Feeling Good: The New Mood Therapy

by Burns, David D.

  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 colleagues1 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.1 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.

  You will see that carbamazepine can sometimes cause problems with coordination. This has been reported in as many as 25 percent of patients. Patients may appear a bit intoxicated and tend to stagger when walking. This sometimes indicates that the dose is too high. Other symptoms of an excess dose include double vision, slurred speech, mental confusion, muscle twitches, tremor, restlessness, and nausea, along with slowed or irregular breathing, a rapid heartbeat and changes in blood pressure. Immediate medical attention is required if these symptoms occur, because in extreme cases overdoses can lead to stupor, coma, and death.

  You may also experience some nausea and vomiting at first. These effects are usually temporary and can usually be managed by raising the dose more slowly and by taking the medication with food. These effects are probably less common than with valproic acid or lithium. Most patients who have been on carbamazepine for several weeks do not report these effects.

  Like the tricyclic antidepressants, carbamazepine can sometimes cause dry mouth or blurred vision. This is because carbamazepine blocks the cholinergic receptors (also called muscarinic receptors) in the brain. These anticholinergic effects are of special concern to patients with glaucoma, who have increased pressure in their eyes, because the carbamazepine may cause the glaucoma to worsen. If you have glaucoma you should have your intraocular pressures monitored closely while taking carbamazepine (or any drug with anticholinergic properties).

  A side effect that involves the kidneys is called the syndrome of inappropriate secretion of antidiuretic hormone (SIADH), or water intoxication. Patients develop a great increase in thirst along with mental confusion and a fall in the levels of sodium in the blood. This side effect has been reported in as many as 5 percent of patients taking carbamazepine. If you develop excessive thirst, your doctor may order an electrolyte test to see if your sodium has dropped. She or he may want to reduce the dose, change to a different medication, or treat you with a drug called demeclo-cycline (Declomycin). This
drug can often correct the problem of low sodium levels in your blood. Your doctor will probably monitor your kidney function from time to time by checking your levels of blood urea nitrogen (BUN) and creatinine.

  Carbamazepine can have some adverse effects on the heart. If you are over fifty years of age you should have an ECG before starting the drug. The ECG should be repeated after you have been stabilized on the drug to make sure no changes of a serious nature have occurred. Carbamazepine often causes a slowing of the heart. These changes appear to be more common in older women. If you have a history of heart disease you may do better to take another mood-stabilizing drug with fewer effects on the heart, such as valproic acid.

  As many as 5 percent to 10 percent of patients taking carbamazepine may develop a rash. You will see in Table 20–12 that any of the mood stabilizers (as well as many antidepressants) can cause a rash, but this is somewhat more common with carbamazepine. It can sometimes help to avoid direct sunlight (which may provoke the rash in some cases), to take an antihistamine, or to change to a different brand of carbamazepine. This is because you may be allergic to an ingredient in the pill other than the carbamazepine itself. On extremely rare occasions, two severe and potentially fatal skin rashes (called Lyell’s syndrome and the Stevens-Johnson syndrome) have been reported in patients taking carbamazepine. Make sure you report any severe skin changes to your doctor immediately.

  Like many other psychiatric drugs, carbamazepine can cause birth defects, especially spina bifida. A number of other fetal abnormalities have also been reported recently, especially when the drug is taken during the first trimester of pregnancy. Therefore, the potential benefit must clearly outweigh this risk if the drug is taken during pregnancy. The risk appears to be significantly higher when carbamazepine is combined with other anticonvulsants. If a pregnant woman definitely needs the drug, some experts recommend folic acid supplements that may reduce the likelihood of birth defects.

  Carbamazepine is secreted in mother’s milk. The concentration of carbamazepine in the milk is approximately 60 percent of the concentration in the mother’s blood, and so the issue of nursing must be discussed with the pediatrician.

  Drug Interactions for Carbamazepine. You can see in Table 20–14 on pages 648–650 that many drugs can influence the blood level of carbamazepine, and vice versa, so you and your physician will have to be very careful in this regard. At the top of the table, drugs are listed that cause carbamazepine level and toxicity to increase. If you are taking any of these drugs, your doctor may need to reduce the dose of carbamazepine. For example, many of the macrolide antibiotics (erythromycin is a common example) can double the blood level and toxicity of carbamazepine.

  You can also see in Table 20–14 that some drugs, such as diuretics (water pills) and other anticonvulsant medications can cause the level of carbamazepine to fall. Your physician may have to give you a larger dose of carbamazepine to compensate for this.

  Just as certain drugs can cause blood levels of carbamazepine to rise or fall, carbamazepine can change the levels of other drugs you are taking. Blood levels of the drugs that are listed next on the table may fall when combined with carbamazepine. This is because carbamazepine stimulates the liver enzymes that metabolize these drugs. As a result, the liver gets rid of these drugs more rapidly than usual. This would be equivalent to pulling out the plug while you are trying to fill the bath; the water may not rise to the proper level.

  One important example would be birth control pills. The consequence of the decreased blood level is that the birth control pills may become ineffective, and you might become pregnant even though you are taking your birth control pills consistently. Levels of other drugs listed in the table that may fall when combined with carbamazepine include some antidepressants, antipsychotic drugs, anticonvulsants, antibiotics, thyroid hormones, and others.

