Third-generation antidepressants

Future Outlook for Antidepressants. Third-generation antidepressants are expected to combine superior efficacy and improved safety, but are unlikely to reduce the onset of therapeutic action in depressed patients (179). Many dmgs in clinical development as antidepressive agents focus on estabhshed properties such as inhibition of serotonin, dopamine, and/or noradrenaline reuptake, agonistic or antagonistic action at various serotonin receptor subtypes, presynaptic tt2-adrenoceptor antagonism, or specific monoamine—oxidase type A inhibition. Examples include buspirone (3) (only... 

Table 70-11 compares second- and third-generation antidepressants for their effects on the enzymes of the CYP450 system. 

Second- and Third-Generation Antidepressants and Cytochrome (CYP) P450 Enzyme Inhibitory Potential... 

Leysen D, Pinder RM Toward third generation antidepressants. Annual Report in Medicinal Chemistry 29 1-12, 1994... 

A critical review by Olver et al. (2001) on so-called third-generation antidepressants (venlafaxine, reboxetine, nefazodone, mirtazapine) covered 30 controlled therapeutic trials and a number of relapse prevention studies. Questions addressed were overall efficacy, speed of onset and safety but, according to this review, none of the third-generation antidepressants was specifically tested with respect to its potential effects on cognitive function in depressed patients. 

Olver, J.S., Burrows, G.D., Norman, T.R. Third-generation antidepressants. Do they offer advantages over the SSRIs CNS Drugs 15, 941-954, 2001. 

Hoping to avoid such side effects as the sleep disruption and the occasional cardiac complications of the tricyclic antidepressants, and following the principle that clean drugs are theoretically preferable to dirty ones, the pharmaceutical industry has developed the selective serotonin reuptake blockers, a third generation of chemical agents to relieve depression. 

Tricyclics and the second- and third-generation agents differ mainly in the degree of sedation they produce (greatest with amitriptyline, doxepin, trazodone, and mirtazapine) and their antimuscarinic effects (greatest with amitriptyline and doxepin Table 30-3). SSRIs are generally free of sedative effects and remarkably safe in overdose. Combined with the ease of once-a-day dosing, these qualities may explain why they have become the most widely prescribed antidepressants. 

A third generation of antidepressants will be needed to advance into an era of higher selectivity to yield even safer and especially more effective compounds. The roadblock may well be still insufficient neurochemical knowledge. Even though the second-generation drugs discussed are safer than were the early compounds, their impact therapeutically... 

Identify the second- and third-generation heterocyclic antidepressants and their distinctive properties. 

Heterocyclics (second- and third-generation antidepressants) Drugs of varied chemical structures several have actions different from those of tricyclic antidepressants or selective serotonin reuptake inhibitors... 

The second-generation antidepressants, particularly RIMAs and SSRJs, are much less toxic ia overdose than the older TCAs and irreversible MAO inhibitors. However, similar to first-generation antidepressants, the therapeutic effect only becomes manifest after several weeks. Up to one-third of depressed patients are nonresponders. Ideally, an antidepressant would combine a more rapid onset of action with greater clinical efficacy and a higher responder rate, as well as even better tolerability. 

This third edition essentially retains the structure of the second edition but its contents have been revised, with considerable changes in some parts. Thus, account is taken of the fact that a new generation of antidepressants has been available for some years, that concepts of the mechanisms of neuroleptic action have altered several times and have led to products with new mechanisms of action, and that therapeutic advances have even been recorded in a field that was only recently considered to be hopeless, namely Alzheimer s disease. New methodological developments, especially in the use of imaging techniques in psychiatry, and changes in opinions on the best possible use of psychopharmaceuticals and their duration of use in schizophrenia and depression have been suitably taken into account. 

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