Feeling Good: The New Mood Therapy

by Burns, David D.

  The drugs near the top of the table may cause lithium levels in the blood to increase. This can lead to more side effects, including lithium toxicity. The dose of lithium may need to be reduced to maintain blood levels in the proper range. These drugs that cause increased lithium levels include several drugs commonly used in the treatment of high blood pressure, such as the so-called ACE inhibitors, the calcium channel blocking agents, and methyldopa (Al-domet). The calcium channel blocking agents in particular may lead to greater lithium toxicity, with symptoms such as tremor, loss of coordination, nausea and vomiting, diarrhea, and ringing in the ears. Caution is required if you combine lithium with any of these drugs.

  Many common non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen (Advil, Motrin, and other trade names) can also cause lithium levels to increase. Several antibiotics raise lithium levels, as does the common antifungal agent metronidazole (Flagyl), which is often used to treat vaginal infections. Several anticonvulsants are also listed in the top portion of Table 20–13. If you are taking any of these medications, you might need lower doses of lithium.

  Table 20–13. Lithium Drug Interactionsa

  aSome information in this table was obtained from Psychotropic Drugs Fast Facts, pp. 213–215.17 This book is an excellent source of information on psychiatric medications.

  If you have high blood pressure, you may also be treated with a diuretic (or water pill). Some diuretics cause lithium levels to increase. The loop diuretics and potassium-saving diuretics in Table 20–13 do not increase lithium levels as much as the thiazide diuretics that are listed there. Not all diuretics cause lithium levels to rise. For example, you can see in Table 20–13 that osmotic diuretics, which work a little differently from the others, can have the opposite effect of causing lithium levels to fall.

  Your doctor may prescribe a low-salt diet if you have high blood pressure. However, a low-salt diet can cause lithium levels to rise. This is because your kidneys will excrete less salt in an attempt to preserve it. Since lithium is also a salt that is chemically very similar to table salt, your kidney will also excrete less lithium. By the same token, if you are sweating a great deal during the summer months, this can have the same effect of depleting your body of salt and causing your lithium levels to increase. Once again, your kidneys will try to preserve salt and lithium as well. Make sure you maintain an adequate intake of salt to compensate for the salt you will lose if you are sweating a great deal.

  The opposite effect can also occur. You can also see in Table 20–13 that if you eat too much salt, it can cause lithium levels to fall. This is because your kidneys will sense that there is too much salt in your blood and will try to get rid of it. Your kidneys will excrete more lithium along with the extra salt.

  In contrast, the drugs listed in the middle of Table 20–13 have the opposite effect of causing lithium levels in the blood to fall. As a result, lithium can lose its effectiveness. You can see that several drugs used in the treatment of asthma reduce serum lithium levels. Caffeine also has the same effect, so if you are a heavy coffee drinker, you may need to cut down on coffee or take higher doses of lithium. Corticosteroids, which are used in many conditions including poison ivy, can also cause lithium levels to fall. The dose of lithium may need to be increased to maintain blood levels in the proper range if you are taking any of these drugs.

  A number of other drug interactions are listed in Table 20–13. Psychiatrists used to think that the combination of lithium with certain antipsychotic medications (especially haloperidol) greatly increased the risk of a toxic effect called NMS (neuroleptic malignant syndrome). NMS consists of severe muscle rigidity and confusion along with elevated temperature, profuse sweating, increases in blood pressure, rapid heartbeat and breathing, trouble swallowing, abnormal kidney and liver function, and other symptoms. However, although any patient on antipsychotic drugs runs a small risk of developing NMS, recent clinical experience has indicated that the likelihood of NMS may be increased only slightly when antipsychotics are combined with lithium. Lithium is now often used in combination with antipsychotic drugs and may enhance their effects in the treatment of schizophrenia, as described above.

  As with most psychiatric drugs, pregnant women should avoid lithium, if possible, because its use has been associated with birth defects involving the heart. This is not an all-or-nothing issue, and the potential benefits must be weighed against the potential hazards. The risk of a heart defect known as Ebstein’s anomaly is twenty times greater than normal in mothers who take lithium, but the likelihood is still less than 1 percent. Other birth defects can also occur, especially when lithium is used during the first trimester of pregnancy. In addition, lithium (as well as some other psychiatric drugs) is secreted in human milk and should be avoided by nursing mothers. If lithium is needed, breastfeeding should be avoided.

  If you or your doctor have any questions about lithium (as well as the other mood stabilizers described below), the lithium information center at the Madison Institute of Medicine, Madison, Wisconsin, can often help.22

  Valproic Acid

  Valproic acid is usually used in the treatment of epilepsy but was recently granted FDA approval for the treatment of bipolar disorder, especially acute mania. You can see in Table 20–1 on page 522 that this drug is prescribed in one of two forms: valproic acid (Depakene) or the slightly more expensive divalproex sodium form (Depakote). The two forms are equally effective. Studies comparing valproic acid with lithium indicate that the two drugs are comparably effective and both appear to be twice as effective as a placebo. Valproic acid, like lithium, also appears to be effective in preventing or reducing future manic episodes. The drug may be especially effective in the treatment of the rapid-cycling form of bipolar disorder. It can help patients who experience mania and depression at the same time (so-called “mixed states”), as well as patients who experience the more common forms of bipolar disorder. It is probably less effective in the prevention and treatment of depression than in the prevention and treatment of mania.

