Feeling Good: The New Mood Therapy
Page 57
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.
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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.
Gabapentin (n = 543)
Placebo (n = 378)
Digestive System
weight gain
2.9%
1:6%
dry mouth
1.7%
0.5%
upset stomach
2.2%
0.5%
Energy
fatigue
11.0%
5.0%
sleepiness
19.3%
8.7%
Nervous System
dizziness
17.1%
6.9%
trouble with coordination
12.5%
5.6%
tremor
6.8%
3.2%
slurred speech
2.4%
0.5%
memory problems
2.2%
0.0%
Eyes
nystagmus (tremor of the eyes)
8.3%
4.0%
double vision
5.9%
1.9%
blurred vision
4.2%
1.1%
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 colleagues1 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.
What If My Antidepressant Does Not Work?
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?
1. Make sure you have given the drug a fair trial. Ask yourself:
• Is the dose adequate?
• Have you taken the drug for an adequate period of time?
2. Make sure there are no drug interactions that are preventing the antidepressant from being effective. Remember that some other drugs can cause your blood level of an antidepressant to fall, even if you are taking the correct dose of the antidepressant. Inform your doctor about any other drugs you are taking.
3. You and your doctor may want to consider one of the augmentation strategies discussed below.
4. If these procedures are not successful, you and your doctor can discontinue the medication and try another type of antidepressant.
5. Psychotherapy along the lines described in this book, either alone or in combination with an antidepressant, can often be far more effective than treatment with drugs alone.
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.
Weather, your personal habits, or other medications you are taking can sometimes influence blood levels of antidepressants or mood stabilizers. For example, if you are sweating a great deal during the summer, your blood level of lithium may rise, so your doctor may need to reduce the dose. If you are a smoker, your body will break down tricyclic antidepressants more rapidly because of the effects of the nicotine. Consequently, you may need a higher dose of these antidepressants. Many other drugs that can also cause a rapid breakdown of tricyclic antidepressants are listed in Table 20–5. In contrast, some drugs on this table can slow the metabolism of tricyclic antidepressant drugs by the liver, leading to excessively high blood levels of the antidepressants. Remember that these drug interactions can work both ways: an antidepressant or mood stabilizer may affect the level or activity of other drugs you are taking, and vice versa.
Before you and your doctor decide that a particular drug is not working, make sure that you review the dose with him or her. Ask about the possibility of drug interactions if you are taking more than one drug. Your doctor may want to order a blood test to ensure that the level in your blood is adequate. Blood-level testing is more commonly done for the mood stabilizers and for the tricyclic and tetracyclic drugs than for other types of antidepressants listed in Table 20–1.
If the blood level is adequate and you have been taking the medication for a sufficient period of time but your antidepressant is still not working, your doctor may try switching you to a different type of antidepressant or may try an augmentation strategy. This involves adding a small dose of a different drug to try to boost the effect of the antidepressant. Several kinds of augmentation strategies currently in vogue are listed in Table 20–16 on pages 664–669. A complete discussion is beyond the scope of this book; I will describe just a couple of them to give you a feel for this approach. Interested readers may want to consult the excellent reference by Schatzberg and his colleagues.1
Two drugs commonly used for antidepressant augmentation are lithium, a drug you’ve learned about in this chapter, and a thyroid hormone called liothyronine (also known as Cytomel, or T3). Your doctor may add 600 mg to 1,200 mg per day of lithium carbonate or 25 to 50 micrograms per day of liothyronine to your antidepressant for several weeks if the antidepressant has not been working adequately. As noted above, lithium is usually used to treat bipolar (manic-depressive) illness, and liothyronine is used to treat people with underactive thyroid glands. However, in this case, the goal is different—the purpose of adding a small dose of lithium or liothyronine is to make the antidepressant more effective. It is not clear why lithium and liothyronine sometimes have this effect of boosting the effectiveness of antidepressants.
A liothyronine trial will usually last for one to four weeks. If you respond positively, your physician may continue the liothyronine for two more months. Then she or he will probably taper you off the augmentation medication over one to two weeks.
The dose of lithium used for augmentation will be adjusted with a blood test so that your blood level will remain in the range of around 0.5 to 0.8 mEq per L. These levels are a little lower than the levels used to treat patients who are experiencing mania. The lower levels have the advantage of having fewer side effects. The lithium augmentation trial will generally last for two weeks. Positive results have been reported when lithium was combined with tricyclics, SSRIs, and MAOIs. Research studies suggest that as many as 50 to 70 percent of patients who do not respond to an antidepressant will respond more favorably when lithium is added. If there is no improvement in your depression, your doctor will probably discontinue the lithium as well as the antidepressant and try another medication.
Some doctors use antidepressant combination therapy for patients with difficult depressions. For example, one new approach is to add an SSRI when a tricyclic does not work, or to add a tricyclic when an SSRI does not work. This combination can cause large increases in the blood level of the tricyclic medication, and so your doctor may decrease the tricyclic first and then check your tricyclic level with a blood test after you start the SSRI. Your doctor may also order an ECG to make sure there are no adverse effects on your heart.
An MAOI might also be combined with a tricyclic antidepressant as a combination antidepressant strategy. This is an advanced form of treatment for the specialist and requires careful teamwork between you and your doctor. You will recall that dangerous reaction
s can result from combining MAOIs with other antidepressant drugs or with lithium. Although the Physician’s Desk Reference advises against such drug combinations, Schatzberg and colleagues report that the combination can be safe and helpful to some patients who fail to respond to single medications.1 To maximize safety, these investigators recommend: (1) the MAOI and tricyclic should be started at the same time; (2) clomipramine should be avoided; (3) the safest tricyclics to use in combination with MAOIs appear to be amitriptyline (Elavil) and trimipramine (Surmontil); (4) among the two commonly prescribed MAOIs, phenelzine (Nardil) appears to be safer than tranylcypromine (Parnate) to use in combination with a tricyclic.
Table 20–16. Antidepressant Augmentation Chart.
You will see quite a number of additional augmentation strategies listed in Table 20–16. My experience with these antidepressant combination and augmentation strategies has been limited, but I have not been impressed with the results. I have tried lithium or thyroid augmentation with a number of patients but none of them seemed to improve. I was not encouraged to continue with this approach. However, if a depressed patient has failed to respond to an adequate trial of several antidepressants, one at a time, from different chemical classes, then a combination of antidepressants or an augmentation strategy might be worth a try.
If you have received an adequate dose of an antidepressant for an appropriate period of time and you are not responding, what antidepressant should you try next? Many physicians will switch you to an antidepressant of a completely different class to maximize the chance of a positive response. This idea makes good sense, since the different antidepressants have slightly different effects on the brain. If you have failed to respond to an SSRI such as fluoxetine (Prozac), your doctor may want to try a tricyclic such as imipramine (Tofranil), for example. Prozac selectively activates the serotonin systems in the brain, whereas imipramine has effects on many different systems.