Feeling Good: The New Mood Therapy (69 page)

^a
Information in this table was obtained from several sources including the
Manual of Clinical Psychopharmacology
¹
and
Psychotropic Drugs Fast Facts
.
¹⁷
These excellent references are highly recommended.

^b
This is a dangerous and potentially fatal syndrome which includes rapid changes in vital signs (fever, oscillations in blood pressure), sweating, nausea, vomiting, rigid muscles, myoclonus, agitation, delirium, seizures, and coma.

Currently, the most popular antidepressant drugs are the selective serotonin reuptake inhibitors, or SSRIs. At this time, five SSRIs are prescribed in the United States. These include citalopram (Celexa), the newest SSRI which was released in the U.S. in 1998, fluoxetine (Prozac), the first SSRI which was released in 1988, and fluvoxamine (Luvox), paroxetine (Paxil), and sertraline (Zoloft). The effects of these SSRIs on the brain are much more specific and selective than the older tricyclic and tetracyclic drugs discussed above. Instead of interacting with many different systems in the brain, these drugs have selective effects on nerves that use serotonin as a transmitter substance.

When it first appeared on the market, there was a great deal of excitement about Prozac because it was chemically
quite different from the older antidepressants. Unlike the tricyclic and tetracyclic drugs, it has specific effects on the serotonergic nerves in the brain. Since a serotonin deficiency was hypothesized to be the cause of depression, it was hoped that Prozac would be dramatically more effective than the tricyclic and tetracyclic drugs which seemed to affect so many different systems in the brain in a less specific manner. It was also expected that Prozac (and the other SSRIs) would have fewer side effects than the tricyclic and tetracyclic drugs. This is because Prozac does not have such strong effects on the histaminic, alpha-adrenergic, and muscarinic receptors.

Only one of these two hopes was fulfilled. Prozac and the other four SSRIs do cause significantly fewer side effects than the tricyclic and tetracyclic antidepressants and are more pleasant to take. For example, they are less likely to cause sleepiness, weight gain, dry mouth, dizziness, and so on. They are also much safer since they are less likely to have adverse effects on the heart, and they are much less likely to result in death if a patient intentionally or unintentionally takes an overdose. The biochemists who created these new drugs deserve credit in this regard.

Unfortunately, the SSRIs are not more effective than the older drugs. As many as 60 percent to 70 percent of depressed patients will improve when treated with SSRIs, and these percentages are no better than the older drugs. Among chronically depressed patients, the probability of responding appears to be lower. The SSRIs also appear to be slightly less effective than the older tricyclic antidepressants for more severely depressed patients. In addition, the amount of improvement is often only partial—the patient may become less depressed, but may not return to full self-esteem and joyous daily living. This is a problem for all the antidepressants, and not just the SSRIs. Although they are no more effective, the SSRIs are dramatically more expensive than the older drugs. In addition, the SSRIs have some new and different side effects described below that were not publicized when they were first released.

Because of their favorable safety record and diminished side effects, though, the SSRIs have truly captured the antidepressant market. More money was spent on Prozac in 1995 ($2.5 billion) than was spent on all other antidepressants in 1991 ($2.0 billion). One reason for the upsurge in popularity is that primary care physicians now feel comfortable prescribing antidepressants because the SSRIs are so safe. As a result, many depressed patients who would not think of going to a psychiatrist or psychologist receive SSRIs from their family physicians.

Because the SSRIs are used so widely and because they have received so much media attention, many people believe they are incredibly powerful and almost magically effective. But this is simply not the case, as noted above. For some depressed people, the SSRIs can be very effective. For many others, they are only somewhat effective. And often they do not seem to have any antidepressant effects at all. It is the same story with all of our currently available antidepressants—they are valuable tools to fight depression but they are often not the entire answer and they are certainly not a panacea for what ails you.

The fact that the SSRIs are not more effective than the older drugs has caused scientists to reconsider the validity of the “serotonin” theory of depression which I described in Chapter 17. You will recall that according to this theory, a deficiency of serotonin in the brain causes depression, and an increase in serotonin should reverse it. If this theory were valid, the SSRIs should cause depressed patients to become undepressed almost immediately—but Prozac can take as many as five to eight weeks to become effective. Regardless of what causes depression or why antidepressants work, the SSRIs have been helpful to many depressed individuals.

Doses of SSRIs
. The doses of the five SSRIs are listed in Table 20–1 on page 520. Unlike the older antidepressants, which are often prescribed in doses that are too low, the SSRIs are often prescribed in doses that are unnecessarily high. Because they have so few side effects, doctors
feel comfortable prescribing high doses and may prescribe more than is really needed. For example, although 20 mg to 80 mg per day was the dose range initially recommended for Prozac, a single dose of 10 mg per day will be sufficient for many patients. Once they are feeling better, many patients need only 5 mg per day, or even less. These smaller doses are much less expensive and will produce fewer side effects.

These low doses are effective because Prozac stays in the body for a much longer period of time than most other drugs—as long as several weeks. When you take Prozac, your blood level continues to increase each day because the Prozac leaves your body so slowly. After a while your blood level becomes quite high. This is why you may need only a tiny dose if you have been taking Prozac for several weeks or more.

