Feeling Good: The New Mood Therapy (57 page)

We can imagine several different ways that antidepressant drugs could influence the receptors on the presynaptic and postsynaptic nerves. For the purpose of this discussion, imagine that the transmitter used by the presynaptic nerve is serotonin, but the same considerations apply to any transmitter. What would happen if we blocked the receptors on the reuptake pump? The presynaptic nerve could no longer pump the serotonin from the synapse back inside. Each time the nerve fired, more and more serotonin would be released into the synaptic region. As a result, the synapse would get flooded with serotonin.

This is precisely how most of the currently prescribed antidepressants work. As you can see in Figure 17–5 on page 449, they block the receptors for the reuptake pumps on presynaptic nerves, and so the transmitters build up in the synaptic region. The end result of this process is similar to the effects of giving the MAOI drugs discussed above. In both instances, the levels of serotonin build up in the synaptic region. When the presynaptic nerve fires, more serotonin than normal will “swim” to the postsynaptic nerve and stimulate it to fire. Once again, we have “turned up” the serotonin system, so to speak.

Is this good? Is this why these antidepressant drugs can improve our moods? That’s the current theory, but no one really knows the answers to this question yet.

Different antidepressants block different amine pumps and some of them have more specific effects than others. The older “tricyclic” antidepressants, such as amitriptyline (Elavil) or imipramine (Tofranil) and others, block the reuptake pumps for serotonin and norepinephrine. (Tricyclic means “three wheels,” like a tricycle, because the chemical structure of these drugs resembles three linked rings.) Therefore, these transmitters build up in the brain if you take one of these drugs. Some tricyclic antidepressants have relatively stronger effects on the serotonin pump, and some of them have relatively stronger effects on the norepinephrine pump. Drugs with stronger effects on the serotonin pump are called “serotonergic” and drugs with relatively stronger effects on the norepinephrine pump are called “noradrenergic.” What do you think we would call a drug with a strong effect on the dopamine pump? If you guessed “dopaminergic,” you would be correct!

Figure 17–5
. Most antidepressants block the reuptake pumps, so serotonin remains in the synapse after the nerve fires. Because serotonin builds up in the synaptic region, the stimulation of the postsynaptic nerve is stronger.

Some of the newer antidepressants, such as fluoxetine (Prozac), differ from the older tricyclic compounds in that they have highly selective and specific effects on the serotonin pump. If we want to use one of our new words, we can say that Prozac is highly “serotonergic” because levels of serotonin will build up in the brain when you take it. However, because Prozac blocks only the serotonin pump, the levels of other transmitters, such as norepinephrine and
dopamine, will not build up. Prozac is classified as a selective serotonin reuptake inhibitor (SSRI for short) because of its selective and specific effects on the serotonin pump. Again, SSRI is an intimidating name with a humble meaning. SSRI means, “this drug blocks only, the serotonin pump and it doesn’t block any other pumps.” Five SSRls are currently prescribed in the United States and I will discuss them in detail in Chapter 20.

Some new antidepressants are not so selective—they block more than one type of reuptake pump. For example, venlafaxine (Effexor) blocks the serotonin and norepinephrine pumps, so it has been called a dual reuptake inhibitor. The drug company that manufactures venlafaxine promotes the idea that this drug may be more effective because the levels of two transmitters (serotonin and norepinephrine) increase, rather than just one. Actually, this is not such a novel feature. As you just learned, most of the older (and much cheaper) antidepressants do exactly the same thing. In addition, there is no evidence that venlafaxine works any better or any faster than the older drugs. However, venlafaxine has fewer side effects than some of the older tricyclic antidepressants. This might justify the increased cost of venlafaxine in some instances.

So far you have learned about the MAOIs and the pump inhibitors, such as the tricyclics and the SSRIs. Are there any other ways that antidepressant drugs might work? If you were a chemist working for a drug company and you wanted to create a completely novel antidepressant, what kinds of effects would your new drug have? One possibility would be to create a drug that directly stimulated the serotonin receptors on the postsynaptic nerves. A drug like this would mimic the effect of the natural serotonin. It would be a kind of counterfeit serotonin. Buspirone (BuSpar) works like this. This drug directly stimulates serotonin receptors on postsynaptic nerves. Buspirone was marketed a number of years ago as the first nonaddictive drug for anxiety, but it also has some mild antidepressant effects. However, its antidepressant and antianxiety properties are not especially strong. As a result, buspirone has not emerged as a particularly popular drug for anxiety or depression.

Figure 17–6
. Serotonin antagonists block the serotonin receptors on the postsynaptic nerve, so the serotonin cannot stimulate the postsynaptic nerve after the presynaptic nerve fires.

