THE ANTIDEPRESSANTS ARE a group of prescription medicines used for the treatment of depression as well as other psychiatric and medical conditions. Man's attempts to treat these disorders date back thousands of years, when the first surgeons drilled holes in the skulls of their patients (who had no anesthesia!) in order to expel "the demons within." Over the centuries, other treatment regimens have included bloodletting, exorcism, voodoo, magic potions, dietary supplements, herbal elixirs, and other home remedies, but no treatment was proved to be truly effective until the latter half of the twentieth century. The legitimacy of the antidepressant medications has withstood the scrutiny of hundreds of rigorously controlled scientific studies, and it is further substantiated by the millions of people all over the world who have benefited from them.
How the antidepressants got their start is an interesting tale, similar to how other discoveries in the field of medicine occurred: from a combination of luck and keen observation. Remember, for example, Sir Alexander Fleming's observation of what happened after a bacterial culture in his laboratory was accidentally contaminated by a mold. This led to the discovery of penicillin and the explosion of research on the antibiotics. The story of the antidepressants is just as fascinating.
It all started in the 1950s. While researching a medicine, iproniazid, to treat tuberculosis, doctors noticed that some of the patients receiving this medicine experienced elevation of their mood (even though their tuberculosis didn't improve). Based on this astute observation, researchers changed course and began studying iproniazid as a possible treatment for depression. One road taken by researchers was to explore the interaction between iproniazid and a medicine called reserpine. Reserpine was used at that time to treat high blood pressure. The researchers were interested in it because one of its side effects was depression. Iproniazid, investigators discovered, reversed some of reserpine's effects, which confirmed the scientists' belief that they were onto something.
Also in the 1950s, a new medicine, imipramine, was being studied as a possible treatment for psychosis. Thorazine had just been discovered to have astonishing antipsychotic effects in people with schizophrenia, and imipramine was chemically similar to Thorazine. As it turned out, imipramine did not help the psychotic symptoms of people with schizophrenia, but it was noted to have some antidepressant effects. As was occurring with iproniazid, imipramine research then changed its course, and shortly thereafter, the first antidepressants were introduced. In the late 1950s, iproniazid and imipramine were released in the United States under the brand names Marsilid and Tofranil.
Efforts to solve the mystery of exactly how the antidepressants work also make an interesting tale. But before we get into that, let's take a quick course in Nerve Chemistry 101. The most important thing to remember is that it takes a chemical reaction for a nerve impulse, traveling along one nerve, to fire off a second nerve. Unlike the chemical reactions created in high school chemistry labs, which seem to take forever and often make students late to their next class, these reactions occur almost instantaneously. The miraculousness of this speed is matched only by the phenomenally small space in which these reactions occur. This space, the gap between the two nerves, is called a synapse. For the last fifty years, antidepressant research has focused more on these chemical reactions in the synapse than on anything else.
The first nerve releases chemicals into the synapse, and these chemicals stimulate receptors on the second nerve, firing off the second nerve and thereby transmitting the neural (nerve) impulse. Because they transmit the neural impulse, these chemicals are called neurotransmitters. The word "neurotransmitter" may be the most important word to know in the field of antidepressant research. However, don't forget that the neurotransmitters stimulate receptors on the second nerve. What happens at the receptor sites is now being investigated as much as the neurotransmitters themselves, so the word "receptor" is becoming equally important.
Now, back to the 1950s again. Scientists knew that reserpine lowered blood pressure via its action, in the circulatory system, on a class of chemicals called the catecholamines. Catecholamines, significantly, are also present in the brain. Perhaps, they theorized, it was reserpine's effect on the catecholamines in the brain that caused the side effect of depression. And since iproniazid could reverse the effect of reserpine, perhaps iproniazid's antidepressant effect was related to its effect on brain catecholamines. Early research results confirmed these suspicions: iproniazid did affect brain catecholamines, which, as it turned out, do function in the brain as neurotransmitters. Researchers also found another neurotransmitter--one called serotonin. But the early studies focused mainly on the catecholamines.
