Feeling Good: The New Mood Therapy (75 page)

Well, by now you may be asking whether it is worth it to take a drug like an MAOI which may seem so complicated and dangerous. This question is especially relevant these days, when so many newer and safer drugs are available. Usually, I would try at least two other drugs first. The SSRI drugs, in particular, often help the same types of patients who used to benefit from the MAOIs. I would like to emphasize, however, that in my experience, the MAOIs can usually be administered safely. I have prescribed them for many patients over the years. When doses are kept at a modest level, the side effects tend to be minimal. And when the MAOIs do work, their effects can be quite phenomenal.

In fact, some of my most impressive successes with medications have been with these MAOI drugs, especially tranylcypromine (Parnate). In addition, I have used these drugs with difficult patients who had experienced many unsuccessful treatments with drugs as well as psychotherapy. When these individuals did improve, the degree of improvement was sometimes extreme. These positive experiences with MAOIs have made a strong impression on me. I believe the enthusiasm of the physicians who use the MAOIs is quite justified. If your physician suggests a medication of this type, it might prove to be well worth the necessary extra effort (taking your blood pressure daily), sacrifice (no pizza!), and self-discipline (avoiding certain foods and medicines).

One last note is that a newer and safer MAOI drug, moclobemide, is being marketed in other parts of the world, including Canada, Europe, and South America. Unlike the MAOIs described above, the effects of moclobemide do not persist after you stop taking it. In addition, it does not seem to interact with tyramine in the diet to nearly the same degree. Dr. Alan Schatzberg and his colleagues
¹
have pointed out that moclobemide appears to have very few side effects and that the risk of serious drug interactions is relatively low. Psychiatrists hope that moclobemide or another new MAOI called brofaromine will eventually be marketed in the United States.

Two antidepressant drugs in the table on pages 514–515 are classified as “serotonin antagonists.” They are trazodone (Desyrel) and nefazodone (Serzone). Their mechanism of action appears to be somewhat different from most other antidepressants. Trazodone and nefazodone can boost serotonin by blocking its reuptake at nerve synapses, much like the SSRIs described above. However, these drugs have less potent effects on the serotonin pump than the SSRIs, or even the older tricyclic antidepressants, and this is probably not how these drugs work.

As described in Chapter 17, trazodone and nefazodone appear to block some of the serotonin receptor sites on postsynaptic nerve membranes. At least fifteen different kinds of serotonin receptors have been discovered in the brain. The two receptors that are blocked by trazodone and nefazodone are called 5-HT
_2A
and 5-HT
_2C
receptors. 5-HT is simply shorthand for serotonin; the number and letter after the 5-HT identify the specific type of receptor. Trazodone and nefazodone indirectly stimulate another type of serotonin receptor called the 5-HT
_1A
receptor. This receptor is thought to be important in depression, anxiety, and violence. According to one theory, the stimulation of these 5-HT
_1A
receptor sites might explain the antidepressant effects of trazodone and nefazodone. In addition, trazodone and nefazodone are effective antianxiety drugs. If you tend to be nervous and worried, like many depressed individuals, these medications may be especially helpful for you.

Doses of Trazodone and Nefazodone
. The starting dose for trazodone is 50 to 100 mg per day. Most patients will do well on 150 mg to 300 mg per day. The starting dose for nefazodone is 50 mg twice per day. The doses of both drugs can be increased very slowly over several weeks to a maximum of 600 mg per day.

Nefazodone and trazodone have short half-lives. The
half-life is the time it takes your body to get rid of half of the drug that is in your system. A drug with a short half-life leaves the blood fairly rapidly and must be taken two or three times per day. In contrast, a drug like Prozac, with an extremely long half-life, leaves your body slowly and needs to be taken only once per day.

As with any antidepressant, you should monitor your mood with a test like the one in Chapter 2 while taking trazodone and nefazodone. This will show whether the drugs are working, and to what extent. If you have not improved substantially after three or four weeks, it may be wise to switch to another drug. Although withdrawal symptoms are quite rare for these medications, it is wise to taper off nefazodone and trazodone slowly, rather than stopping them suddenly. This is good advice with any antidepressant.

Side Effects of Trazodone and Nefazodone
. The most common side effects of these two drugs are listed in Table 20–10 on page 601. One common side effect is stomach upset (such as nausea). This side effect is also common with the SSRIs and other drugs that stimulate the serotonin systems in the brain. The upset stomach is more likely when nefazodone and trazodone are taken on an empty stomach, and so it can be helpful to take them with food, just like the SSRIs.

Trazodone and nefazodone can also cause dry mouth in some patients. Both drugs can also cause a temporary drop in blood pressure when you stand up, resulting in dizziness or light-headedness. Trazodone is much more likely to cause these problems than nefazodone. Elderly people are more prone to dizziness and fainting, and so nefazodone may be a better choice for them. As discussed above, several things can alleviate this problem: get up more slowly; walk in place when you get up so as to “pump” blood back to your heart from your legs; use support stockings; and take adequate amounts of fluid and salt to prevent any dehydration. Talk to your doctor if you have problems with dizziness or other side effects; she or he may be able to lower the dose.

Table 20–10
. Side Effects of Serotonin Antagonists
^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.

