Feeling Good: The New Mood Therapy

by Burns, David D.

  • intense euphoria, often with irritability;

  • incredible energy with constant exercising or restless, agitated body movements;

  • very little need for sleep;

  • nonstop, pressured talking;

  • racing thoughts that skip from subject to subject;

  • grandiose delusions (for example, the sudden belief that one has a plan for world peace);

  • impulsive, reckless, and inappropriate behaviors (such as spending money foolishly);

  • inappropriate, excessive flirtatiousness and sexual activity;

  • hallucinations (in severe cases).

  These symptoms are usually unmistakable and often so uncontrollable that the patient may require hospitalization with medication treatment. Following recovery, the individual usually returns to absolutely normal functioning again. These distinct features of bipolar illness make genetic research relatively straightforward, since it is usually not difficult to determine when individuals have the disorder and when they do not. In addition, this disorder usually begins fairly early in life, with the first episode often occurring by the age of twenty to twenty-five.

  In contrast, the diagnosis of depression is much less obvious. Where does normal sadness end and clinical depression begin? The answer is somewhat arbitrary, but the decision will have a big impact on the results of research. Another difficult question genetic researchers face is this: How long should we wait before we decide whether or not a person has developed a clinical depression during his or her life? Suppose, for example, that an individual with a strong family history of depression dies in an auto accident at the age of twenty-one without ever having had an episode of clinical depression. We might conclude that she or he did not inherit the tendency for depression. But if that individual had not died, she or he might have developed an episode of depression later on in life, since a first episode of depression can often occur when you are older than twenty-one.

  Problems like this are not insurmountable, but they do make genetic research on depression difficult. In fact, many previously published studies on the genetics of depression are quite flawed and do not permit us to make any unambiguous conclusions about the importance of heredity versus environment in this disorder. Fortunately, more sophisticated studies are now under way, and we may have better answers to these questions during the next five to ten years.

  Is Depression Caused by a “Chemical Imbalance” in the Brain?

  Throughout the ages, humans have searched for the causes of depression. Even in ancient times there was some suspicion that blue moods were due to an imbalance in body chemistry. Hippocrates (460–377 B.C.) thought that “black bile” was the culprit. In recent years scientists have spearheaded an intensive search for the elusive black bile. They have tried to pinpoint the imbalances in brain chemistry that might cause depression. There are hints about the answer, but in spite of increasingly sophisticated research tools, scientists have not yet discovered the causes of depression.

  At least two major arguments have been advanced to support the notion that some type of chemical imbalance or brain abnormality may play a role in clinical depression. First, the physical (somatic) symptoms of severe depression support the notion that organic changes might be involved. These physical symptoms include agitation (increased nervous activity such as pacing or hand-wringing) or enormous fatigue (motionless apathy—you feel like a ton of bricks and do nothing). You also may experience a “diurnal” variation in your mood. This refers to a worsening of the symptoms of depression in the morning and an improvement toward the end of the day. Other physical symptoms of depression include disturbed sleep patterns (insomnia is the most common), constipation, changes in appetite (usually decreased, sometimes increased), trouble concentrating, and a loss of interest in sex. Because these symptoms of depression “feel” quite physical, there is a tendency to think that the causes of depression are physical.

  A second argument for a physiologic cause for depression is that at least some mood disorders seem to run in families, suggesting a role for genetic factors. If there is an inherited abnormality that predisposes some individuals to depression, it could be in the form of a disturbance in body chemistry, as with so many genetic diseases.

  The genetic argument is interesting but the data are inconclusive. The evidence for genetic influences in bipolar manic-depressive illness is much stronger than the evidence for genetic influences in the more common forms of depression that afflict most people. In addition, lots of things that do not have genetic causes run in families. For example, families in the United States nearly always speak English, and families in Mexico nearly always speak Spanish. We can say that the tendency to speak a certain language also runs in families, but the language you speak is learned and not inherited.