What became known as the catecholamine hypothesis postulated that the success of the antidepressants had something to do with their affecting (possibly increasing the level of) catecholamines in the synapse. Here is a simplified version of the theory: In a normal brain, without any antidepressant present, after the catecholamines do their job of stimulating the receptors in the synapse, a portion of the catecholamines is reabsorbed back into the first nerve again. This process is called reuptake. Additionally, another portion of the catecholamines is broken down by an enzyme--the first step in the journey to the kidneys and eventual elimination from the body. When an antidepressant is present, however, the reuptake and/or the breakdown process is inhibited, resulting in an increased level of catecholamines in the synapse.
Excitement grew as investigators conducted studies to test the hypothesis. Was there just a deficiency of neurotransmitters in the synapse in depressed people to begin with? Did the antidepressants then correct this deficiency, raising the neurotransmitters to a normal level, thereby "fixing" the depression? Unfortunately, this theory was too easy an answer and didn't pan out in reality. The results of the studies just didn't fit the hypothesis. In fact, as often happens in research, there were more questions raised than answers found. To this day, researchers are still unable to find a hypothesis that puts all the pieces of the puzzle together and explains everything.
Fortunately, though, while much of the early research attention was on the catecholamines, some resolute researchers doggedly pursued this other neurotransmitter called serotonin. By the 1980s, medications had been developed that affected primarily serotonin, not catecholamine, neurotransmission.
Still other investigators focused their efforts on the receptors on the second nerve. They found a variety of different receptors and learned that the brain, its jumbled mass of interconnected nerves, and the entire body all respond differently, depending on which receptors are stimulated more (or less) than others. Before long, the serotonin receptors they discovered numbered in the double digits.
Research reached new heights as the 1980s gave way to the 1990s. Invaluable advocacy groups helped protect indispensable government grants, which were annually threatened by budget trimmers. For the first time in history, pharmaceutical companies were making significant profits from antidepressant sales. Competition in the private sector intensified and accelerated the pace of research as these companies raced to find better medicines. Scientists began designing "designer drugs"--a far cry from the serendipitous discoveries of doctors researching tuberculosis, high blood pressure, and schizophrenia in the 1950s. Proactively, chemists altered the architecture and chemical properties of molecules in order to produce a desired effect on the neurotransmitters and receptors.
Despite the huge amount of time, energy, and money that went into new antidepressant research in the 1990s, many of the older medicines still remain on the market today. Just as penicillin continues to be a dependable weapon in our arsenal of antibiotics, so does Tofranil continue to be a reliable weapon in our antidepressant arsenal. Though iproniazid is now off the market, a dozen or so other antidepressants were introduced in the 1960s and 1970s. They, like Tofranil, have withstood the test of time, and continue to be reliable and effective antidepressants. They are the "old faithful" antidepressants.
The old faithful antidepressants, though, have a relatively broad, wide-spectrum effect on neurotransmitters and receptors (and the rest of the body as well). Therefore, they are more likely to have other consequences in the body besides the desired effects. These other consequences include sleepiness, dry mouth, constipation, weight gain, blurred vision, increased heart rate, and a drop in blood pressure (and therefore, light-headedness or even fainting) upon standing.
Although all the searching in the 1980s and 1990s never found exactly how the antidepressants work, it did result in the birth of medicines called the new generation antidepressants. These medicines have a narrower, more focused effect on the neurotransmitters and receptors. Their "smart bomb" precision allows them to be just as effective as the old faithful antidepressants, but with fewer side effects on the rest of the body.
Currently, one of the new generation antidepressants is usually prescribed before an old faithful antidepressant, though sometimes a patient may need more of a broad-spectrum effect and an old faithful antidepressant will therefore be prescribed first. Prozac was the first new generation antidepressant in the United States. It was introduced in 1988 and primarily affects serotonin. Currently, about ten new generation antidepressants have received FDA approval and are available in the United States.
Excerpted from The Antidepressant Sourcebook by Andrew L. Morrison MD. Copyright © 1999 by Andrew Morrison, M.D.. Excerpted by permission of Main Street Books, a division of Random House LLC. All rights reserved. No part of this excerpt may be reproduced or reprinted without permission in writing from the publisher.