The cause of Clinical depression has long been a mystery to physicians and researchers. Many different theories have been proposed, but no conclusive evidence has been put forth. However, most of what we know about depression stems from the results of certain drugs which have been successful in treating the clinically depressed. These anti--depressants have led to the assumption that depression is most likely due to a chemical imbalance (of neurotransmitters) which somehow leads to the symptoms of depression. To try and write a paper on all the theories of depression would be endless, as would be a study on all the different types of anti-depressants. Therefore I have tried to focus my paper on the serotonin hypothesis for depression, and more specifically how the serotonergic anti-depressants have backed up this theory. Of course, Any paper on serotonin-based anti-depressants must include the popular Prozac. Because of the excitement And controversy surrounding Prozac, I decided to channel most of my paper into the action of this so-called "wonder drug".

Fluoxetine is a second-generation anti-depressant which was developed and marketed as PROZAC by the drug company Eli Lilly. This drug is increasingly being prescribed by physicians as the primary anti-depressant when a patient requires pharmacotherapy. This is mainly due to fluexotine’s reduced side affects as compared with the older tricyclic anti-depressants. Fluoxetine is known to act as a selective serotonin reuptake inhibitor in brain synapses where serotonin is the neurotransmitter. However, an exact mechanism has not born elucidated. Information about serotonin synapses and neurotransmission is continuing to be understood. Many clinical and animal studies have been invaluable in allowing us to gain more understanding of the way in which anti-depressants (such as fluoxetine) effect brain neurochemistry. The pertinent findings will be explained, and their implications on future anti-depressants will be addressed.

Many clinical studies have been used to suggest a role for serotonin in the propensity for depression or suicidal tendencies. Most of these studies measured the level of serotonin in the CSF in certain individuals. Results established a link between reduced serotonin neurotransmission and aggression, impulsivity, depression, and suicidal tendencies. Other data, using markers in presynaptic and postsynaptic serotonergic neurons have shown that reduction in serotonin neurotransmission is a biochemical "risk factor" for suicide (1).

Other clinical studies have implicated fluoxetine’s effects on serotonin neurotransmitters, based on the fact that serotonin is synthesized from the essential amino acid tryptophan. Patients taking fluoxetine who were in remission from major depression were given a special diet which was tryptophan-free. This rapidly decreased plasma serotonin levels, and after a short period of time (as little as 30 minutes) many of the patients began to have signs of specific depressive symptoms. Later, the reappearance of more general depressive symptoms were observed in a majority of the patients. Thus it was shown that fluoxetine has a profound effect on the neurotransmitter serotonin, and decreased serotonin leads to loss of efficacy of the drug and relapse of depression (2). This was in concurrence with other studies, some of which used specific serotonin-synthesis inhibitors instead of tryptophan-free diets.

The last 20 years have seen an explosion of research on the involvement or serotonin (5-Hydroxytryptamine) in the central nervous system. There are many reasons why the precise role of serotonin and anti-depressant functions have not been found. There has been a lack of specificity of clinically available probes, as well as vast limitations on clinically assessing brain serotonin function in humans. Nevertheless, many studies nave conclusively found that fluoxetine (and other antidepressants) enhances the concentration of serotonin in the CNS.

Recent studies on serotonergic synapses in the brain nave been fruitful due to the advancement of molecular biological assay techniques. Many post-synaptic serotonin receptors nave been cloned, and a large (and growing family of receptors has been categorized. There are three main families which are the 5HT₁ , 5HT₂ , and 5HT₃ receptors. Each of these is further divided into subclasses (e.g. 5HT_1a). Autoradiographic studies nave shown that the highest concentration of these receptors are found in the dentate gyrus, region Ca1 of the hippocampus and in the raphe nuclei. The discovery and elucidation of these receptors is extremely important, because they theoretically provide a target which could be manipulated to alter serotonin neurotransmission in a very specific way. Studies on serotonin receptors show that they likely activate the G1-- protein, leading to an increased activity of adenylate cyclase. This was elucidated using receptor agonists, which led to an inhibited adenylate cyclase activity (3). Although exact knowledge of the mechanism of serotonergic neurotransmission is still in the beginning stages, research is allowing pharmacotherapy to have a profound effect on people’s lives.

Other important studies have lead to the possible mechanism of action of fluoxetine, and how it differs from the action of other anti-depressants. Most antidepressants lead to an increase of serotonergic neurotransmission, but by different mechanisms. One study was done in the dorsal raphe of the brain (of a rat), which has the highest number of serotonin neurons. Two criteria were examined in the study: 1) the firing rate of serotonin neurons, and 2] the responsivity of the serotonin autoreceptor which plays a major role in the reuptake of serotonin from the synaptic cleft.

The firing rate of serotonin neurons is crucial because it exerts an important role in controlling serotonin release in post-synaptic regions. This part of the experiment used a complex electrophysiologic apparatus. Following 2 days of treatment with fluoxetine, the firing rate to the serotonin neurons had markedly decreased. After 7 days, the neuronal firing activity had partially recovered, and at 14 days the firing activity was back to normal. This surprising finding gives a very realistic explanation as to why fluoxetine has a delayed therapeutic activity in most patients (4).

