white cells, platelets, or red blood cells. These include fever, sore throat or sores in your mouth (indicating possible infection), bruising or bleeding (indicating a possible drop in the platelets in your blood), or fatigue along with pale lips and finger nails (suggesting anemia).

On extremely rare occasions, carbamazepine can cause a dangerous and potentially fatal failure of the bone marrow. In these cases, all your blood cells may drop to dangerously low levels. Recent estimates of severe and dangerous bone marrow failure range from approximately one patient in 10,000 to one in 125,000, so you can see that this complication is very rare.

When carbamazepine was first introduced, this possibility frightened many physicians, who were understandably reluctant to use the drug. Neurologists have been by far the largest group of doctors prescribing carbamazepine because it can be so valuable in the treatment of epilepsy as well as trigeminal neuralgia (facial nerve pain). Neurologists have now had vast experience with this drug and are quite comfortable with its use. More psychiatrists are also starting to recognize that this medication can be used safely.

Side Effects of Carbamazepine
. A number of common or significant side effects of carbamazepine are listed in Table 20–12 on pages 624–625. Tiredness is the most common side effect, especially at the start of treatment. A third of patients experience tiredness, and some (5 percent) also complain of weakness. Raising the dose more slowly can
minimize these effects. Usually the drowsiness will wear off over time. The drowsiness is usually not due to anemia, but just to the sedative properties of the drug.

Approximately 10 percent of patients report dizziness, especially when standing. This is due to a temporary drop in blood pressure because blood tends to pool in your legs when you rise. As a result, there is not enough blood for your heart to pump to your brain, and you get dizzy. This can usually be minimized by standing more slowly and exercising your legs (such as walking in place) immediately when you stand up. This “squeezes” blood from your legs to your heart so your heart can pump the blood to your brain.