We think we know some of the underlying brain chemistry as it relates to Major Depression. Throughout the nervous system, electrical impulses are transmitted from nerve to nerve by chemical substances called neurotransmitters. There are a host of different chemicals that serve as neurotransmitters. Those that concern us most are named serotonin, norepinephrine, and dopamine. In very specific parts of the brain, most especially a small region called the hypothalamus (located at the base of the brain about an inch behind the eyes) deficiencies of neurotransmitters appear to be the chemical mechanism by which Major Depression occurs.   Antidepressant medications appear to work by causing the concentration of neurotransmitters to be returned to normal. Note that this is a model of how we understand these complex chemical problems in the brain. Models are not ultimate truth, but the concepts they represent help us understand what is happening in the brain.   Here are illustrations of how we think Serotonin is involved in depression and how a class of antidepressant drugs called Selective Serotonin Reuptake Inhibitors (SSRI’s) work. Examples of SSRI drugs are Prozac, Zoloft, Paxil, Celexa, and Lexapro.   Serotonin is manufactured in the nerve cell and then it is released into the area between nerve cells, the so-called synaptic cleft. There it suffers one of three fates:   1. It traverses the nerve space and makes the next nerve "fire." That is to say, it does its job.   2. It fails to traverse synaptic cleft and is taken back up into the nerve that released it. A process called reuptake.   3. It is inactivated by an enzyme in the synaptic cleft called mono-amine oxidase.   Illustration 1 shows how this works in a healthy nerve transmission process     Illustration 2 shows the process when Major Depression is present. Note that fewer Serotonin molecules are present in the synaptic cleft and hence fewer make it to the next neuron to make it "fire."     Illustration 3 shows how an SSRI drug blocks the reuptake of Serotonin thus causing the concentration in the synaptic cleft to be increased. Consequently more serotonin makes it to the receptor sites on the next nerve cell and the functioning returns to normal.     These illustrations are taken from a patient instruction booklet, Depression, an Illness that Can Be Treated, published by Pfizer Company, the manufacturer of Zoloft.   Not all antidepressant drugs can be illustrated so neatly. Many have more subtle and specific functions on both the sending and receiving neurons.   An older group of antidepressants which we have used from their inception in the late 1950’s are called tri-cyclic antidepressants. We applied this name to this class of antidepressant medications because of similarities in their chemical structure. These were (and still are) effective antidepressants. The problems with taking them included numerous unpleasant side effects, lethality in overdose and slowness in onset of action. Their mechanism of action has yet to be fully understood. However the net result of taking these medications was that there was a more efficient firing of one nerve to the next and that restored the depressed brain to normal.   Plus, there is a group of antidepressant drugs called Mono Amine Oxidase Inhibitors (MAOI’s). These drugs work by inhibiting the enzyme, mono amine oxidase, in the synaptic cleft so the concentration of the neurotransmitters is increased as a result of fewer neurotransmitter molecules being inactivated by this naturally occurring enzyme. Note that these drugs are used infrequently because of other complications that occur when they are used including problems of interactions with numerous other medications and dietary restrictions that must be observed while taking them.