The second part of the experiment used lysergic acid diethylamide {LSD}, a potent serotonin autoreceptor agonist which was administered intravenously. The autoreceptor was then tested for responsiveness to the agonist. This autoreceptor is believed to mediate an inhibitory effect of serotonin on its own release. The findings were that after 14 days of fluoxetine treatment, the autoreceptor sensitivity was markedly decreased. The serotonin post-synaptic receptors were also tested, but no change In their sensitivity could be observed. Hence, the desensitization of the somatodendritic autoreceptor allows for greater amounts of serotonin to be released after long-term treatment with fluoxetine. Exactly how this works is uncertain, but the p-trifluoromethyl group of fluoxetine (and its electron withdrawing effect) appears to be important in the mechanism (5).- By contrast, other anti-depressants (tricyclics, MAO s) given the same experimental conditions did not lead to a change in sensitivity of the serotonin autoreceptor. In fact, they led to an increased sensitivity in the post-synaptic serotonin receptor, which is the reason for their serotonin enhancement capacity. There were similar changes in the neuronal firing activity with the use of other anti-depressants (which also have a delayed therapeutic effect) (6). Hence, this study and others like it have provided feasible explanations for fluoxetine’s specificity and how its mechanism (and therefore side effects) differ from other anti-depressants.

Fluoxetine has gained is popularity with psychiatrists due to its reduced side-effects (as compared with other anti-depressants). The reason for this seems to stem from fluoxetine’s high selectivity for serotonin neurotransmitters. It appears to have little or no effect on other neurotransmitters such as norepinephrine and dopamine. In vitro studies have shown that fluoxetine has only a weak affinity for a₁-adrenergic, a₂ adrenergic, b-adrenergic, H₁ and H₂, opiate, muscarinic, GABA, and dopamine receptors (7). Hence fluoxetine has fewer side effects associated with these neurotransmitters (which other anti-depressants exhibit). Fluoxetine shows minimal cardiovascular side effects, due mainly to the absence of substantial anti-cholinergic activity. Many of the tricyclic anti-depressants cause an increase in heart rate. There are also no adverse side effects associated with the blocking or muscarinic cholinergic receptors (such as dry mouth, blurred vision, constipation, confusion). Fluoxetine is also shown to be less sedative than other anti-depressants, due to the lack of histamine receptor (H₁ and H₂) inhibition.

There are a few adverse side effects seen in patients receiving fluoxetine treatment. The main one is involved with the GI tract, where nausea is often times reported. The nausea is usually mild and goes away within a few weeks. Fluoxetine also decreases REM sleep, as do most other anti-depressants. In fact, this may contribute to the anti-depressant activity of the drug. Fluoxetine may cause weight loss, which is significant when treating persons afflicted with anorexia. Finally, an advantage of fluoxetine (not underestimated by psychiatrists treating depressed-patients) is the fact that it is much less lethal in mass doses (such as swallowing the whole bottle of pills) than are other popular anti-depressants. This makes it a relatively safer drug to prescribe than the others on the market (8).

A final word needs to be said on the reports which surfaced in l990 about the linkage between fluoxetine use and obsessions with suicide. These reports received wide publication around the world. However, studies done by the FDA, meta-analysis, opinion, and experience, indicated there was no increased risk of suicide while taking fluoxetine(9).

In conclusion, it is apparent that serotonin plays a crucial role in mediating the anti-depressant response in patients with clinical depression. Most anti-depressants have a common effect of enhancing serotonin neurotransmission. However, these chemically different drugs each have a different mechanism. Studies have been reported linking fluoxetine to the desensitivity of the serotonin autoreceptor. This is markedly different from the mechanism of other anti-depressants. The unique qualities of fluoxetine as a serotonin reuptake inhibitor are special for serotonin neurotransmission. This is the key to its advantages over other less specific anti-depressants. Exactly how increased serotonin content leads to remission from depression is still unclear. However, it is clear that fluoxetine (and other drugs; have had an enormous impact of the lives of many.

BIBLIOGRAPHY:

Beasely, C. M. et. al. Fluoxetine and suicide: a meta-analysis of controlled trials of treatment of depression. British Medical Journal, 1991,303:685-692.

Bleir, P., de Montigny, C. & Caput, Y. A role for the serotonin system in the mechanism of action of antidepressant treatments: pre-clinical evidence. Journal of Clinical Psychiatry. April 1990, 51(4): 14-21. (cited as 4 & 6)

Butler, J. & Leonard, B. E. Clinical and experimental studies on fluoxetine: effects on serotonin uptake. Int. Clinical Psychopharmacology, Jan. 1990, 5(1): 41-48.

Charney, D. S., Delgado, P. L., Price, L. H. Aghajanian, G. K., Landis, H., Heninger, G. R. Serotonin function and the mechanism of antidepressant action. Archives of General Psychiatry, May 1990, 47 (5): 411-418. (cited as 2)

Gonzalez-Heydrich, J., Paroutka, S. J. Serotonin receptor and reuptake sites; pharmacological significance. Journal of Clinical Psychiatry, 1990; 51(4): 5-12. (cited as 1 & 3)

Greenfield, D. P. & Brown, J. A. What about Prozac? New England Journal of Medicine, June 1992, 89(6):445-446. (cited as 9)

Hyman, S. E. & Nestler, E. J. The Molecular Foundations of Psychiatry. Washington Amer. Psych., 1993. (cited as 7 & 8)

Nathan, R. S., Perel, J. H., Pollock, B. G. & Kupfer, D. J. The role of neuropharmacologic selectivity in antidepressant action. Journal of Clinical Psychiatry, Sept. 1990, 51(9): 367-372.

Price, L. O., Charney, D. S., Goodman, W. K., Krystal, J. H., Woods, A. N. & Heninger, G. R. Clinical data on the role of serotonin in the mechanism of action of antidepressant drugs. Journal Clinical Psychiatry, April 1990, 51: 44-50. (cited as 5)

Richelson, E. Antidepressant and brain neurochemistry. Mayo Clinic Proc., Sept. 1990, 65(9): 227-236.

Somni, R. W., Crismon, M. L. & Bowden, C. L. Fluoxetine: a serotonin-specific, second-generation antidepressant, Pharmacotherapy, Jan.-Feb. 1987, 7(1): 1-15.