Feeling Good: The New Mood Therapy (82 page)

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.

About half of a dose of gabapentin disappears from the body within five to seven hours, so it must be taken several times per day rather than all at once. If you take a high dose of gabapentin on a single occasion, a smaller proportion of the dose will be absorbed from your stomach and intestinal tract into your blood. For example, only 75 percent of a single 400-mg dose is absorbed, as compared with 100 percent of a 100-mg dose. From a practical point of view, this should not be a concern if you are taking gabapentin
since you will be taking the medication several times per day in divided doses.

There is no evidence that men and women require different doses because of differences in metabolism, but individuals over seventy years of age may need only about half the doses used for younger people. This is because of changes in kidney function that occur with aging. Because the kidneys excrete gabapentin, individuals with impaired kidney function will require smaller doses.

Unlike lithium, carbamazepine, and valproic acid, blood testing does not appear necessary with gabapentin. This is another advantage of this medication.

Side Effects of Gabapentin
. The main side effects are listed in Table 20–15 on pages 656–657. You can see that they include sleepiness, noted above, along with dizziness, tremor, problems with coordination, weight gain, and some visual side effects. All of these side effects will be more pronounced at higher doses and less noticeable at lower doses. Overall, the side effect profile of gabapentin is very favorable, especially when compared with the other currently available mood stabilizers.

In the studies cited in Table 20–15, gabapentin was given to patients with epilepsy who were already receiving one or more other anticonvulsants. Therefore, the side effects that were actually due to the gabapentin were lower. The best way to get a more realistic estimate of any side effect is to subtract the percentage seen in the placebo group from the percentage seen in the gabapentin group. For example, 11.0 percent of the gabapentin group experienced fatigue, whereas 5.0 percent of the placebo group experienced this side effect. The difference in these two numbers is 6.0 percent. This is a better estimate of the true incidence of fatigue that can be attributed to gabapentin.

Like nearly all psychiatric drugs, gabapentin should be used with great caution in pregnant women. Although there are no well-controlled studies of the effects of gabapentin on the developing fetus in pregnant women, fetal abnormalities
have been observed when gabapentin was administered to pregnant mice and rabbits. Although animal studies do not always predict human responses, gabapentin should be used in pregnancy only if the need is great and if the potential benefit outweighs the potential risk to the developing fetus. Although it is not yet known whether gabapentin is secreted into human milk, many drugs are secreted into human milk; consequently, gabapentin should probably not be used by mothers who are nursing. Certainly, you should discuss this risk with your physician.

Drug Interactions for Gabapentin
. Gabapentin has one unusual and desirable property; it is not metabolized by the liver, but is excreted unchanged by the kidneys directly into the urine. For this reason, it does not seem to interact in adverse ways with other drugs. You will recall from previous discussions that all the antidepressants and mood stabilizers have fairly complicated interactions with lots of other drugs. This is because these drugs compete with each other for certain metabolic enzymes in the liver. With gabapentin, this is not a problem, so it is much safer to combine gabapentin with other medications. In fact, many experts believe that gabapentin has no metabolic interactions at all with other drugs. One benefit is that gabapentin can be combined with other mood stabilizers for patients with difficult cases of bipolar illness or epilepsy who have not responded to other medications.

The properties of gabapentin are certainly very appealing. Is there a downside? Sometimes problems with new medications surface after the medication has been in widespread use for a period of time and the initial excitement has worn off. Gabapentin may be no exception. One concern already voiced by some neurologists and psychiatrists is that the drug may not be particularly effective for either epilepsy or bipolar illness. This would be disappointing, since the drug has so few side effects or interactions with other drugs. A colleague with considerable experience with gabapentin told me she is using it primarily to help anxious patients with insomnia, because it has excellent sedative and relaxing properties and is not habit-forming. Unfortunately, she feels it may not be powerful enough to be a primary mood stabilizer for bipolar patients, but it may have value when it is used in combination with other medications.

Table 20–15
. Side Effects of Gabapentin (Neurontin)

Note:
The information in this table was adapted from the 1998
Physician’s Desk Reference (PDR
). In these studies, gabapentin or placebo was given to individuals with epilepsy who were already taking at least one other drug for epilepsy. The side effects in individuals not taking other drugs are likely to be less. Only the more common side effects are listed.

