Feeling Good: The New Mood Therapy

by Burns, David D.

  Again, these are big words with simple meanings. “Up-regulation” means “more receptors,” and “down-regulation” means “fewer receptors.” We could also say that up-regulation means turning the system up, and down-regulation means turning the system down—just like a radio.

  It is known that antidepressant drugs usually require several weeks or more to become effective. Researchers have been trying to figure out why. Some researchers have speculated that down-regulation may account for the antidepressant effects of these drugs. In other words, antidepressants may work not because they boost the serotonin system, as originally proposed, but because they turn the serotonin system down after several weeks. This would imply that decreased serotonin levels might not be the cause of depression after all. Depression might instead be due to increased serotonin activity in the brain. Antidepressant drugs may correct this after several weeks because they turn the serotonin system down.

  How well established and proven are these theories? Not at all. As I have suggested, it is awfully easy to make up a theory, but much harder to prove it. To date, it has not been possible to validate or disprove any of these theories in a convincing way. In addition, there are no clinical or laboratory tests we could give to groups of patients or to individual patients that will reliably detect any chemical imbalance that causes depression.

  The main value of the current theories is to stimulate research so that our knowledge of brain function will become more sophisticated over time. Eventually, I believe we will develop much more refined theories and far better tools for testing them.

  Now you may be thinking, “Is that all there is to it?” Do scientists just sit around and say, “Depression could be due to an excess or a deficiency of this or that transmitter or receptor in the brain?” On some level, that really is all there is to it. Part of the problem is that our models of the brain are still very primitive, and so our theories of depression are not yet very sophisticated either.

  It may turn out that depression is not due to problems with any transmitter chemical or receptor. We may one day discover that depression is actually more of a “software” problem, and not a “hardware” problem. In other words, if you have a computer, you know that computers crash all the time. Sometimes this results from a problem with the hardware. For example, your hard drive may become defective. But more often, there’s a problem with the software—a bug that makes the program work poorly in certain situations. So with regard to brain research on depression, we may be looking for a problem in the “hardware” (for example, a chemical imbalance we are born with) whereas the real problem is in the “software” (for example, a negative thinking pattern based on learning). Both kinds of problems would be “organic,” since brain tissue is involved, but the solutions to them would be radically different.

  Another major problem facing depression researchers is the chicken-versus-the-egg dilemma. Are changes we measure in the brain the cause of the depression or the result? To illustrate this problem, let’s conduct a thought experiment involving a deer in a forest. The deer is happy and contented. Imagine that we have a special machine that allows us to visualize the chemical and electrical activity in the deer’s brain. We might have, for example, a futuristic portable brain imaging machine that can work from a distance, like the laser guns the police use to see how fast you’re driving. However, the deer does not know we are monitoring its brain activity. Suddenly, the deer spots a pack of hungry wolves approaching. Panic strikes! Our brain imaging machine detects instantaneous massive changes in the electrical and chemical activity in the deer’s brain. Are these chemical and electrical changes the cause of the fear or the result of the fear? Would we say the deer is afraid because it has developed a sudden “chemical imbalance” in its brain?

  Similarly, there are all kinds of chemical and electrical changes in the brains of depressed patients. Our brains change quite dramatically when we feel happy, angry, or frightened. Which brain changes result from the strong emotions we feel, and which brain changes are the causes? Separating cause from effect is one of the thorniest challenges facing depression researchers. This problem is not impossible to solve, but it is not easy, and those eager to endorse the current theories about depression do not always acknowledge it.

  Clearly, the research necessary to test any of these theories can be daunting. One significant problem is that it is still very difficult to get accurate information about the chemical and electrical process in the human brain. We can’t just open up the brain of a depressed individual and look inside! And even if we could, we really wouldn’t know where or how to look. But new tools, such as PET (positron emission tomography) scanning and MRI (magnetic resonance imaging), do make such research possible. For the first time, scientists can begin to “see” the activity of nerves and chemical processes inside the brains of human beings. This research is still in its infancy, and we can look forward to a great deal of progress in the next decade.

  How Do Antidepressant Drugs Work?

  The modern era of research on the chemistry of depression got a big boost accidentally in the early 1950s when researchers were testing a new drug for tuberculosis called iproniazid.1 As it turned out, iproniazid was not an effective treatment for tuberculosis. However, the investigators noticed pronounced mood elevations in a number of patients who received this drug, and hypothesized that iproniazid might have antidepressant properties. This led to an explosion of research by drug companies who wanted to be the first to develop and market antidepressant drugs.

  Researchers knew that iproniazid was an inhibitor of the MAO enzyme discussed previously. The drug was therefore categorized as an MAO inhibitor, or MAOI for short. Several new MAOI drugs that were similar in chemical structure to iproniazid were developed. Two of them, phenylzine (Nardil) and tranylcypromine (Parnate), are still in use today. A third MAOI called selegiline (trade name Eldepryl) has been approved for the treatment of Parkinson’s disease. This drug is also occasionally used in the treatment of mood disorders. Odier new MAOIs in use abroad may eventually be marketed in the United States.

  The MAOIs are no longer prescribed nearly as frequently as they used to be. This is because they can cause dangerous elevations of blood pressure if the patient combines them with certain foods such as cheese. The MAOIs can also cause toxic reactions when combined with certain drugs. Because of these hazards, newer and safer antidepressants have been developed. These new drugs work quite differently from the MAOIs. Nevertheless, the MAOIs can be extremely helpful for some depressed patients who do not respond to other medications, and they can be used safely if the patient and doctor follow a number of guidelines that I will spell out in Chapter 20.

