“The man who sees his neighbor only as an aggregate of atoms cannot have the same conception of his real self. He thus arrives necessarily at a fundamental contradiction.” - F. Husemann (1)
Throughout history, depression was thought of simply as a flawed character condition. Fifty years ago, pharmaceutical treatments for depression did not exist. A major breakthrough occurred in 1974, when a study by scientists at Eli Lilly and Company concluded that a cause of depression is a chemical imbalance manifested by a malfunctioning serotogenic system (2). Many researchers and doctors asserted that “depression is not a moral weakness, nor mental sloth, but a true brain disease that can be successfully treated” (3).The treatment took the form of a series of drugs which are collectively known as antidepressants. Most of the literature on these drugs takes a one sided approach on what causes depression and how a “single action” molecule can treat it. At the same time, often the same article, asserts that depression is a “whole body” illness that affects a person’s physical and mental health, taking hostage of his/her whole existence (4). One molecule must have the ability to treat this condition, successfully alleviating all bad thoughts, curing the physical troubles that go along with it, and in effect, correcting the state of depression. But like with everything in life, it is just not that simple.
Any inquiry into the depth of the nervous system has to begin with the understanding of its complexity. Many accounts of depression and the working of antidepressants, view human beings as “aggregation of atoms” and often fail to recognize the “real self,” which must at least encompass the complex and often incomprehensible interactions of those atoms.
Pablo Picasso, one of the most famous artists, asserted that “every act of creation is first of all an act of destruction.” In the study of the nervous system, and how it is affected by various chemicals, the act of creation can be viewed as the uncovering of the truth. But this inquiry has to begin with the recognition of our lack of understanding, that is, we must destroy our prejudices of the certainty of our knowledge. In the following paper I will point out our current awareness of the state of depression and how and why antidepressants are thought to work. Also I will present some of the contradicting issues which arise from implications of what we know and what we do not know about the state of depression and the medium of its conduction - the nervous system.
Before accessing the condition, it is important to define some of the major symptoms, that together make up what doctors refer to as depression. The physiological symptoms include “feeling sad or anxious most of the day, every day, losing interest in activities you once enjoyed, feeling worthless, guilty, or hopeless, feeling irritable or restless all the time, having trouble concentrating, making decisions, or remembering, having hallucinations (false perceptions) or delusions (false beliefs), and finally, having repeated thoughts of suicide or death or actually making a suicide plan or attempt”(4). The physical symptoms include: “sleeping too much or too little or waking too early, feeling drained of energy or physically slowed down, feeling tired or weak all the time, losing weight (when not dieting) or gaining weight, having headaches, digestive disorders, or chronic pain that doesn't respond to medical treatment”(4). There is much more, but this gives a general idea of a depressed person’s mental and physical state and points to the fact that depression is “a whole body disease.”
According to the latest hypothesis, depression is caused by a low level of a neurotransmitter serotonin in specific areas of the brain (5). Serotonin is made up of groups of neurons which emit axons that enervate other neurons throughout the entire nervous system. Neurons communicate through electrical signals which travel between their axons. The fact that anatomically serotonin can send signals to various neurons can account why the lack of it may bring about various symptoms of depression. For example, serotonin’s axons reach neurons in the cortex, area of the brain which is thought to account for thinking and sleeping functions, the midbrain which controls appetite, and the hypothalamus, which is involved with hormonal functioning of the entire body (3). Lack of serotonin would prevent transmission of various signals between neurons and this could account for various symptoms of depression (6). For instance, if a specific signal is not send to the brain, one may have trouble sleeping or concentrating.
The connection between depression and serotonin level in the brain was noticed when patients taking a drug Reserpine for hypertension, began to experience symptoms of depression. One of the effects of Reserpine is, in fact, a release of serotonin from pre-synaptic stores. This impairs the serotogenic communication pathway (5). Also many clinical studies on the spinal fluid which bathes the brain tissue of persons who died with depression, in some cases after suicide, support that serotonin’s function in the brains of depressed individuals is impaired or reduced (3).
If one isolates this observation from the workings of the entire system, that is, if one assumes that depression is caused simply by a deficiency of a single chemical, then one can develop a substance that increases the level of this chemical. Consequently, the nervous system can be “cured” and all of the symptoms of depression will be alleviated. Such reasoning became the basis for antidepressant known as Prozac. I will use Prozac as an example since its chemistry and influence is representative of the most widely used antidepressants, collectively known as Selective Serotonin Receptor Inhibitors (7).
