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Biology 202
2000 Third Web Report
On Serendip

Melancholia

Elissa Braitman

2300 years ago Greek doctors first described a mental condition in which the sufferer had no appetite, exhibited aggressive behavior (often resulting in suicide), had trouble sleeping, and was generally unhappy. This condition, known as "melancholia," worsened in the autumn months and was more serious in some people who seemed to have an "inate predisposition" for it (3)... Another condition, "mania," characterized by elevated mood and energy and flightiness, was also observed and recognized as having a connection to melancholia by the mid-second century A.D. A medieval Arabic text, based partially on works of the ancient Greeks, suggested that genetics play a role, as well (3). Thus, both depression and bi-polar disorder were recognized two thousand years ago and have been studied ever since then.

Types of Depression-
According to the DSM-IV, there are at least eight varieties of depression. The two main, and probably most severe, types are unipolar (classical depression) and bipolar (manic-depression). People with unipolar depression, a disease affecting about 35-40 million Americans (or 5-12% of men and 10-20% of women) at some point in their lives, have a sense of apathy, hopelessness, and guilt, sleep and appetite disturbances (sleeping all day or insomnia, eating a lot or nothing at all), indecisiveness, and trouble in concentrating (2)(9)(10). 25% of these people attempt suicide within five years of the onset of depression (9)(10), (11) Bipolar depression affects fewer people than the unipolar variety (only about 1% of the population of the U.S., with an equal percentage of men and women) and is characterized by a cycling between depressed and manic states. During the manic state, bipolar people can be talkative, easily distractable, require little or no sleep, and participate in activities with likely negative consequences (e.g. spending sprees, attempts at athletic feats, etc)(9)(10)(2)(1). Those who experience "rapid cycling" go through four or five cycles in a year but some have cycles that last only a couple of days (2). This cycling is also dependent on seasons; spring and summer are more common times for mania, fall and winter for depression. Evidence has also suggested that depression with an onset in adolescence nearly always indicates that the individual has bipolar depression (1).

Causes-
Although we have a better sense of the causes of this family of diseases than the ancient Greeks did, many aspects are still not understood. At the present time, genetics, neurotransmitters, and hormones all seem to play a role.

Genetic studies have shown that both types of depression are passed down from parents to children. The fact that several genes in combination are responsible for a predisposition to depression has made finding the exact genetic cause a challenge. Studies have suggested that chromosomes 18 and 21 contain sites that have a connection to bipolar depression but these have not been proven.

Elsewhere, scientists have been studying the role of monoamine neurotransmitters (such as norepinephrine and serotonin) in depression. It has been noted that depressed patients have low levels of monoamines in their brains. This was discovered accidentally when some patients, treated with a drug for hypertension that was known to eliminate monoamines, developed severe depression. Another accidental discovery revealed an improvement in depressed patients who happened to be treated with a drug for tuberculosis that prevents monoamine enzymatic destruction. In these cases, the level of monoamines remained high because they were not being destroyed by monoamine oxidase.

Studies have implied that, in depressed patients, norepinephrine is deficient in some circuits of the brain. These circuits are located in the locus coeruleus region of the brain stem and project to various parts of the brain. One of those parts is the limbic system, responsible for emotion regulation. The belief that norepinephrine is linked to depression is based on a low concentration of the indirect norepinephrine markers (by-products in waste) found in depressed people. Also, suicide victims have an abnormally high level of norepinephrine receptors (a low level of neurotransmitter causes post-synaptic cells to increase the number of receptors for that neurotransmitter, in order to compensate for the low concentration). Finally, more recently-designed drugs prevent reuptake of norepinephrine and, therefore, alleviate the symptoms of depression (11).

Another neurotransmitter, serotonin (or 5-hydroxytryptamine, 5HT), has also been connected to depression (5). A decrease in synaptic serotonin seems to result in the low concentrations of norepinephrine. The neurons that produce serotonin are located in the brain stem but project to other neurons in the brain and throughout the central nervous system (among these, the neurons that control norepinephrine production/secretion, the hypothalamus-- important for appetite and sleep, the amygdala--emotions, and other areas responsible for higher processes). Cerebrospinal fluid in depressed people contains fewer serotonin by-products (therefore, less actual serotonin is present in the brain), and a larger number of serotonin receptors-- 13 different types total-- are found in their brain tissue (for the same reason as with norepinephrine explained above). The decreased amount of serotonin in the synapse appears to be due to two types of presynaptic molecules, autoreceptors and reuptake transporters. Autoreceptors inhibit production of serotonin while reuptake transporters absorb serotonin that is produced. Drugs that prevent this reuptake of serotonin from the synaptic cleft,the tricyclics, appear to result in more normal synaptic concentrations of serotonin (3)(11).. The fact that depressed people suffer from a higher incidence of heart attack and stroke may be because of this lack of serotonin. Blood vessels get clogged because of platelet activation and clumping. Depressed people seem to be subject to a greater number of platelet activation signals than normal people. These signals are affected by serotonin levels(11).

