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:
• clinical tests for the chemical imbalance that causes depression (if, indeed, such an imbalance actually exists);
• tests to detect the genetic abnormalities that make certain individuals more vulnerable to depression as well as manic-depressive illness;
• safer medications with fewer side effects—as you will learn in Chapter 20, significant advances have already been made in this area;
• drugs and psychotherapeutic treatments that are more effective and faster-acting;
• drugs and psychotherapeutic treatments that minimize or entirely prevent relapses of depression following recovery.
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.”
Chapter 18
The Mind-Body Problem
(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.
There is often intense competition between the “drug therapy” camp and the “talking therapy” camp. On the average, psychiatrists are more likely to be in the drug therapy camp. This is because psychiatrists are first trained as physicians (M.D.s). They can prescribe medications, and they are more likely to be influenced by the medical model of diagnosis and treatment. If you are depressed and you go to a psychiatrist, there’s a good chance that she or he will tell you that your depression is caused by a chemical imbalance in your brain, and will recommend treatment with an antidepressant medication. If your family physician treats your depression, drug treatment is also very likely. This is because many family physicians have little training in psychotherapy and very little time to talk to patients about the problems in their lives.
In contrast, psychologists, clinical social workers, and other types of counselors are more likely to be in the talking therapy camp. They do not have medical training and cannot prescribe medications.2 Their education usually focuses more on the psychological and social factors that may cause depression. If you are depressed and you go to a therapist in the talking therapy camp, she or he is more likely to focus on your upbringing, your attitudes, or stressful events such as the loss of love or the loss of your job. Your therap
ist will probably also recommend psychotherapeutic treatment, such as cognitive behavioral therapy. However, there are many exceptions to this generalization. Many nonmedical therapists believe that biological factors do play a role in depression, and many psychiatrists are gifted psychotherapists. Psychiatrists and nonmedical therapists sometimes work together in teams so that their patients can benefit from both types of treatment.
Nevertheless, the split between the mind (psychological) and body (biological) schools is sharp, and the dialogue between them is often intense, combative, and bitter. Political and financial considerations sometimes seem to influence the tone of these discussions more than scientific findings. Some recent studies suggest that these arguments may amount to much ado about nothing and that the dichotomy between the mind and the brain may be illusory. These studies indicate that antidepressant drugs and psychotherapy may have similar effects on our minds and on our brains—in other words, they might work in the same way.
For example, in a classic study published in the Archives of General Psychiatry in 1992, Drs. Lewis R. Baxter, Jr., Jeffrey M. Schwartz, Kenneth S. Bergman, and their colleagues at UCLA School of Medicine studied changes in the brain chemistry of eighteen patients with obsessive-compulsive disorder (OCD). Half of these patients were treated with cognitive behavioral therapy (and no drugs) and half were treated with antidepressant drugs (and no psychotherapy).3 The patients in the no-drug group received individual and group psychotherapy that had two main components. The first component was exposure and response prevention. This is a behavior therapy technique which involves encouraging patients not to give in to their compulsive urges to check locks, to wash their hands repeatedly, and so forth. The second component was cognitive therapy along the lines described in this book. Remember that patients in this group did not receive any medications at all.
These investigators used positron emission tomography (PET scanning) to study the metabolic rate for sugar (glucose) in various brain regions before and after ten weeks of treatment with either drugs or psychotherapy. This method of brain scanning assesses the activity of the nerves in different areas of the brain. One brain region they were particularly interested in was the caudate nucleus on the right half of the brain.
Both treatments were effective: the majority of patients in both groups improved, and there were no significant differences in the two treatments. This was not surprising; previous researchers have also reported that drugs and cognitive behavioral psychotherapy have similar effects in the treatment of OCD. However, the results of the PET study were quite surprising. The investigators reported comparable reductions in the activity in the right caudate nucleus in the successfully treated patients regardless of whether they were treated with drugs and no psychotherapy, or psychotherapy and no drugs. In addition, the symptoms and thinking patterns of the two groups improved to a similar degree—neither treatment was superior. Finally, the amount of improvement in symptoms was significantly correlated with the degree of change in the right caudate nucleus. In other words, patients who improved the most had, on average, the greatest reductions in brain activity in the right caudate nucleus. The reduced activity meant that the nerves in this region of the brain had calmed down, regardless of whether they were treated with drugs or psychotherapy.
One implication of this study is that excessive activity in the right caudate nucleus might play a role in the development or maintenance of the symptoms of obsessive-compulsive disorder. A second important implication is that antidepressant medications and cognitive behavioral therapy might be equally effective in restoring the structure and function of the brain back to normal.