Another major side effect of trazodone is that it makes you sleepy. This is why it is best taken at night. If you are taking another antidepressant, your doctor may also prescribe a small dose of trazodone at bedtime in order to promote sleep. This is because some antidepressants, such as Prozac and the MAOIs, tend to be stimulating and may interfere with sleep. Trazodone is not addictive and it will not cause dependency or addiction the way some sleeping pills do. The calming, sedative effects of trazodone also help to reduce anxiety. If you tend to be worried and high-strung, this may be a good drug for you. Nefazodone is much less sedating than trazodone, and is not a useful medication for insomnia. In fact, it can occasionally have the opposite effect of causing restlessness, in much the same way that the SSRIs do.

Another adverse side effect of trazodone is called “priapism.” Priapism is an involuntary erection of the penis. Fortunately, this side effect is quite rare, occurring in approximately one male patient out of 6,000. It has been reported in only a few hundred cases so far. Personally, I have never seen a case of priapism, but men who take trazodone should be aware that it is remotely possible. If the priapism is not treated right away, it can lead to damage to the penis and permanent impotence (the inability to get an erection). Some patients require surgery to correct the priapism. Injecting a drug like epinephrine directly into the penis can sometimes counteract the priapism if you catch it quickly enough. If this unusual side effect does occur, or if you are beginning to notice an erection that will not go away, contact your doctor or go to an emergency room right away. Nefazodone, on the other hand, does not cause priapism.

Priapism sounds frightening, but I do not mean to discourage men from taking this medication. If you read the
Physician’s Desk Reference
carefully, you will see that there is a remote chance of a dangerous side effect from nearly any drug you might take, including aspirin. Priapism is a very unlikely side effect of trazodone and can be treated at any emergency room if you act rapidly when the symptom first develops.

Some patients taking these drugs report visual “trails” or afterimages when they are looking at objects that are moving. This side effect is also quite unusual and similar in some respects to the visual images reported by individuals who take LSD, but not dangerous. These visual trails are more common with nefazodone than with trazodone and occur in slightly more than 10 percent of patients taking this drug. They often improve over time.

Drug Interactions for Trazodone and Nefazodone
. As noted earlier, some drug combinations can be dangerous because one drug causes the level of the other drug in your blood to become excessively high. Nefazodone has the effect of raising the blood level of a number of drugs. These include commonly prescribed drugs for anxiety, including many of the minor tranquilizers such as alprazolam (Xanax), triazolam (Halcion), buspirone (BuSpar) and others. As a result, you should be very cautious when combining these drugs with nefazodone, because you could become excessively sleepy.

Trazodone will also enhance the sedative effects of other sedative drugs because trazodone itself will make you sleepy. Consequently, trazodone or nefazodone can enhance the sedative effects of any drug that makes you sleepy, such as alcohol, barbiturates, sleeping pills, painkillers, some major tranquilizers (neuroleptics), and some antidepressants. Be very cautious if you combine any sedative agents with nefazodone or trazodone, especially if you are driving or operating dangerous machinery.

Nefazodone can increase the levels of several tricyclic
antidepressants in your blood, especially amitriptyline (Elavil), clomipramine (Anafranil), and imipramine (Tofranil), so the doses of these drugs may need to be lower than usual.

If nefazodone is combined with one of the SSRIs, there is the possibility that a metabolite of nefazodone called mCPP (m-chlorophenylpiperazine) could build up in your blood. This substance may lead to agitation or feelings of panic or unhappiness. If you are switching from an SSRI to nefazodone, mCPP could also build up because the effects of the SSRIs can persist in your body for several weeks after you stop taking them. Neither trazodone nor nefazodone should be combined with an MAOI antidepressant because this combination could trigger the serotonin syndrome (hyperpyretic crisis) described previously.

If you are taking nefazodone, make sure you inform your psychiatrist about any blood-pressure medication you are taking, and inform your general medical doctor as well. Your blood pressure may drop more than expected if you combine trazodone with a blood-pressure medication. If your blood pressure does drop too much, you may notice dizziness when you suddenly stand up. Many psychiatric medications can also lower the blood pressure, including many of the tricyclic antidepressants as well as a number of the major tranquilizers (neuroleptics). If these drugs are combined with trazodone or nefazodone, the drop in blood pressure may be pronounced.

Trazodone can also cause increased blood levels of the anticonvulsant, phenytoin (Dilantin) as well as the heart medication, digoxin (Lanoxin). These combinations can lead to toxic blood levels of phenytoin or digoxin. Make sure your doctor monitors your blood levels of phenytoin or digoxin carefully if you take trazodone, as excessively high levels can be dangerous.

The effects of trazodone on the blood thinner, warfarin (Coumadin) are unpredictable. The levels of warfarin may
increase or decrease. If the warfarin levels increase, you may have a greater tendency to bleed, and if the warfarin decreases, your blood may have a greater tendency to clot. Your doctor can monitor any changes with blood tests and adjust the dose of warfarin if necessary.

Even more dangerous are the previously described interactions between nefazodone and two commonly prescribed antihistamines that are given for allergies (terfenadine, trade name Seldane) and astemizole (trade name Hismanal). Nefazodone causes the levels of these two antihistamines to increase, which can result in potentially fatal changes in heart rhythms. Nefazodone should not be combined with cisapride (trade name Propulsid, a stimulant for the gastrointestinal tract) for the same reason—sudden fatal heart failure can result.

Three other types of antidepressant drugs are listed in the Table of Antidepressants on pages 514–515. These include bupropion (Wellbutrin), venlafaxine (Effexor), and mirtazapine (Remeron). They are somewhat different from each other and from the antidepressants already discussed.