Finally, hormones appear to have a part in depression. First of all, in depressed patients, the response to the substances released by the hypothalamus that normally stimulate release of growth and thyroid-stimulating hormone is abnormal. Also, it appears that their hypathalmic-pituitary-adrenal axis (HPA)--activated in times of stress-- is unregulated. Normally, the hypothalamus produces a lot of corticotropin-releasing factor (CRF). Then, the pituitary secretes adrenocorticotropic hormone (ACTH) and this causes the kidneys to release cortisol, allowing for the fight-or-flight response (all non-essential body functions are shut down). Depressed people not only have enlarged adrenal and pituitary glands, but also a high concentration of cortisol is found in their blood, urine, and cerebrospinal fluid. This is indicative of frequent activation of the HPA axis. The concentration of CRF (it functions to decreases appetite and increase alertness) in the cerebrospinal fluid, as well as the genes that code for its production, is also higher than normal. When given to lab animals, CRF induces behavior very much like that exhibited by depressed humans (11).

Imaging of both unipolar and bipolar patients shows differences in the brains as compared to non-depressed people. For example, bipolar brains have more bright spots (indicating loss) in the thalamus, brain stem, and basal ganglia-- areas associated with mood. The size of the hippocampus (responsible for memory and emotion) is also decreased. Studies have shown that the cells of the hippocampus can be destroyed by the frequent presence of cortisol. It is believed that these missing areas have some function in serotonin/ norepinephrine activity. Not surprisingly, positron emission tomography (PET) show variance in brain activity, as well. Imaging will be used in the near future to develop more effective treatments for sufferers of depression.(11)

Treatment-
Unlike some other neurobiological diseases, both unipolar and bipolar depression can be treated in 80% of cases with antidepressant medications. But the fact that it takes at least two or three weeks to feel any positive effects and the side effects are disagreeable makes the recovery process a difficult one. The length of treatment and likelihood of future incidents depend on the number of prior depressive episodes (three or more results in lifetime treatment due to the high probability of future incident of depression). All of these medications act on the production of neurotransmitters. Some are selective serotonin reuptake inhibitors (SSRIs)-- such as Prozac and Paxil-- that prevent synaptic reuptake by enzymes (3)(4).

Non-drug therapies are also encouraged for those suffering from milder forms of depression. These include exercise, psychotherapy, support groups, cognitive therapy, acupuncture, meditation, phototherapy, electroconvulsive therapy, dietary supplements (since vitamin deficiences seem to have an effect on depression, as well), and herbal medicine (10).

One type of herbal treatment is Hypericum perforatum, a.k.a. St John's wort, a plant with yellow-orange flowers that is found all over North America and Europe (6). Already used for over two thousand years as a treatment for various health problems, in Germany, St John's wort is prescribed for depression in greater frequency than regular antidepressants. Its active ingredient, hypericin, is a reuptake inhibitor of serotonin, dopamine, and norepinephrine. Studies have shown that it is effective in alleviating the symptoms of mild and moderate depression without the side effects associated with antidepressant drugs. Also, it costs significantly less than those drugs (7).

Two other treatment options are the amino acids tyrosine and phenylalanine. Both are precursors to norepinephrine and dopamine that act to increase the levels of those neurotransmitters in the brain. Tyrosine takes effect much faster than either St John's wort or antidepressants but can raise blood pressure(8).

Conclusion
As a disease that has cost the US over 40 billion dollars a year (in productivity losses), lots of money and time have been devoted to the study of depression, in order to find effective treatments. In the future, scientists hope to find markers to diagnose individual patients with the specific type of depression that they have (e.g. one caused by lack of serotonin versus one caused by an abundance of CRF). As people have different biochemical reasons for being depressed, a medication that works for one person may not work for another. So, if the exact cause can be determined on an individual basis, the treatment can be tailored to that person and the result will be a healthier population (11). As Charles Nemeroff notes "the mind does not exist without the brain." Looking at depression, the semester-long question of whether or not the brain is equal to behavior is clarified by considering the causes of this disease. That is, while environmental events (abuse or neglect in early childhood, a life-changing incident later in life, etc) can trigger the onset of depression, a predisposition to it is found in the brain chemistry (11). And this predisposition means that it is only a matter of time before the symptoms of depression manifest themselves. Therefore, there is no way to prevent this onset from the environmental side, only from within the brain, itself. The one question that remains after doing this research is "Why does it take so long (2-6 weeks) to feel the positive effects of antidepressant medications?" The only thing I can guess is that, since most medications work to prevent the reuptake of serotonin in the synapses, and there are many synapses, it takes a long time for a complete changeover to occur. And, the negative side effects are a result of the body's adjustment period. Or, perhaps, the body (i.e. the brain) just needs time to get used to the resulting chemical changes. Whatever the case, depression is a disease that was recognized long ago but only recently understood at some level.

WWW Sources

1)Bipolar Depression--Highlights of the First International Conference on Bipolar Disorder, This provides a lot of specific information on drug treatment and a bit of general information on the disease.

2)Bipolar and Depression Frequently Asked Questions, This has a description of the symptoms.

3)Depression and Fatigue,This has symptoms and causes, as well as historical information.

4)Virtual Hospital--Clinical Psychopharmacology Seminar SSRI,This has information on the pharmocology of SSRIs..

5)Serotonin,This is a description of serotonin.

6)the Hypericum Home Page,This has information about St John's Wort.

7)The Health Gazette,This has additional information about St John's Wort.

8)Ask Dr Weil, This talks about tyrosine and phenylalanine treatments.

9)A Biochemical Illness,This gives general information on depression.

10)Health Library,This covers different types of depression, treatment options, the role of anxiety, etc.

11)The Neurobiology of Depression,This is a Scientific American article with detailed information on causes.

12)Science News,This is an article on depression and creativity.




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