  Sometimes the drug interactions work in both directions. A drug may cause the blood level of carbamazepine to fall, and carbamazepine may in turn cause the blood level of the other drug to fall. For example, if you are taking an antipsychotic medication like haloperidol (Haldol), which is often also given for mania, the haloperidol may cause the level of carbamazepine to fall. At the same time the carbamazepine may cause the blood level of haloperidol to drop substantially. As a result, it may seem that neither drug is working properly, and the mania may not be controlled adequately. Your physician may need to do blood tests to determine the levels of both drugs so that the doses can be adjusted properly. Carbamazepine probably has similar effects on other antipsychotic drugs as well.

  Finally, several other potentially dangerous drug interactions with carbamazepine are listed at the bottom of the table. In particular, carbamazepine must not be combined with any of the MAOIs discussed on page 564 because of the risk of the potentially fatal serotonin syndrome.

  Table 20–14. Carbamazepine 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.

  Although Table 20–14 is lengthy, it is not comprehensive because new drugs and new information about drug interactions are constantly emerging. As noted previously, only a small percentage of the potential drug interactions have been studied, and our knowledge about them is rapidly expanding. Other drugs may have important interactions with carbamazepine, so make sure your physician knows of all the medications you are taking. Ask specifically if any of them interact with carbamazepine.

  Other Mood Stabilizing Agents

  Until recently, lithium, valproic acid, and carbamazepine were the main drugs used for the treatment of bipolar illness. Recently, new drugs have been synthesized which may soon be available to treat patients with this disorder. Many of these new drugs are actually anticonvulsants that were designed for the treatment of epilepsy. At least two of them are already being used in the treatment of bipolar (manic-depressive) illness, and many others will undoubtedly become available in the next several years. It seems likely that at least some of them will provide powerful new tools for treating bipolar illness and possibly other psychiatric disorders as well.

  These new drugs (as well as the three mood stabilizers discussed previously) are quite different from the antidepressants because they do not significantly increase levels of serotonin, dopamine, and norepinephrine in the brain. Instead, they seem to stimulate a transmitter substance called GABA (gamma-amino butyric acid) or inhibit a transmitter substance known as glutamate. GABA and glutamate are used by a large percentage of the nerves in the brain. The anticonvulsants that stimulate GABA tend to cause sleepiness. Medications in this category include valproic acid, discussed above, as well as gabapentin (Neurontin), tiagabine (Gabitril), vigabatrin (Sabril), and several others. The anticonvulsants that inhibit glutamate tend to cause stimulation and anxiety. Medications in this category include felbamate (Felbatol), lamotrigine (Lamictal), topiramate (Topamax), and several others.

  Although it is not known for certain why or how these drugs prevent epilepsy or stabilize manic-depressive illness, it is known that the GABA system and the glutamate system in the brain tend to compete with one another. This may be why drugs that stimulate GABA or inhibit glutamate are helpful for epilepsy and for bipolar illness.

  Most anticonvulsant drugs also inhibit sodium transport across nerve membranes in the brain. Sodium, as you know, is present in table salt. It is known as an ion, because it carries a tiny positive electrical charge when it is dissolved in a fluid. The electrical impulses of nerves result when ion channels in the nerve membranes open up and positively charged ions like sodium and potassium suddenly rush across the membrane. These ion fluxes create the electrical impulses in the nerves. Because these drugs inhibit the sodium channels, they may stabilize nerve conduction in the brain by making nerves less excitable. Because nearly all anticonvulsants have this property, they are sometimes classified as “sodium blockers.” The sodium-blocking effects may
also explain why these new drugs can prevent seizures and stabilize manic-depressive illness.

  Of course, all new drugs have unforeseen benefits and hazards, and the new anticonvulsant drugs are no exception. Quite a bit of testing will be necessary before we can identify which ones have most promise for patients with epilepsy and bipolar illness. There is considerable excitement about one of the new drugs, called gabapentin (Neurontin), because it seems to have very few side effects, an excellent safety record, and few if any toxic interactions with other drugs. In addition, it does not require blood testing like the three mood stabilizers discussed above.

  So far, the FDA has approved gabapentin only for the treatment of epilepsy. Although it has not yet been officially approved for psychiatric disorders, many psychiatrists are beginning to prescribe gabapentin for patients with difficult bipolar illness who have not responded to other medications. Its eventual role will have to be determined by clinical experience and by controlled outcome studies.

  At least eight studies of the use of gabapentin in mood disorders were published in 1997, and many more will undoubtedly be published in subsequent years. In these studies, gabapentin was reported to be effective for many patients with bipolar illness. Gabapentin also appeared to have antidepressant and antianxiety properties, and it may be useful in the treatment of chronic pain (including migraine headaches), as well as PMS (premenstrual syndrome), panic disorder, and social phobia.

  Doses for Gabapentin. The current dose of gabapentin for epilepsy is 300 mg to 600 mg three times daily, for a total dose range of approximately 900 to 2000 mg per day. In studies of bipolar patients, the average dose was about 1700 mg per day, with some investigators giving doses as high as 3600 mg per day.

  The absorption of gabapentin from the stomach and intestinal tract is not affected by food. However, the antacid Maalox can reduce the absorption of gabapentin from the stomach by about 20 percent. Therefore, you should wait at least two hours after taking Maalox before you take gabapentin.