The empirical formula of Prozac is C17 H18 F3 NO HCl. The presence of trifluoromethyl substituent (F3) seems to contribute to the drug’s high selectivity and thus its ability to inhibit the re-uptake of serotonin (7). A major mechanism for inactivating serotonin in the brain is its re-uptake by the neuron which released it. Prozac, acts by preventing the re-uptake of serotonin into the nerve terminals. It is thought to accomplish this by actually binding to receptors in the pre synaptic cell, thus blocking the re-uptake of the neurotransmitter. The reason for this is its specificity, it seems to have the right “shape” for fitting into these receptors. By inhibiting the re-uptake process, Prozac enhances the action of serotonin (3). Also the drug may interfere directly with the enzymes which eliminate serotonin from the synapses (7). In either case, with serotonin back in the system, everything seems to fall into place and depression in affect should be cured.
One of the major advocates of Prozac are doctors themselves. They have good evidence that the drug works. Clinical trials report that over 68% of patients with depression who took Prozac, showed significant improvements in their symptoms, compared with 38% of control group treated with placebo (9). However, many doctors, wrongly assert that “neuroscience, coupled with informed clinical observations, is closing in on the underlying mechanism for severe depression” (3).It is reassuring for a patient who is prescribed the drug to hear this, but the truth is that researchers and doctors while seeing the obvious results of the drug, do not exactly know why it works.
First of all, antidepressants do not work in all of the patients. From the depression hypothesis it would follow that as long as proper levels of serotonin are restored, symptoms of depression should cease. An important fact one must consider is that there are much more factors and interactions that occur in the nervous system. There are many other neurotransmitters that depression is associated with, some that we likely do not even know about. But at least two others are associated with depression- epinephrine and norepinephrine (7). However, Prozac’s effect on these is not known. So the fact that all chemicals can not be accounted for could explain why some people are not “treated by antidepressants.”
Another area of contradiction lies in the side effects of antidepressants like Prozac. The most interesting of these are anxiety, nervousness, and insomnia. These are the symptoms that Prozac is supposed to treat! In one study, anxiety was reported in 14% of patients taking Prozac and only 7% of patients that were treated with placebo. Thoughts of suicide were also reported as a side effect of the drug and many suicidal patients claimed that their drive increased upon taking Prozac! (7).Various implication could be drawn from this. If a substance which is supposed to treat anxiety is in fact causing it in some patients, then perhaps there is more to anxiety and other aspects of depression than a mere problem with the serotogenic system.
Also, it is interesting to note that a person taking Selective Serotonin Receptor Inhibitors shows improvements in his/her state only after several weeks of treatment. This aspect can be attributed to the possible existence of an alternate, or perhaps a different regulatory mechanism that controls serotogenic transmission (2). If this was not the case, one would expect that as soon as the inhibiting substance is in the system, it will do its thing and serotonin levels will be restored if not immediately, within a few days for sure. But this is obviously not the case. These are the types of glitches doctors are often hesitant to contemplate. They are mostly concerned with alleviating the disease in majority of their patients, which seems to be working.... for whatever reason.
It has been mentioned that “serotogenic antidepressants may be particularly useful to some consumers with a character disorder along with depression. Such serotogenic antidepressants may also be particularly useful in some consumers with headaches, and some consumers with obsessive compulsive disorder”(9). This is a rather humorous way to say that the operation of these drugs and their effects on various behaviors and physical symptoms is by no means precisely known. While progress was made, scientists are no where near understanding the workings of the brain.
Any inquiry which aims at the truth is like an act of creation which Picasso alluded to. As a first step to creation one must be ready to destroy his/her preconceived notions. For me that destruction entailed a deliberate effort to part with my conception of the organization of the nervous system. Partly because of my background in chemistry, I often attribute mechanisms of chemical reactions which take place in the nervous system as an explanation for its functioning. It made complete sense to me how an absence of a chemical could account for a malfunctioning system. As Husemann points out, I was used to thinking of the nervous system as an “aggregate of atoms.” By being skeptical and by admitting the fact that there is at least one contradiction to the predominant theory of depression, was for me the first step to a deeper understanding of the nervous system, that is, it was the first step to creation.
2)Team Projects on www for Biological Basis of Behavior -1998
3) The Harvard Mahoney Neuroscience Institute Letter
5)Fluoxetine - My favorite drug
6)Health Center:Depression -Biological Cause
7)Team Projects on www for Biological Basis of Behavior -1998
8)Medical Sciences Bulletin
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This paper reflects the research and thoughts of a student at the time the paper was written for a course at Bryn Mawr College. Like other materials on Serendip, it is not intended to be "authoritative" but rather to help others further develop their own explorations. Web links were active as of the time the paper was posted but are not updated.