Why is it that buspirone is not more effective for depression? Scientists don’t actually know the answer. Remember, though, that there are at least fifteen different kinds of serotonin receptors throughout the brain. All of these receptors have different functions that are not yet fully understood. Perhaps drugs that stimulated different kinds of serotonin receptors would have stronger antidepressant effects. As you might have gathered, things get complicated fairly quickly as we learn more and more about how the brain works.

If you were a drug company chemist, you could also create drugs that blocked the serotonin receptors on the postsynaptic nerves, as illustrated in Figure 17–6 above. Because such drugs would prevent the natural serotonin from having its effects, they would theoretically make depression worse. In fact, drugs that block serotonin receptors have been created. Two of them are called nefazodone (Serzone) and trazodone (Desyrel). Although they are categorized
as “serotonin antagonists,” these drugs are also used as antidepressants.

Some drugs have complex effects on several kinds of pre- and postsynaptic nerve receptors. Mirtazapine (Remeron) is another new antidepressant that has been available in the United States since 1996. Mirtazapine appears to block serotonin receptors on the postsynaptic nerves, but it also stimulates receptors on presynaptic nerves that use norepinephrine as a transmitter. This causes an increase in the release of norepinephrine by these nerves. So when you take mirtazapine, the serotonin system gets turned down and the norepinephrine system gets turned up.

The antidepressant effects of nefazodone, trazodone, and mirtazapine are exactly the opposite of what you might predict from the serotonin theory. Although they turn the serotonin system off, they are antidepressants. How can this be possible? If you are starting to get confused, join the club! Remember that there are many types of serotonin receptors in the brain and they all have different kinds of effects. Remember, too, that there are many high-speed and complex interactions among the different circuits in the brain. When we perturb one system of nerves in one region of the brain, we almost instantly create changes in thousands or millions of other nerves in other regions of the brain. In the final analysis, even the world’s top neu-roscientists do not have a very clear understanding of why or how these drugs relieve depression.

In summary, most of the currently prescribed antidepressants have effects on the serotonin, norepinephrine, or dopamine systems. Some of them are highly selective for one transmitter system, and others have effects on many transmitter systems. However, the effects of the currently prescribed antidepressants on these three systems do not really account for their beneficial effects in a very consistent or convincing way. For example, you have learned that some antidepressants stimulate serotonin levels, some of them block serotonin receptors, and some of them seem to have no effects at all on serotonin. And yet they all work about
equally well. Clearly, the models I have drawn in Figures 17–4 to 17–6 are overly simplified, and current theories about how antidepressant medications work appear to be incomplete at best

I do not mean to sound overly negative. Keep in mind that I am not challenging the effectiveness of the currently prescribed antidepressant drugs; I am simply saying that our theories about how these drugs work do not account for all the facts.

Fortunately, most neuroscience researchers now acknowledge this. The focus of research has expanded greatly. Instead of focusing narrowly on levels of one or another biogenic amine, researchers are pursuing a wide variety of strategies which focus on regulatory mechanisms throughout the brain, and new theories have been proposed. These theories deal with other transmitters in the brain, or with a variety of pre- or postsynaptic receptors, or with “second messenger” systems within the nerves, or with ion flux across nerve membranes, as well as with neuroendocrine systems, immune systems, and biological rhythm abnormalities. I believe the wider net that has now been cast will eventually lead to much better understanding of how the brain regulates moods.

Sophistication in brain research has accelerated tremendously and will accelerate even more rapidly in the next decade. This research will hopefully lead to improvements such as these:

Although our current level of understanding is still primitive, an important scientific effort has been launched. One day this effort may even lead us to the identification of the mysterious “black bile.”

(
Notes and References appear on pages 682–687.
)

Ever since the time of the French philosopher, René Descartes, scholars have been puzzled by the “mind-body problem.” This is the idea that as human beings we have at least two separate levels of existence—our minds and our bodies. Our minds consist of our thoughts and our feelings, which are invisible or ethereal. We know they are there because we can experience them, but we do not know why or how they exist.

In contrast, our bodies consist of tissue—blood, bones, muscle, fat, and so forth. The tissue ultimately consists of molecules, and the molecules are ultimately made up of atoms. These building blocks are inert—presumably, atoms have no consciousness. So how can the inert tissue in our brains give rise to our conscious minds, which can see, feel, hear, love, and hate?

According to Descartes, our minds and bodies must be connected in some manner. Descartes called the portion of the brain that links these two separate entities the “seat of the soul.” For centuries, philosophers have tried to locate the “seat of the soul.” In the modern era, neuroscientists continue this search as they attempt to figure out how our brains create emotions and conscious thoughts.

The belief that our minds and bodies are separate is reflected
in our treatments for problems such as depression. We have biological treatments, which work on the “body,” and psychological treatments, which work on the “mind.” Biological treatments usually involve medications, and psychological treatments usually involve some type of talking therapy.