Another new anticonvulsant, lamotrigine (Lamictal) has also been approved by the FDA for the treatment of epilepsy. Like gabapentin, lamotrigine has been used in the treatment of treatment-resistant bipolar illness. Dr. Alan F. Schatzberg and colleagues
¹
point out that very few formal studies of lamotrigine have been conducted in psychiatric patients, and so the reports of its effectiveness are still mainly anecdotal. In addition, lamotrigine has some significant and troubling side effects. In particular, rashes and skin reactions occur in as many as 5 percent or more of the adults taking lamotrigine. While most of these rashes are not dangerous, lamotrigine can cause a severe and life-threatening skin reaction known as the Stevens-Johnson syndrome in 1 percent to 2 percent of cases. These skin reactions are more common in pediatric patients than in adults, and so lamotrigine should not be given to individuals under sixteen years of age. Taking lamotrigine at higher doses or in combination with other drugs, such as valproic acid, may make these feared skin reactions more likely. In premarketing trials, five patients taking lamotrigine died from liver failure or multiorgan failure.

Lamotrigine causes many other side effects such as headache and neck pain, nausea and vomiting, dizziness, loss of coordination, sleepiness, trouble sleeping, tremor, depression, anxiety, irritability, seizures, speech problems, memory difficulties, runny nose, rashes, itching, double vision, blurred vision, vaginal infections, and others. Lamotrigine also has a number of interactions with other drugs because it is metabolized by the liver. Because it has many side effects, including some dangerous ones, lamotrigine must be used with great caution. Until we learn more about it, it should probably be reserved for patients who have
failed to respond to the better-established mood stabilizers discussed above.

As I have emphasized, I would recommend taking a mood test like the one in Chapter 2 to monitor your response to any treatment, including medications or psychotherapy. You can take the test once a week or even more frequently, and keep track of your scores. Your scores will show whether and to what extent the treatment is working. The goal of treatment is to get these scores reduced substantially. Ultimately, you want your scores to be in the range considered normal and ideally in the range considered happy.

If a drug doesn’t help, or helps only somewhat, what should you do?

Let’s examine each of these principles. First, you need to be certain the dose is sufficient. If for any reason your blood level of an antidepressant is too low, then the probability of a positive drug response will be diminished. However, a dose that is too high might also be less effective. This is because the side effects at excessively high doses may counteract the antidepressant effects. Concerns about the doses of antidepressant drugs are important because different people can metabolize these drugs quite differently. In other words, given a particular drug at a particular dose, different people can have dramatically different levels of the drug in their blood. In fact, the levels of a tricyclic antidepressant may differ by as much as thirty times in two different people who both receive comparable doses of the same drug. This can happen even if the two people are the same sex, height, and weight.

These differences in blood levels can result from differences in the ways people absorb a drug from their gastrointestinal tracts and from differences in how fast people get rid of a drug from their blood. Genetics can play a role. For example, approximately 5 percent to 10 percent of the Caucasian population in western Europe and the United States lack the liver enzyme called CYP2D6 (in the P450 family), and 20 percent of the Asian population lack the enzyme called CYP2C19.
²³
These enzymes help to metabolize a wide variety of drugs including many antidepressants. Individuals who lack either of these enzymes may develop dramatically higher blood levels of certain antidepressants because their liver enzymes cannot get rid of these drugs nearly as rapidly as the average individual.

Medical conditions such as liver, kidney, or heart disease can have an impact on the blood level of antidepressants. Age can also be important. On the average, children and
elderly individuals require lower doses of most medications including antidepressants. You may recall, for example, that individuals over sixty-five may develop blood levels of several SSRIs, citalopram (Celexa), fluoxetine (Prozac) and paroxetine (Paxil), that are approximately 100 percent greater than the blood levels of younger individuals taking identical doses. Sometimes gender can play a role as well. As noted previously, men may develop blood levels of fluoxetine (Prozac) or sertraline (Zoloft) that are 30 percent to 50 percent lower than women taking similar doses of these medications.