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 Antidepressantsa
aThe + 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:
• Barbiturates can cause the level of bupropion in the blood to fall. This could make the bupropion ineffective.
• Phenytoin (Dilantin) can also cause bupropion levels to fall, thus making the bupropion less effective. However, phenytoin is most often prescribed for epilepsy, and so patients taking phenytoin are not likely to receive bupropion.
• Cimetidine (Tagamet) may increase bupropion levels in the blood. This can increase the likelihood of side effects or toxic effects, including seizures.
• Bupropion must not be combined with the MAOIs because of the risk of a hypertensive crisis.
• L-dopa increases the side effects of bupropion; caution is required when these drugs are combined.
Venlafaxine (Effexor)
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.1 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.
But let’s see what happens in a real-life situation. Suppose your dose is 75 mg per day. You could take either one of the regular 37.5 mg pills in the morning and a second 37.5 mg pill in the evening, for a total cost of $2.17 per day, or one of the 75 mg extended-release pills once per day. As noted above, the cost of the 75 mg extended-release pills will also be $2.17 per day. Either way, Effexor is very expensive, since the daily dose may be as high as 375 mg per day. The high price is especially striking when you compare the cost of Effexor with the cost of many of the generic tricyclic antidepressants that are just as effective and available for less than ten cents per day.
As with any antidepressant, it is best to taper off venlafaxine slowly. At least two weeks are recommended, and some patients may require as much as four weeks.
Side Effects of Venlafaxine. The side effects of venlafaxine are listed in Table 20–11 on pages 608–609. As you can see, they are similar to the SSRI compounds described above. The most common side effects of venlafaxine are nausea, headache, sleepiness, insomnia, abnormal dreams, sweating, nervousness, and tremor. Venlafaxine can also cause the same types of sexual difficulties as the SSRIs, including a loss of interest in sex and difficulties achieving orgasm. These sexual side effects tend to be quite common, just as with the SSRIs. In spite of the claim that venlafaxine has fewer side effects than the older tricyclic antidepressants, this drug can nevertheless cause dry mouth and dizziness in some patients. The dizziness is particularly likely if you go off the drug too quickly.
One distinct type of side effect seen with venlafaxine is an increase in blood pressure. However, the blood-pressure increases are typically seen only at higher doses (225 mg per day or above). Nevertheless, if you have problems with your blood pressure, you and your doctor should monitor your blood pressure carefully, and this drug may not be a good choice for you. At doses less than 200 mg per day, the likelihood of an increase in blood pressure is only about 5 percent. The probability increases to 10 percent or 15 percent at doses greater than 300 mg per day. Blood-pressure increases of 20 to 30 mm of mercury have been observed, for example.
Drug Interactions for Venlafaxine. Because venlafaxine is relatively new, information about its interactions with other drugs is still relatively limited. Venlafaxine appears to be less likely to interact in adverse ways with other medications you are taking. Several drugs may cause blood levels of venlafaxine to increase, and so lower doses of venlafaxine may be needed. These include:
• some tricyclic antidepressants;
• the SSRI antidepressants;
• cimetidine (Tagamet).
Venlafaxine may cause the blood levels of several of the major tranquilizers to increase. These include trifluoperazine (Stelazine), haloperidol (Haldol), and risperidone (Risperdal), and so lower doses of these drugs may be needed. In theory, these drugs could also cause blood levels of Venlafaxine to increase.
Venlafaxine must not be combined with MAOI antidepressants because of the danger of the serotonin syndrome (hyperpyretic crisis) described on page 576. Remember that it takes up to two weeks for the effects of an MAOI to clear out of your body, so a two-week drug-free period will be required if you stop taking an MAOI and then start taking venlafaxine. In contrast, if you go off venlafaxine and then start taking an MAOI, a one-week drug-free period should be sufficient, because venlafaxine leaves the body fairly rapidly.