  I don’t mean to discount the importance of genetic factors. Recent studies of identical twins who were separated at birth and raised in different families show that many traits we think of as being learned are actually inherited. Even such personality traits as a tendency toward shyness or sociability appear to be partly inherited. Personal preferences, such as liking a particular flavor of ice cream, may also be strongly influenced by our genes. It seems plausible that we may also inherit a tendency to look at things either in a positive, optimistic way or in a negative, gloomy way. Much more research will be needed to sort out this possibility.

  How Does the Brain Work?

  The brain is essentially an electrical system that is similar in some ways to a computer. Different portions of the brain are specialized for different kinds of functions. For example, the surface of the brain toward the back of your head is called the “occipital cortex.” This is where vision takes place. If you had a stroke mat affected this region of the brain, you would have trouble with your vision. A small region on the surface of the left half of your brain is called “Broca’s area.” This is the part of your brain that allows you to talk to other people. If this part of your brain were injured by a stroke, you would have difficulty talking. You might be able to think of what you wanted to say, but find that you had “forgotten” how to speak the words. A primitive part of your brain called the “limbic system” is thought to be involved in the control of emotions such as joy, sadness, fear, or anger. However, our knowledge of where and how the brain creates positive and negative emotions is still very limited.

  We do know that nerves are the “wires” that make up the electrical circuits in the brain. The long thin part of a nerve is called the “axon.” When a nerve is stimulated, it sends an electrical signal along the axon to the end of the nerve. A nerve is much more complex than a simple wire, however. For example, a nerve may receive input from tens of thousands of other nerves. Once it is stimulated, its axon may send out signals to tens of thousands of other nerves.

  Figure 17–1. When the presynaptic nerve fires, packets of serotonin molecules (neurotransmitters) are released into the synapse. They swim over to the receptors on the surface of the postsynaptic nerve.

  This is because the axon can divide and send out many branches. Each of these branches also divides into even more branches, in much the same way that the trunk of a tree divides into more and more branches. Because of this branching tendency, a single nerve in the brain may send out signals to as many as 25,000 other nerves that are located throughout the entire brain.

  How do the nerves in your brain communicate their electrical signals to other nerves? To understand this, take a look at Figure 17–1 above. You can see a simplified diagram of two nerves. The region where they meet is called the “synapse.” You may not be familiar with that term, but don’t feel intimidated by it. It just means the space between two nerves. The left-hand nerve is called the “presynaptic nerve” and the right-hand nerve is called the “postsynaptic nerve.” Again, these terms do not have any other fancy or special meanings. They merely refer to the nerve that ends (presynaptic nerve) or begins (postsynaptic nerve) on the left or right edge of the synap
se in the figure.

  The communication of the electrical signal across this synapse is important to our understanding of how the brain works. The synaptic region between the presynaptic nerve on the left and the postsynaptic nerve on the right is filled with fluid. This discovery was a major breakthrough in the history of neuroscience. When you think of it, this discovery is not so surprising since our bodies are made up primarily of water. However, scientists were puzzled because they knew that the electrical impulses of nerves were too weak to travel across the synaptic fluid. So how does the presynaptic nerve on the left in Figure 17–1 send its electrical signal across the fluid-filled synapse to the postsynaptic nerve?

  As an analogy, imagine that you are hiking and you come to a river. You really need to get to the other side, but the water is too deep. Furthermore, there’s no bridge and it’s too far to jump. How do you get to the other side? You might need a canoe, or you might have to swim for it.

  Nerves face a similar problem. Because their electrical impulses are too weak to jump across synapses, the nerves send little swimmers across with their messages. These little swimmers are chemicals called “neurotransmitters.” The nerve in Figure 17–1 uses a neurotransmitter called serotonin.

