Feeling Good: The New Mood Therapy (76 page)

Bupropion was supposed to be introduced in the United States in 1986, but its release was delayed until 1989 because a number of patients with bulimia (binge-eating followed by vomiting) who were treated with this drug had seizures. Further studies indicated that the danger of seizures was related to the dose of bupropion and that the risk was much lower in patients who did not have eating disorders, so the drug was released again. Because of the increased seizure risk with bupropion, the manufacturer recommends that this drug not be prescribed to anyone with a history of epilepsy, a major head injury, a brain tumor, bulimia, or anorexia nervosa.

Bupropion does not affect the serotonin system in the
brain. Instead, it seems to work by potentiating the norepinephrine system, much like the tricyclic antidepressant called desipramine (Norpramin). There is also some evidence that it may stimulate the dopamine system in the brain, but these effects are much weaker, and it is not clear whether they contribute to the antidepressant effects of bupropion. Nevertheless, bupropion is sometimes classified as a “combined noradrenergic-dopaminergic antidepressant,” because of its effects on the norepinephrine and dopamine systems.

Bupropion is used to treat depressed outpatients and inpatients over the entire range of depression severity. Preliminary studies suggest that it may also be useful for a number of other problems, including smoking cessation, social phobia, and attention deficit disorder. These widespread effects of bupropion do not mean this drug is special, however. Nearly all antidepressants have been reported to be at least partially effective for a wide array of problems including depression, all of the anxiety disorders, eating disorders, anger and violence, chronic pain, and many other problems as well. One possible interpretation for these findings is that these drugs may not really be specific antidepressants. Instead, they may have widespread effects throughout the brain.

A new use for bupropion is to enhance the effects of the SSRI antidepressants. Suppose, for example, that you are taking a drug like Prozac but you have not responded to it adequately. Instead of switching you to a new drug, your doctor may add a low dose of bupropion in an attempt to enhance the effect of the Prozac. Bupropion, in doses of up to 225 mg to 300 mg per day, has been added to SSRI antidepressants in an attempt to combat the sexual side effects of SSRIs, such as loss of libido and difficulties having orgasms.

In my clinical experience, the effects of these drug combinations have often been disappointing. I would usually prefer to try another medication rather than combining drugs when a medication does not work. I am personally
concerned that in some instances patients may be in danger of being overmedicated by physicians who are a bit too enthusiastic about adding more and more drugs in larger and larger doses. Also, because I rely so heavily on psychotherapeutic interventions in my own clinical work, I do not feel so much pressure to find a solution from drugs alone. Therefore I do not feel quite so much concern when one or more medications fails to work. I simply switch to another medication and continue to try a variety of new psychotherapeutic strategies, a combination that I find most successful.

Doses of Bupropion
. You can see in Table 20–1 on pages 518–523 that the usual dose range for bupropion is 200 to 450 mg per day. At doses below 450 mg per day, the risk of seizures appears to be about four patients per 1000. However, the risk is ten times higher at doses above 450 mg per day—four patients per 100 will experience seizures. Whenever possible, it is good to keep the dose in the lower range to minimize the chance of seizures. In addition, no single dose should ever be greater than 150 mg.

Side Effects of Bupropion
. The most common side effects of bupropion are listed in Table 20–11 on pages 608-609. Unlike the tricyclics, bupropion does not cause dry mouth, constipation, dizziness, or tiredness. It also does not stimulate the appetite. This is a big bonus for patients who have been bothered by weight gain. However, some patients have reported upset stomach (nausea).

Bupropion is also somewhat activating and can cause insomnia. Therefore, it may be relatively more effective for depressed patients who tend to feel tired, lethargic, and unmotivated—the stimulating effect may help get you moving. In this regard, it is similar to some of the tricyclic antidepressants (for example, desipramine), the SSRIs (for example, Prozac) and the MAOIs (for example, tranylcypromine).

Table 20–11
. Side Effects of Other Antidepressants
^a

^a
The + to + + + ratings in this table refer to the likelihood that a particular side effect will develop. The actual intensity of the side effect will vary among individuals and will also depend on how large the dose is. Reducing the dose can often reduce side effects without reducing effectiveness.

Drug Interactions for Bupropion
. Because bupropion can substantially increase the risk of seizures, it should not be combined with other drugs that can also make a person more vulnerable to seizures. This includes many psychiatric drugs such as the tricyclic and tetracyclic antidepressants, the SSRIs, the two serotonin antagonists (trazodone and nefazodone), and many of the major tranquilizers (neuroleptics). In addition, there is a greatly increased risk of seizures when alcoholics suddenly stop drinking or when individuals abruptly stop taking minor tranquilizers (benzodiazepines such as Xanax or Valium), barbiturates, or sleeping pills. Bupropion is therefore especially risky for alcoholics and for individuals taking sedatives or tranquilizers regularly.