Like most published studies, this one had some fairly significant flaws. One problem is that any brain changes you observe in a particular psychiatric disorder might simply represent “downstream” effects rather than true causal effects. In other words, the increased neural activity in the right caudate nuclei of patients with obsessive-compulsive disorder might simply reflect a more general pattern of distress throughout the brain and may not be the cause of the symptoms, as we have discussed above.
Another problem was that the number of patients studied was extremely small, and the number of brain regions the investigators studied was fairly large, so it is possible—even likely—that these findings were the result of chance. This possibility is consistent with the fact that other investigators have reported different patterns of brain activity in patients treated with antidepressant medications. This is why replications with more patients conducted by independent investigators are needed before the results of any study can be accepted. In spite of these limitations, the report by Dr. Baxter and his colleagues was the first of its kind and may open the door to an important new type of integrated research on the ways that drugs and psychotherapy can influence brain function and emotions.
Other studies have shown that antidepressants may actually work by helping depressed patients change their negative thinking patterns. Indeed, in an investigation conducted at Washington University School of Medicine in St. Louis, Drs. Anne D. Simons, Sol L. Garfield, and George E. Murphy randomly assigned depressed patients to treatment with either antidepressants alone or cognitive therapy alone. They studied changes in the negative thinking patterns of both groups of patients. They discovered that the negative thinking of patients who responded to the antidepressants improved as much as the negative thinking of depressed patients who responded to the cognitive therapy.4 Remember that the drug patients received no psychotherapy and the cognitive therapy patients received no medications. Thus this study indicated that antidepressant drugs change negative thinking patterns in much the same way that cognitive therapy does. The effect of antidepressant drugs on attitudes and thoughts may explain their antidepressant effects just as well or even better than more biological explanations of their effects on different transmitter systems in the brain.
These remarkable studies suggest that we might do better to let go of this “mind-body” split and begin to think about how these different treatments may be working in tandem on the mind and on the brain. This combined approach could foster a greater sense of teamwork among therapists and researchers approaching the problem from different angles and may lead to more rapid advances in our understanding of emotional disorders. Even if there is some type of genetic or biological disorder in at least some depressions, psychotherapy can often help to correct these problems, even without medications. Many research studies, as well as my own clinical experience, have confirmed that severely depressed patients who appear very “biologically” depressed with lots of physical symptoms often respond rapidly to cognitive therapy alone without any drugs.5
It can work the other way as well. I have worked with many depressed patients who were still stuck after I had tried numerous psychotherapeutic interventions. When I prescribed an antidepressant medication, many of these patients started to turn the corner, and the psychotherapy began to work better. It seemed as if the medication really did help them change their negative thinking patterns as they recovered from the depression.
If Depression Is Inherited, Doesn’t It Mean We Should Treat It with Drugs?
In Chapter 17 we talked about the fact that we don’t yet know how strong the genetic influences are in the more common forms of depression that do not involve mania. But suppose scientists eventually discover that nearly all forms of depression are inherited, at least in part. Would it mean we should treat depression with drugs?
The answer is: not necessarily. For example, a blood phobia is thought to be at least partially genetic, but it can nearly always be treated quickly and easily with behavior therapy. The treatment of choice for most phobias is to expose the person to the frightening situation and to urge them to face it and endure the anxiety until the fear diminishes and disappears. Most patients are so frightened that they resist the treatment at first, but if they can be persuaded to hang in there, the success rate is extraordinarily high.
I can attest to this
personally. While growing up, I was terrified of blood. When, in medical school, it was time to draw blood from each other’s arms, I felt so unenthusiastic that I dropped out of medical school. For the next year, I decided to work in the clinical laboratory of the Stanford University Hospital so I could try to get over my fear. They gave me a job doing nothing but drawing blood out of people’s arms and I had to do this all day long. The first few times I had to draw blood, it made me very anxious, but after those initial anxious moments, I got used to it. Pretty soon, I loved my new job. This shows that at least some genetic tendencies can respond to a behavioral treatment without drugs.
To state an even more commonplace example, we all inherit a tendency to have a particular type of body. Some of us are genetically taller or shorter than others. Some of us have larger frames, others have smaller frames. But our diets and habits hugely influence the types of bodies we have as adults. Many professional bodybuilders were skinny and embarrassed about their looks when growing up. This motivated them to go to the gym and work out. This intense effort transformed many of them into champions. Their genes may have greatly influenced what they were born with, but their behaviors and determination dominated where they ended up.
The opposite is also true. If it turned out that depression was entirely caused by the environment and that there were no genetic influences, this would not minimize the potential value of antidepressant drugs. For example, if you are exposed to someone with a strep throat, you may get a strep throat because streptococcal bacteria are so infectious. We can say that the causes of your strep throat are almost entirely environmental and not genetic. Nevertheless, we would still treat your strep throat with an antibiotic, and not with behavior therapy!
Feeling Good: The New Mood Therapy Page 39