  You can see in Figure 17–1 that when the presynaptic nerve fires, it releases many tiny packets of serotonin into the synapse. Once released, these chemical messengers migrate or “swim” through a process called diffusion across the fluid-filled synapse. At the other side of the synapse, the serotonin molecules become attached to receptors on the surface of the postsynaptic nerve. This signal tells the postsynaptic nerve to fire, as illustrated in Figure 17–2 on page 436.

  Different kinds of nerves use different kinds of neurotransmitters. There are a great many of these neurotransmitters in the brain. Chemically, many of them are categorized as “biogenic amines” because they are manufactured from amino acids in the foods we eat. These amine transmitters are the brain’s biochemical messengers. Three of the amine transmitters in the limbic (emotional) regions of the brain are called serotonin, norepinephrine, and dopamine. These three transmitters have been theorized to play a role in many psychiatric disorders and have been intensively studied by psychiatric researchers. Because these chemical messengers are called biogenic amines, the theories linking them to depression or mania are sometimes referred to as the biogenic amine theories. But we are getting ahead of ourselves.

  Figure 17–2. The serotonin molecules become attached to the receptors on the postsynaptic nerve. This stimulates the nerve to fire.

  How does a chemical messenger cause the postsynaptic nerve to fire once it becomes attached to the nerve? Let’s imagine for a moment that the chemical transmitter in the presynaptic nerve is serotonin. (I could have chosen any of them, since they all work in a similar manner.) On the surface of the postsynaptic nerve there are tiny areas called “serotonin receptors.” You can think of these receptors as locks because they cannot be opened up without the right key. These receptors are on the membranes that form the outer surface of nerves. These nerve membranes are something like the skin that covers your body.

  Now, think of the serotonin as the key to the lock on the postsynaptic nerve. Just like a real key, the serotonin works only because it has a specific shape. There are many other chemicals floating around in the synaptic region, but they will not open the serotonin lock because they do not have the right molecular shape. Once the key fits into the lock, the lock opens up. This triggers additional chemical reactions that cause the postsynaptic nerve to fire electrically. When the nerve fires, the serotonin (the key) is released from the receptor (the lock) on the postsynaptic nerve and ends in the synaptic fluid again. Finally, it “swims” back to the presynaptic nerve (again, through a process called diffusion), as illustrated in Figure 17–3 above.

  Figure 17–3. The serotonin molecules swim back to the presynaptic nerve where they are pumped back inside. Once inside, MAO destroys them.

  The serotonin has done its job, and the presynaptic nerve needs to get rid of it; otherwise it will hang around in the synapse and it might swim back to the postsynaptic nerve again. This could create confusion, because the postsynaptic nerve may think there is a new signal and it may get stimulated to fire again.

  To solve this problem, the presynaptic nerve has a pump on its surface. Once the serotonin swims back, it attaches to a receptor (another “lock”) on the surface of the presynaptic nerve and it is pumped back into the nerve by something called the “membrane pump” or the “reuptake pump,” as you can see in Figure 17–3.

  After the serotonin is pumped back inside, the presynaptic nerve can recycle it or it can destroy the excess serotonin if it already has enough saved up for the next electrical signal. It destroys the excess serotonin through a process called “metabolism,” which means changing one chemical into another chemical. In this case, the serotonin is changed into a chemical that can be absorbed into the bloodstream. The enzyme in the nerve that performs this service is called monoamine oxidase, or MAO for short. The MAO enzyme transforms the serotonin into a new chemical called “5-hydroxyindoleacetic acid,” or 5-HIAA. That is another big name, but you can simply think of 5-HIAA as the waste product of the serotonin. The 5-HIAA leaves your brain, enters your bloodstream, and is carried to your kidneys. Your kidneys remove the 5-HIAA from your blood and send it to your bladder. Finally, you get rid of the 5-HIAA when you urinate.

  That’s the end of the serotonin cycle. Of course, the presynaptic nerve must continually manufacture a new supply of serotonin to use in nerve-firing so that the total amount of serotonin does not get depleted.

  What Goes Wrong in Depression?