Mirtazapine (Remeron)
Mirtazapine (Remeron) was released in the United States in 1996. It also enhances both norepinephrine and serotonin activity, but through a different mechanism from venlafaxine. Premarketing studies suggest that mirtazapine may be effective for mildly depressed outpatients and for more severely depressed inpatients as well. It may also be particularly helpful for depressed patients who are very anxious or nervous.
Doses of Mirtazapine. The dose range for mirtazapine is 15 to 45 mg per day. Most physicians will prescribe a smaller amount at first (7.5 mg per day) and then slowly increase the dose. Because mirtazapine causes sleepiness in more than 50 percent of the people who take it, it can be given once a day at bedtime, usually in doses of 15 to 45 mg per day. Some physicians report that mirtazapine is less likely to cause less sleepiness when the dose is increased. This is the opposite of what you might expect intuitively. It is because the drug may have some stimulating effects at the higher doses. We will have to wait until there is more clinical experience with this drug to see if this is really true.
Side Effects of Mirtazapine. The side effects of mirtazapine are listed in Table 20–11 on pages 608–609. You can see that it blocks the histaminic, alpha-adrenergic, and muscarinic receptors in much the same way that the older tricyclic antidepressants do. Therefore, the side effect profile of mirtazapine is very similar to the tricyclics, especially amitriptyline, clomipramine, doxepin, imipramine and trimipramine (see Table 20–2). The more common side effects include tiredness (54 percent of patients) noted above, increased appetite (17 percent), weight gain (12 percent), dry mouth (25 percent), constipation (13 percent), and dizziness (7 percent). Keep in mind that these figures are somewhat inflated because they do not take into account the placebo effect. For example, 2 percent of patients on placebo also report weight gain, and so the true incidence of weight gain that can be attributed to the mirtazepine would be 12 percent minus 2 percent, or 10 percent. Mirtazepine is not likely to cause the stomach upset, insomnia, nervousness, and sexual problems commonly seen with the SSRIs such as Prozac.
Mirtazapine has some unique adverse effects not shared with other antidepressants. It can, in rare cases, cause your white blood cell count to fall. Because these cells are involved in fighting off infections, this could make you more vulnerable to a variety of infections. If you develop a fever while taking this drug, make sure you contact your physician immediately so that he or she can obtain a complete blood count. Mirtazapine can sometimes cause an increase in levels of
blood fats such as cholesterol and triglycerides. This could be a problem if you are overweight or have a heart condition or if your cholesterol and triglycerides levels are already elevated.
Drug Interactions for Mirtazapine. Because mirtazapine is relatively new, very little information about its drug interactions is available. It must not be combined with the MAOI antidepressants because of the risk of the serotonin syndrome (hyperpyretic crisis). Because it can be quite sedating, it will enhance the effects of other sedative drugs. These include alcohol, major and minor tranquilizers, sleeping pills, some antihistamines, barbiturates, many other antidepressants, and the antianxiety drug buspirone (BuSpar). The increased sleepiness you experience when these substances are combined with mirtazapine could lead to difficulties with coordination and concentration. This might be hazardous when driving or operating dangerous machinery.
Mood Stabilizers
Lithium
In 1949, an Australian psychiatrist named John Cade observed that lithium, a common salt, caused sedation in guinea pigs. He gave lithium to a patient with manic symptoms and observed dramatic calming effects. Tests of the effects of lithium in other manic patients yielded similar results. Since that time, lithium has slowly gained popularity throughout the world. It has been used successfully in the treatment of a number of conditions, including:
Acute manic states. Although lithium is used to treat patients with severe mania, they will usually be treated with more potent, faster-acting drugs at the same time until the severe symptoms of mania have subsided. These other drugs include the antipsychotics (also known as major tranquilizers or neuroleptics) such as chlorpromazine (Thorazine), as well as benzodiazepines (also called “minor tranquilizers”) such as clonazepam (Klonopin) or lorazepam (Ativan). These additional drugs are used until the mania has been brought under control. Once the severe manic symptoms subside, the other drugs are discontinued and the patient continues taking the lithium to prevent future mood swings.
Feeling Good: The New Mood Therapy Page 53