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Biological Causes of Depression

Biological causes of clinical depression continue to be studied extensively. Great progress has been made in the understanding of brain function, the influence of neurotransmitters and hormones, and other biological processes, as well as how they may relate to the development of depression.

Brain Function in Depression

The brain is the "command center" of the human body. It controls the basic functions of our bodies, our movements, and our thoughts and emotions. Researchers studying clinical depression tend to look at several aspects of brain function including the structures of the limbic system and the function of neurotransmitters within neurons.

Limbic System

Those who research clinical depression have been interested in a particular part of the brain called the limbic system. This is the area of the brain that regulates activities such as emotions, physical and sexual drives, and the stress response. There are various structures of the limbic system that are of particular importance. The hypothalamus is a small structure located at the base of the brain. It is responsible for many basic functions such as body temperature, sleep, appetite, sexual drive, stress reaction, and the regulation of other activities. The hypothalamus also controls the function of the pituitary gland which in turn regulates key hormones. Other structures within the limbic system that are associated with emotional reaction are the amygdala and hippocampus. The activities of the limbic are so important and complex that disturbances in any part of it, including how neurotransmitters function, could affect your mood and behavior.

Neurotransmitters and Neurons

To understand what happens in the brain when a person becomes clinically depressed as well as how antidepressant medications work, it is first important to learn a bit about the function of neurons and neurotransmitters. Within the brain, there are special chemicals called neurotransmitters that carry out many very important functions. Essentially, they help transfer messages throughout structures of the brain's nerve cells. These nerve cells, called neurons, are organized to control specialized activities. We each have somewhere between 10-100 billion neurons within our brains. Whenever we do anything, react, feel emotions, think, our neurons transmit messages in the form of electrical impulses from one cell to another. These electrical impulses travel across the neurons at an amazing rate of speed- less than 1/5,000 of a second. Because they move so quickly, our brains can react instantaneously to stimuli such as pain.

A neuron is made up of a cell body, an axon, and numerous branching dendrites. Chemical messages pass through the brain by traveling through these neuronal structures. First, it begins as an electrical impulse that is picked up by one of the dendrites of the neuron. Next, the impulse moves through the cell body then travels down the axon. When it reaches the axon the electrical impulse is changed to a chemical impulse. These chemical impulses, or neurotransmitters, released by the axon have the duty of carrying messages from one neuron to another. When the message is picked up by the dendrite of a neighboring neuron, it is changed back in to an electrical impulse and process begins again. Neurons do not actually touch one another. Instead, the chemical messenger passes from one neuron to another through a small narrow gap, called a synapse, which separates the neurons.

Neurotransmitters travel from neuron to neuron in an orderly fashion. They are specifically shaped so that after they pass from a neuron into the synapse, they can be received onto certain sites, called receptors, on a neighboring neuron. Neurotransmitters can fit a number of different receptors, but receptor sites can only receive specific types of neurotransmitters. Upon landing at the receptor site of neuron, the chemical message of the neurotransmitter may either be changed into an electrical impulse and continue on its way through the next neuron, or it may stop where it is. In either case the neurotransmitter releases from the receptor site and floats back into the synapse. It is then removed from the synapse in one of two ways. The neurotransmitter may be broken down by a chemical called monoamine oxidase, or it may be taken back in by the neuron that originally released it. The latter case is called reuptake.

Of the 30 or so neurotransmitters that have been identified, researchers have discovered associations between clinical depression and the function of three primary ones: serotonin, norepinephrine, and dopamine. These three neurotransmitters function within structures of the brain that regulate emotions, reactions to stress, and the physical drives of sleep, appetite, and sexuality. Structures that have received a great deal of attention from depression researchers include the limbic system and hypothalamus.

Theories about how neurotransmitters may be related to a person's mood have been based upon the effects that antidepressant medications can have on relieving depression in some people. It is believed that these medications are effective because they regulate the amount of specific neurotransmitters in the brain. However, the role that neurotransmitters play in the development or treatment of clinical depression is not completely clear. For instance, it has been shown that many people who are depressed have low levels of the neurotransmitter norepinephrine. The use of some antidepressants can increase the level of norepinephrine in the brain, and subsequently relieve depressive symptoms. One the other hand, it has also been shown that some other people who are depressed have high levels of norepinephrine. This same scenario may be true for other neurotransmitters. Another reason that the effects of neurotransmitters are not clear-cut has to do with the fact that antidepressant medications do not work for everyone. If there were a direct causal link between the level of a neurotransmitter in the brain and depression, then we would expect a much higher rate of success with medication. Further, although antidepressant medications can change the level of a neurotransmitter in the brain immediately, it normally takes a few weeks for a person with depression to feel better. What is seems to boil down to is that there appears to be a strong relationship between neurotransmitter levels in the brain and clinical depression, and that antidepressant medications work for a great many people, but we are not absolutely certain of the actual relationship between neurotransmitters and depression.