Many nonpsychiatric drugs (for instance, corticosteroids) can also increase the risk of seizures. Therefore, great caution must be exercised if bupropion is combined with any of these drugs, especially if the dose of bupropion is high. Make sure you check with your pharmacist or druggist about drug interactions if you are taking any other medication along with bupropion.

There are several other kinds of drug interactions you need to consider if you are taking bupropion:

This is a relatively new antidepressant that is in a distinct class from other antidepressant medications. Released in 1994, it is called a “dual uptake inhibitor” or “mixed uptake inhibitor.” This has a very simple meaning. It leads to increases in two types of chemical messengers (also called neurotransmitters) in the brain—serotonin and norepinephrine—by blocking the pumps that transport them back into the presynaptic nerves after they are released into the synapses.

As you will recall from Chapter 17, this capacity to increase levels of two different types of chemical messengers is not new. Many of the older and cheaper tricyclic antidepressants, such as Elavil (amitriptyline) also do this. The more important difference with venlafaxine is that it has fewer side effects because it does not stimulate the histaminic, alpha-adrenergic, and muscarinic brain receptors that cause tiredness, dizziness, dry mouth, and so forth. However, as you will see below, venlafaxine has quite a number of side effects of its own. Some of these, such as nausea, insomnia, and sexual difficulties, are similar to the SSRI antidepressants, and some (such as tiredness) are similar to the tricyclic antidepressants.

It has been claimed that the onset of action may be faster with venlafaxine because of its dual effects on serotonin and norepinephrine receptors. This does not seem likely, because the older tricyclic antidepressants also have dual effects on serotonin and norepinephrine receptors in the brain, but do not have rapid antidepressant effects. Research is now in progress to try to determine whether venlafaxine really does work any more rapidly.

Although a faster-acting antidepressant would represent an important breakthrough, we should probably not become
too optimistic about this. Claims about the superior properties of new antidepressants have often not been substantiated by careful, systematic, independent research after the drugs have been available on the market for a period of time. In addition, you will see below that venlafaxine must be started at low doses and increased very slowly to prevent side effects from developing. For most patients, this will prevent the drug from having any rapid antidepressant effects.

Studies are in progress to examine the larger question of whether drugs with dual action have stronger antidepressant effects than SSRIs for certain types of patients, especially severely depressed patients who are hospitalized. This is important because the SSRIs (such as Prozac) which are now so popular have not been particularly effective for these patients. In one study, venlafaxine was more effective than Prozac in the treatment of inpatients with “melancholic” depression. “Melancholic” depression refers to a more severe depression with many organic features, such as waking up too early and a loss of appetite and sexual drive. Individuals with melancholic depressions may also have anhedonia along with feelings of guilt that can become extreme or even delusional. Anhedonia refers to a severe loss of the capacity to experience pleasure or satisfaction.

Like all antidepressants, venlafaxine is beginning to be used for a number of other disorders as well. These include chronic pain disorder as well as adult attention deficit disorder (ADD). Remember that all, or nearly all, antidepressants have been used for a great variety of disorders, so it is not likely that the effects of venlafaxine are superior for chronic pain or for ADD.

Doses of Venlafaxine
. Some experts recommend starting venlafaxine at 18.75 mg twice per day, which is only half the starting dose recommended by the manufacturer, in order to minimize the likelihood that nausea will develop.
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Then the daily dose can be slowly increased by
37.5 mg every third day until a total dose of 150 mg per day or above is reached. Most patients respond to a total dose of 75 mg to 225 mg per day. Higher doses tend to be more effective, but they are associated with more side effects.

Earlier when discussing SSRIs, we talked about the half-life of drugs—this is the time required by the body to eliminate one half of the drug in your body. Venlafaxine has a short half-life—meaning that it leaves your body in a matter of hours. Therefore, you must take the medication two or three times per day to maintain an adequate level in your bloodstream.

The manufacturer has recently marketed an extended (slow) release version of venlafaxine (called Effexor XR) that you need to take only once per day, which is more convenient. As you can see in Table 20–1 on page 521, the extended release capsules appear to be more costly, but this is really an illusion. For example, you can see in the table that the average wholesale price of a hundred of the 75 mg capsule of Effexor is $118.66, whereas the price of a hundred of the 75 mg extended-release capsules is $217.14, or almost twice as much. When I first saw these figures, I naturally concluded that the extended-release capsules were twice as expensive as the regular pills.