Serotonergic mechanisms of depression.

Data gathered for the past 30 years suggest 5-HT abnormalities in depression, but it is still unknown whether serotonin has a major causal role. Depression is often regarded as a result of defective serotonergic function, but it is also possible that this defect is an indication of an ineffective compensatory response to abnormally high serotonergic function. Abnormal 5-HT function could be a result of disturbances at various pre- and postsynaptic levels. The disturbances reported at most of these levels are largely subject to dispute. Specific abnormalities can occur in specific subgroups and can be either state or trait dependent. Nevertheless, 5-HT hypotheses have been helpful for the development of drugs, although even here there is disagreement as to their actual mechanism of action. Two recent developments can help to clear up these uncertainties. First, the discovery of many types of 5-HT receptors and the increasing availability of drugs specifically related to them provides new adaptable research tools as well as the possibility of new therapies. Second, data provided by studies of humans and by animal models suggest that vulnerability to depression depends on disturbances of both 5-HT and the hypothalamohypophysial axis.