The reason we do not know more about the effects of neurotransmitters has to do with that fact that they are so difficult to study. Neurotransmitters are present in very small quantities, they are only available in certain locations within the brain, and they disappear very quickly once they are used. Because they are removed so fast, they cannot be measure directly. Researchers can only measure what is left over after their use in the brain. The substances that remain are called metabolites and they can be found in blood, urine, and cerebrospinal fluid. By measuring these metabolites, researchers can gain an understanding of the effects of changes in neurotransmitters in the brain.

It is unknown whether changes in levels of neurotransmitters cause the development of depression or depression causes changes in neurotransmitters. It may happen both ways. Researchers believe that our behavior can affect our brain chemistry, and that brain chemistry can affect behavior. For instance, if a person experiences numerous stressors or traumas this may cause his or her brain chemistry to be affected, leading to clinical depression. On the other hand, that same person may learn how to change depressed thoughts and behavior and cope with stressful events. Doing this may also change brain chemistry and relieve depression.

Hormones and the Endocrine System

Another area of research in determining the causes of clinical depression is focused on the endocrine system. This system works with the brain to control numerous activities within the body. The endocrine system is made up of small glands within the body, which create hormones and release them into the blood. The hormones that are released into the body by the glands regulate processes such as reaction to stress and sexual development. It has been found that a great number of people who are depressed have abnormal levels of some hormones in their blood despite having healthy glands. It is believed that such hormonal irregularities may be related to some depressive symptoms such as problems with appetite and sleeping since they play a part in these activities. Further clues to the role of the endocrine system has to do with the fact that those who have particular endocrine disorders sometimes develop depression, and some individuals who are depressed develop endocrine problems despite having healthy glands.

The endocrine system usually keeps the hormonal levels from becoming excessive through an intricate process of feedback, much like a thermostat in a home. Hormonal levels in the body are constantly monitored. When a specific hormone rises to particular level the gland stops producing and releasing the hormone. When an individual is depressed this feedback process may not function as it should.

Problems with hormone levels may be intertwined with the changes in brain chemistry that are seen in clinical depression. The endocrine system is connected with the brain at the hypothalamus which controls many bodily activities such as sleep, appetite, and sexual drive. The hypothalamus also regulates the pituitary gland that, in turn, controls the hormonal secretion of other glands. The hypothalamus uses some of the neurotransmitters that have been associated with depression as it manages the endocrine system. These neurotransmitters, serotonin, norepinephrine, and dopamine all have a role in the management of hormone function.

The development of clinical depression may be a symptom of a disorder present within organs that produce hormones. Such conditions include thyroid disorders, Cushing's syndrome, and Addison's disease.


Of those individuals who are clinically depressed, about one-half will have an excess of a hormone in their blood called cortisol. Cortisol is secreted by the adrenal glands. Located near the kidneys, the adrenal glands assist us in our reactions to stressful events. Cortisol may continue to be secreted even though a person already has high levels in his or her blood. This hormone is believed to be related to clinical depression since the high levels usually reduce to a normal level once the depression disappears.

The hypothalamus may be the culprit when it comes to excessive levels of cortisol in the blood. It is responsible for starting the process that leads to the secretion of cortisol by the adrenal glands. The hypothalamus first manufactures corticotrophic-releasing hormone (CRH). The pituitary gland is then stimulated into releasing adrenocorticotrophic hormone (ACTH). This hormone then makes the adrenal glands secret cortisol in the blood. When the endocrine system is functioning properly, the hypothalamus monitors the level of cortisol that is in the blood. When the level rises, the hypothalamus slows down its influence on the pituitary gland in production of CRH. When cortisol levels become reduced, the hypothalamus causes the pituitary gland to produce more CRH. In a person who is depressed, the hypothalamus may continuously influence the pituitary to produce CRH without regard to the amount of cortisol that is in the blood.

Other research concerning cortisol has shown that the timing of the release of this hormone may be problematic in those who are depressed. People who are not depressed tend to have secretions of cortisol at certain times of the day. Cortisol levels are highest at approximately 8:00 a.m. and 4:00 p.m., and then lowest during the night. This normal cycling of cortisol levels does not occur in some people who are depressed. For instance, they might have a consistent level of cortisol all the time, or highest amounts in the middle of the night.

Cortisol levels can be tested using something called a dexamethasone suppression test (DST). This is not a test for depression since some people who are depressed may not be identified by the results of the test, but it can be used to confirm a diagnosis of depression in some people. This test involves giving a dose of dexamethasone, a synthetic cortisol, to an individual before he or she goes to sleep at night. At 8:00 a.m. the next morning, the person's blood is tested for cortisol. It is tested again at 4:00 p.m. In healthy individuals cortisol levels drop at first, but then return to normal as the hypothalamus compensates for the dexamethasone in the blood. In those who are severely depressed, approximately one-half will have abnormal results. Cortisol secretion may not be reduced by the hypothalamus, or there may be no change at all after receiving the synthetic cortisol.



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