Over 30 years ago, the first antidepressants were introduced. These were the tricyclic antidepressants (TCA's), such as amitriptyline and imipramine, the monoamino oxidase (MAOI) inhibitors, exemplified by phenelzine and paryline. Despite their well-established efficacy in the treatment of major depression (TCA's) or the atypical depressions (MAO inhibitors), the high frequency of side effects and cardiotoxicity associated with the TCS's, particularly in overdose, and the possibility of a hypertensive crisis resulting from an interaction between MAO inhibitors and primary amine-containing foods precipitated the search for therapeutically effective antidepressants that were better tolerated and less toxic.Antidepressants with selectivity for inhibiting the reuptake of noradrenaline (norepinephrine), the SBRI's, or serotonin (5-hydroxytryptamine, 5-HT), SSRI's, were subsequently developed and shown to be equieffective with the first-generation drugs (TCA's and MAO inhibitors), but were much safer in overdose and better tolerated.Realization that the older MAO inhibitors such as phenelzine were liable to precipitate hypertension (and possibly stroke) in patients consuming high quantities of tyramine-containing foods contributed to the search for safer MAO inhibitors. The subsequent discovery that MAO exists in two major forms (MAO-A and -B) which can be distinguished by their substrate affinities for noradrenaline and serotonin (A form) or dopamine (B form), led to the development of selective MAO-A and -B inhibitors. Examples of selective MAO inhibitors include moclobemide, a so-called reversible inhibitor of MAO-A (RIMA), and selegiline, a selective MAO-B inhibitor which is used as an adjunct to L-dopa in the treatment of Parkinson's disease. The advantage of such drugs lies in their greater safety should a patient eat a larger quantity of tyramine-containing food. The discovery of the RIMA;s has indeed resulted in the restitution of MAO inhibitors in the treatment of major depression.The latest antidepressants are reported to derive their therapeutic benefits from simultaneous action on more than one neurotransmitter system in the mammalian brain. These agents include mirtazepine and setiptiline. However, only mirtazepine has been extensively studied so far and, because of its apparent selectivity for alpha 2-adrenoceptors and some serotonin receptor subtypes, it has been called a noradrenergic and specific serotonergic antidepressant. By contrast, venlafaxine and milnacipran are effective antidepressants that inhibit both noradrenaline and serotonin uptake.Novel drugs in development include a series of 5-HT receptor partial agonists (such as ipsapirone and zalospirone) and agents showing selectivity for their inhibitory action on dopamine reuptake (such as bupropion). A more detailed list of the novel second-generation antidepressants that have either been marketed or are in clinical development is shown in Table 1.