To understand this better, let’s go back to the bathtub analogy I introduced in Chapter 19 to explain drug interactions. Let’s imagine that the Prozac you are taking is like the water going into the bathtub, but the hole in the bottom of the tub is tiny. Over time, the water level increases, because more water goes into the tub than goes out. The water level can be compared to the level of the Prozac in your blood. After four to five weeks, the water level finally gets up to the correct therapeutic range. Now you can turn the faucet down quite a bit so that the level in the tub does not continue to increase and overflow. This would be analogous to reducing the dose of Prozac after you have been on it for several weeks. Paradoxically, you are now taking much smaller doses than when you first started taking the Prozac, but your blood level is far higher.

Technically, we say that “steady state” has been reached. Steady state means that the blood level remains more or less constant, because the amount you take each day is similar to the amount that your body eliminates each day. The other four SSRIs do not have this property, because they leave the body much faster than Prozac. You generally cannot reduce the doses after several weeks.

The effectiveness of very low doses of Prozac is now
well known among the psychiatric profession, but I first learned this from my patients soon after Prozac was released onto the market. Many patients reported that after they had been on Prozac for a month or two, they seemed to need only tiny doses, often as little as one tenth of a pill per day, and sometimes even less. At first I thought these patients had overly lively imaginations, but soon many patients were reporting the same thing. I advised them to take one Prozac pill, grind it up, and dissolve it in water or apple juice to store in the refrigerator. Then they adjusted their dose of Prozac by drinking a certain amount of the fluid each day. So, for example, if you have dissolved one 20 mg pill in some apple juice and you drink one tenth of the juice each day, this would correspond to a dose of 2 mg per day. But if you try this, make sure you label the juice clearly so that no one drinks your Prozac for breakfast! Also, make sure you talk it over with your doctor and that she or he approves of what you are doing.

It is also important for you to know that after you stop taking Prozac, it will stay in your body for a long time because it leaves your body so slowly. This would be like a bathtub that takes an extraordinarily long time to empty out after you pull the plug because the drain is plugged up. After you are no longer taking the Prozac, significant levels will remain in your blood for as many as five weeks or more before the drug is entirely cleared out of your system. Many medications can be dangerous to mix with Prozac. You must not take these specific medications until you have been off the Prozac entirely for at least five weeks. For example, tranylcypromine (Parnate) is an antidepressant known as an MAO inhibitor that will be discussed below. Tranylcypromine (as well as other MAO inhibitors) can cause dangerous and potentially fatal reactions if mixed with Prozac. After you stop taking Prozac, a delay of at least five to eight weeks will be necessary before you can safely start taking tranylcypromine.

The other SSRIs, such as citalopram (Celexa), fluvoxamine (Luvox), sertraline (Zoloft) and paroxetine (Paxil), leave the body more rapidly than Prozac but they are still
metabolized rather slowly. For example, if you stop taking one of these drugs, it will take your body approximately one day to get rid of one half of the amount in your body. It will take approximately four to seven days for most or all of the drug to leave your body. This is much faster than Prozac. Therefore, these other SSRIs drugs do not build up to such high levels in your blood after you have been taking them for more than a few weeks. Because they go in and out of your blood more rapidly, they are usually taken several times per day, whereas Prozac can be taken once a day.

Age can also influence your dose requirements if you are taking an SSRI. For example, levels of citalopram (Celexa), fluoxetine (Prozac), and paroxetine (Paxil) are approximately twice as high in older individuals (over 65 years of age) than in younger individuals. If you are taking one of these drugs and you are over 65, you will need a lower dose. Blood levels of sertraline (Zoloft) are also higher in older individuals, although the differences are not as pronounced. In contrast, fiuvoxamine (Luvox) blood levels do not seem to be affected by age.

Sometimes gender can play a role as well. For example, the blood levels of fluoxetine (Prozac) are 40 percent to 50 percent lower in males than in females. Similarly, young men develop blood levels of sertraline (Zoloft) that are 30 percent to 40 percent lower, on the average, than young women. Men may need relatively higher doses of these drugs, whereas women may need relatively lower doses.

Health problems can also influence your dose requirements. Individuals with liver, kidney, or heart disease may not get rid of SSRIs as rapidly, and so smaller doses may be needed. Make sure you ask your doctor about this if you are being treated for a liver, kidney or heart ailment.

Side Effects of SSRIs
. The most frequent side effects of the five SSRIs are listed in Table 20–5 on pages 553–554. As noted above, the side effects of the SSRIs are milder than the older drugs, and this is the reason for their enormous popularity. They are less likely than the tricyclic antidepressants to cause dry mouth, constipation, or dizziness. They do not stimulate the appetite when you first start taking them; if anything, some patients taking SSRIs lose weight in the beginning. Unfortunately, when the SSRIs are taken for a prolonged period of time, their side effects sometimes increase. For example, some patients taking these agents report increases in appetite and weight gain after a while, even though they lost weight at first.

Table 20–5.
Side Effects of SSRI Antidepressants

Note
: This table was adapted with permission from Preskorn
²³
and from the prescribing information for citalopram. Only the more common side effects of each drug are listed. The numbers in the table represent the percent of patients receiving the drug who reported each side effect minus the percent of patients on placebo who reported the same side effect. For example, if 20% of patients on Prozac reported nervousness as a side effect, while 10% of patients on placebo reported this same side effect, the number 10% would appear in this chart. This would be an estimate of the “true” nervousness actually caused by Prozac. For each side effect, the drug or drugs with the highest percentages are indicated in boldface.