  First of all, let me reemphasize that scientists do not yet know the cause of depression or any other psychiatric disorder. There are lots of interesting theories, but none of them has yet been proven. One day, we may have the answer and look back on the thinking of this era as a quaint historical curiosity. However, science has to start some-where, and research on the brain is moving forward at an explosive rate. New and very different theories will undoubtedly emerge in the next decade.

  The explanations in this section will be very simplified. The brain is enormously complex and our knowledge about how it works is still extremely primitive. There is a vast amount we do not know about the brain’s hardware and software. How does the firing of a nerve or a series of nerves get translated into a thought or a feeling? This is one of the deepest mysteries of science, as amazing to me as questions about the origin of the universe.

  We won’t even attempt to answer those questions here; for the moment, our goals are much more humble. If you understood Figures 17–1 to 17–3, it should be pretty easy for you to understand current theories about what goes wrong in depression.

  You have already learned that nerves in the brain send messages to each other with chemical messengers called neurotransmitters. You also know that some of the nerves in the limbic system of the brain use serotonin, norepinephrine, and dopamine as their chemical messengers. Some scientists have hypothesized that depression may result from a deficiency of one or more of these biogenic amine transmitter substances in the brain, while mania (states of extreme euphoria or elation) may result from an excess of one or more of them. Some researchers believe that serotonin plays the most important role in depression and mania; others believe that abnormalities in norepinephrine or dopamine also play a role.

  A corollary of these biogenic amine theories is that antidepressant drugs may work by boosting the levels or activity of serotonin, norepinephrine, or dopamine in depressed patients. We will talk some more about how these drugs work in a little while.

  What would happen if a chemical messenger such as serotonin became depleted from the presynaptic nerve in Figure 17–1? Then this nerve could not send its nerve signals properly across the synapses to the postsynaptic nerve. The wiring in the brain would develop faulty connections, and the result would be mental and emotional static, much
like the music that comes out of a radio with a loose wire in the tuner. One type of emotional static (serotonin deficiency) would cause depression, and another type of static (serotonin excess) would cause mania.

  Recently, these amine theories have been modified quite a bit. Some scientists no longer believe that a deficiency or excess of serotonin causes depression or mania. Instead, they postulate that abnormalities in one or more of the receptors on the nerve membranes may lead to mood abnormalities. Examine Figure 17–2 again, and imagine that there is something wrong with the serotonin receptors on the postsynaptic nerve. For example, there might not be enough of them. What would happen to the communication between the nerves? Although there might be plenty of serotonin molecules in the synapse, the postsynaptic nerves might not fire consistently when the presynaptic nerves fired. And if there were too many serotonin receptors, this could have the opposite effect of causing overactivity in the serotonin system.

  To date, at least fifteen different kinds of serotonin receptors have been identified throughout the brain and more are being identified all the time. All these receptors probably have different effects on hormones, feelings, and behavior. Scientists do not have a very clear picture of what any of these different receptors do, nor do they know if abnormalities in any of them play a causal role in depression or mania. Research in this area is evolving at an extremely rapid pace, and we will have better information about the physiologic and psychological effects of these many serotonin receptors in the near future.

  Although our knowledge about the role of serotonin receptors in brain function is still quite limited, there is evidence that the number of receptors on the postsynaptic nerves may change in response to antidepressant drug therapy. For example, if you give a drug that boosts the levels of serotonin in the synapses between the nerves, the number of serotonin receptors on the postsynaptic nerve membranes will decrease after a few weeks. This might be a way that the nerves attempt to compensate for the excess stimulation—the nerves are trying to turn down the volume of the signal, so to speak. This kind of reaction is called “down-regulation.” In contrast, if you deplete the serotonin from the presynaptic nerve in Figure 17–1, much less serotonin will be released into the synapse. After several weeks, the postsynaptic nerves may compensate by increasing the number of serotonin receptors. The nerves are trying to turn up the volume of the signal. This kind of reaction is called “up-regulation.”