best comparable to TCAs in this respect. (Figure 1.) For a detailed discussion on the mechanism of action of the different, drug classes see ref 8. Finally, in our classification we call third-generation drugs (TGAs) novel compounds that are in most cases characterized by nonmonoaminergic mechanisms (although some of these have been in development for quite a while).

TGAs will be analyzed in the last chapter of this article, dealing with new targets for the development, of antidepressants. Figure 1 Main classes of antidepressant drugs from the 1960s to present times. FGA, first-generation antidepressant; SGA, Inhibitors,research,lifescience,medical second-generation antidepressant; TGA, third-generation antidepressant (only the main classes of antidepressants Inhibitors,research,lifescience,medical in development

are reported … Monoamine hypothesis of depression: inconsistencies As addressed above, the monoamine hypothesis of depression and mood disorders was mainly based on the mechanism itself of the first antidepressant drugs, MAOIs and TCAs. Additional evidence was based on the prodepressive effect of the antihypertensive reserpine, which depletes storage vesicles containing noradrenaline and other monoamines. The basic version of the hypothesis stated that depression was due to reduced availability of monoamines, particularly Inhibitors,research,lifescience,medical noradrenaline and serotonin, and that antidepressants exerted their therapeutic action by increasing the extracellular availability of monoamines, particularly Inhibitors,research,lifescience,medical at. synaptic

level.9 However, the hypothesis was soon criticized because it was evident that increased availability of monoamines, due to inhibition of reuptake or metabolism, developed in a matter of hours, could not be the direct, mechanism Inhibitors,research,lifescience,medical of the therapeutic effect, which develops only after several weeks. Therefore, in the following decades, with the progress of pharmacological research, updated versions of the hypothesis have followed, as schematized in the following section. Evolution of antidepressants The monoamine hypothesis has much evolved from the 1960s to present times, along with the revolutionary changes that have affected the neurosciences (Table I). Part, of CX-5461 in vitro the increased knowledge of intracellular, gene expression, and synaptic mechanisms has been incorporated into the hypothesis, contributing to building up its present version. However, it. is the opinion of these click here authors that pharmacological research on psychiatric disorders has still insufficiently taken advantage of the translation al opportunities offered by the present state of neuroscience research, and that this is one of the reasons for the present lack of new drugs in psychiatry (for a discussion of this issue sec rets 3,10). Table I Evolution of hypotheses on the pathophysiology/pharmacotherapy of mood disorders.