Mechanism Of Action

Early biochemical theories of depression were in large part based on the knowledge of drug action. The observation that the tricyclic agents increased the availability of norepinephrine and serotonin suggested that depression resulted from a deficit in these neurotransmitters (Bunney and Davis 1965; Prange 1965; Schildkraut 1965). This work stimulated interest in the role of these neurotransmitters in the etiology of depression, and several abnormalities were identified. Yet, it remains unclear which, if any, of these abnormalities play a central role in causing depression or are responsible for the vulnerability to becoming depressed.

Recent challenge studies in depressed patients do confirm that the actions of antidepressant drugs are mediated by serotonin and norepinephrine. For example, administration of a tryptophan-free diet rapidly depletes serotonin and, in depressed patients who have been successfully treated, causes relapse (Delgado et al. 1990). In addition, tryptophan depletion caused relapse in patients who were treated with serotonergic agents, whereas those who were treated with norepinephrine reuptake inhibitors were relatively unaffected. Alternatively, administration of AMPT, which interrupts the synthesis of catecholamines, caused relapse in patients who were being successfully treated with noradrenergic agents but not those receiving serotonergic drugs (Delgado et al. 1993). Tryptophan depletion in untreated depressed patients, however, had no effect on the patients' depression. These studies provide supporting evidence that serotonin and norepinephrine mediate antidepressant effects, but they do not necessarily imply that alterations in these neurotransmitter systems are central to the pathophysiology of depression.

The synaptic effects of tricyclic and tetracyclic agents on norepinephrine and serotonin transporters and receptors were described in detail earlier (see section "Pharmacological Profile" earlier in this chapter).

The early theories of depression that focused on depletion of norepinephrine or serotonin suggested that it might be possible to identify "serotonergic" and "noradrenergic" depressions and that such identification would help the clinician select the appropriate type of antidepressant (Beckmann and Goodwin 1975; Maas et al. 1972). A number of studies investigated the predictive value of urinary MHPG, a metabolite of norepinephrine, but a definite predictive link with a noradrenergic antidepressant was not established. Some of these studies were, in part, hampered by the use of agents such as amitriptyline and imipramine, which are not very selective. However, even those studies that examined the ability of MHPG to predict response to more selective agents, such as zimelidine, fluoxetine, and desipramine, failed to demonstrate clear predictive utility (Bowden et al. 1993; Potter 1984). The data, taken together, suggest that urinary MHPG is not a clinically useful predictor. Nevertheless, these studies do not rule out the possibility that there are depressions in which serotonin or norepinephrine plays a relatively more prominent role.

More recently, research into the mechanism of action of the tricyclics and other antidepressant drugs has shifted to include consideration of factors affecting postsynaptic signal transduction (Manji et al. 1995). These factors include coupling of G proteins to the adrenergic receptor or to adenylyl cyclase and the activity of membrane phospholipases and protein kinases. Other novel targets, including glucocorticoid receptors (Barden 1996), neurotrophic factors (Duman et al. 1997), and gene expression (Lesch and Manji 1992; Nibuya et al. 1996; Schwaninger et al. 1995), have been explored.

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