  The iproniazid discovery helped to usher in a new era of biological research on depression. Scientists were eager to find out how the MAOIs worked. It was known that the MAOIs prevented the breakdown of serotonin, norepinephrine, and dopamine, the three chemical messengers that are concentrated in the limbic regions of the brain. Scientists hypothesized that a deficiency in one or more of these substances might cause depression and that antidepressant drugs might work by increasing the levels of these substances. This is how the biogenic amine theories actually originated.

  Now let’s see how much you’ve learned about how the brain works. Look at Figures 17–1 to 17–3 again. When the presynaptic nerve fires, serotonin is released into the synapse. After it attaches to a receptor on the postsynaptic nerve, it swims back to the presynaptic nerve, where it is pumped back inside this nerve and destroyed by the MAO enzyme. Now ask yourself this question: What would happen if we prevented the MAO enzyme from destroying the serotonin?

  As you have probably guessed, the serotonin would accumulate in the presynaptic nerve, because this nerve is always manufacturing new serotonin. If this nerve could not get rid of its serotonin, the concentration of serotonin in the nerve would continue to increase. Whenever the presynaptic nerve fired, it would release much more serotonin than usual into the fluid-fil
led synaptic region. The excess serotonin in the synapse would cause a greater-than-expected stimulation of the postsynaptic nerve. This would be the chemical equivalent of turning up the volume on the radio. These effects of the MAOI antidepressants are illustrated in Figure 17–4 on page 446.

  Could this be the reason the MAOI drugs cause a mood elevation? This is possible, and scientists have hypothesized that this is exactly how these MAOI drugs work. Research studies have confirmed that when these MAOI drugs are given to humans or animals, brain levels of serotonin, norepinephrine, and dopamine do increase. However, it is not known for certain if the antidepressant effects result from an increase in one of these biogenic amines, or from some other effect of these drugs on the brain.

  Can you think of another theory about why or how these MAOI drugs might work? Does the increase in mood have to result from the extra stimulation of the postsynaptic nerve, or could there be another possible explanation? Think about what you read about down-regulation in the previous section and see if you can come up with an answer before you read any further.

  Figure 17–4. MAOIs block the MAO enzyme inside the presynaptic nerve, so serotonin levels increase. The excess serotonin is released into the synaptic region whenever the nerve fires. This provides a stronger stimulation of the postsynaptic nerve.

  You probably recall that the effects on the postsynaptic nerves after several weeks can be the opposite of the effects on these nerves when you first take a drug. All the extra serotonin in the synapse may cause a down-regulation of the postsynaptic serotonin receptors after several weeks, and this down-regulation may correspond to the antidepressant effects. (Remember that although some scientists think depression results from a serotonin deficiency, others believe depression results from increased brain serotonin activity.) If you thought of this, it shows you are really learning your neurochemistry. You get an A-plus on this pop quiz!

  If you said that the antidepressant effects of the MAOI drug could result from effects on some other system in the brain, you also get an A-plus. These theories about how the antidepressant drugs relieve depression are not proven facts. The effects of the MAOIs on the brain are vastly more complex than the simple model depicted in Figure 17–4. The effects of any antidepressant are probably not limited to one specific region or one specific type of nerve in the brain. Remember that each nerve in the brain connects with many thousands of other nerves, and all of them in turn connect with thousands of others. When you take an antidepressant, there are massive changes in numerous chemical and electrical systems throughout your brain. Any of these changes could be responsible for the improvement in your mood. Trying to figure out exactly how these drugs work is still a little like looking for a needle in a haystack. But the important thing for the moment is that these drugs do seem to help some depressed patients, regardless of how or why they work.

  As I have mentioned, many new and different kinds of antidepressant drugs have been developed and marketed since the 1950s. Unlike the MAOIs, the newer antidepressants do not cause a buildup of transmitters like serotonin in the presynaptic nerve depicted in Figure 17–4. Instead, they mimic the effects of the brain’s natural transmitter substances by attaching to receptors on the surfaces of the presynaptic or postsynaptic nerves.

  To understand how these newer antidepressants can do this, remember our analogy of the lock and the key. A natural transmitter substance is like a key, and the receptor on the surface of the nerve is like a lock. The key is able to unlock the lock only because it has a certain shape. But if you were a magician, like the famous Harry Houdini, you could easily pick the lock and open it without the key.

  An antidepressant medication is like a counterfeit key that a drug company has manufactured. Because the chemists know the three-dimensional shape of a natural transmitter like serotonin, norepinephrine, or dopamine, they can create new drugs that have a very similar shape. These drugs will fit into the receptors on the surfaces of nerves and mimic the effects of the natural transmitters. The brain does not know that an antidepressant is in the lock—the brain has been tricked into thinking that the natural transmitter chemical is attached to the receptor on the surface of the nerve.

  In theory, the artificial key (the antidepressant) can do one of two things when it becomes attached to the receptor. It can either open the lock, or it can jam the lock without actually opening it. Drugs that open the locks are called “agonists.” Agonists are simply drugs that mimic the effects of the natural transmitters. Drugs that jam up these locks are called “antagonists.” Antagonists block the effects of the natural transmitters and prevent them from being effective.

  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) b
locks 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.