  Doses for Valproic Acid. It is best to start valproic acid gradually, in order to minimize the side effects. The dose on the first day might be 250 mg administered with a meal. During the first week, the dosage can be gradually raised up to 250 mg given three times a day. As with any medication, the dose you receive may be slightly different depending on your size, gender, and clinical symptoms. For example, a man who weighs 160 pounds might be started on 500 mg twice a day.

  During the second and third weeks, the dose may be slowly increased further. Most patients end up with a total daily dose in the range of 1,200 to 1,500 mg, given in divided doses (for example, 400 mg three times per day). Individual doses can vary widely. Some patients respond to as little as 750 mg per day and others need as much as 3,000 mg per day. As with any drug, doses outside the normal range are occasionally needed.

  Some improvement should be observed within two weeks of attaining a therapeutic blood level. If you respond to valproic acid, your doctor may suggest that you remain on it for an extended period of time, just like lithium.

  Blood Testing. Your doctor will order blood tests to adjust your dose of valproic acid. Initially your doctor may order a blood test once a week until your dose and blood level are stabilized. After that you will need a blood test only every month or two.

  The blood should be drawn approximately twelve hours after your last dose, just like the lithium blood test. Most patients take valproic acid in divided doses twice a day. If so, the blood can be drawn in the morning, before you take your first daily dose. Most physicians think that a blood level of 50 to 100 micrograms per ml is therapeutic, but others are comfortable with blood levels up to 125 mcg per ml, especially if the patient is acutely manic. Of course, more side effects are observed at the higher blood levels.

  Prior to treatment, your doctor will probably order a blood test to check your liver enzymes, a bleeding test, and a complete blood count (which includes a platelet count). Thes
e additional blood tests are performed because in rare cases valproic acid can cause hepatitis (an inflammation of the liver) as well as bleeding problems. From time to time after you have been on valproic acid, your doctor will repeat these tests to make sure that no changes have occurred. Many physicians feel that it is probably necessary to check the blood count and liver enzymes only every six to twelve months, especially if the patient has been educated to report immediately any signs or symptoms that indicate a liver inflammation, as described below. You should also tell your doctor if you notice any excessive bleeding or easy bruising.

  Temporary increases in liver enzymes have been reported in as many as 15 percent to 20 percent of patients during the first three months of treatment. In most cases, these elevations are not considered serious. Nevertheless, if your liver enzymes do change, your doctor will probably reduce the dose of valproic acid and continue to monitor the liver enzymes. Your doctor will also want you to be educated about the symptoms of hepatitis so you can contact him or her immediately if they develop. Jaundice is the classic symptom. Jaundice is a condition in which your urine becomes dark and your skin and eyes become yellow in color. In addition, your bowel movements become pale. When the liver becomes inflamed, the pigment that normally causes your bowel movements to become brown gets backed up in your blood, staining your eyes, skin, and urine. Other symptoms of hepatitis include fatigue, nausea, a loss of appetite, tiredness, and weakness. Fortunately, hepatitis only rarely complicates treatment with valproic acid and can usually be treated successfully, especially if you notify your physician right away.

  Although the liver inflammation is nearly always mild, it is important to watch carefully for these symptoms because they could, in theory, progress to fatal liver failure. This complication has been observed in infants and is rarely seen in adults. It usually occurs in individuals taking other anticonvulsants at the same time. In fact, some experts assert that it has not been seen in adults who take only one anticonvulsant.17

  Side Effects of Valproic Acid. The side effects of valproic acid are listed in Table 20–12 on pages 624–625. On the average, valproic acid is usually better tolerated by patients than lithium because it has fewer side effects. Sleepiness is a common side effect. Taking more of your daily dose in the evening before you go to bed can often prevent the sleepiness from being problematic. Valproic acid can also cause stomach upset which can take the form of nausea, vomiting, cramping, or diarrhea. These effects on the gastrointestinal tract are less common and can often be helped by taking a drug like Pepcid twice a day. Drs. J. S. Maxmen and N. G. Ward indicate that the frequency of stomach upset is greater with valproic acid (15 percent to 20 percent) than with the enteric-coated divalproex sodium (10 percent) tablets, and so a switch to divalproex sodium may help if these symptoms are troublesome.17

  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.1

  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.17

  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:

  • antacids;

  • non-steroidal anti-inflammatory drugs such as aspirin, ibuprofen (Advil, Motrin), and others;

  • cimetidine (Tagamet);

  • erythromycin (Erythrocin);

  • felbamate (Felbatol), an anticonvulsant;

  • lithium. Valproic acid also causes lithium levels to rise, and so the toxic effects of both drugs can increase;

  • some antipsychotic drugs, especially phenothiazines such as chlorpromazine (Thorazine);

  • SSRI antidepressants such as fluoxetine (Prozac) and fluvoxamine (Luvox).

  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

  Carbamazepine (Tegretol) was introduced in the 1960s as a treatment for a certain t
ype 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.1 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.