Certain of the newer antidepressants act as selective serotonin reuptake inhibitors (SSRIs) and apparently produce their salutary effects by increasing the amount of serotonin that is functionally active in the synapse (they also raise the concentrations of norepinephrine). For these reasons, serotonin and its neuronal pathways are also currently implicated in the genesis of depression. However, the reader should be reminded that only 2 decades ago it was widely held that depletion of norepinephrine fulfilled this role. It is also not yet clear which neurochemical alterations are primary and which modulate other systems. For example, reports suggest that substance P plays an important role in the causation of depression (Kramer et al) and that blockade of substance P receptors has antidepressant effects. Why there is a delay of several weeks in the improvement of depression related to the taking of the various antidepressants is unexplained by any of the neurochemical models.
Another set of observations that has continued to capture interest implicates a disorder of hypothalamic–pituitary–adrenal axis function (summarized by Schlesser et al). It had been found several decades ago that the parenteral administration of 1 to 2 mg of dexamethasone failed to suppress serum cortisol secretion while the patient was ill with endogenous depression, but did so after recovery. In a comparable series of reactive depressions, there was a normal suppression of cortisol secretion. Originally, the dexamethasone suppression test was believed to separate the 2 large groups of depressed patients and to predict the response to drug therapy. However, subsequent studies have shown that the specificity of this test was far less than earlier reports had indicated (Amsterdam et al; Insel et al). Accumulated evidence indicates that 50 percent of severely depressed patients do not show suppression of cortisol secretion, and a positive test can be obtained in a significant number of patients with other psychiatric disorders.
The failure of dexamethasone suppression has been attributed to hyperactivity in the hypothalamic pituitary axis and a corresponding increase in secretion of corticotropin-releasing hormone, adrenocorticotropic hormone (ACTH), and glucocorticoids. Elevated levels of glucocorticoids have been theorized to impede neurogenesis in the medial temporal lobe, and perhaps to explain or exaggerate the loss of hippocampal neurons demonstrated in some studies of the brains of deceased depressed patients. A proposal that ECT acts by elevating levels of neurotrophic factors is at least consistent with this view and with the hypothesis that one component of recovery from depression is in some way associated with restoration of normal neuronal architecture in regions of the hippocampus and the hypothalamus (Chen). Although highly speculative, perhaps some of these changes explain the delay in improvement after the administration of antidepression drugs.
At the present time, it must also be conceded that there is no reliable biologic test for depression. One must resort to clinical analysis not only for diagnosis but also for the differentiation of special types of depressive reactions.