Integration of Hypotheses Regarding the Pathophysiology of Depression

Integration of Hypotheses Regarding the Pathophysiology of Depression

The several pathophysiologic hypotheses just described are not mutually exclusive. It is evident that the monoamine, neuroendo-crine, and neurotrophic systems are interrelated in important ways. For example, HPA and steroid abnormalities may contribute to sup-pression of transcription of the BDNF gene. Glucocorticoid recep-tors are found in high density in the hippocampus. Binding of these hippocampal glucocorticoid receptors by cortisol during chronic stress states such as major depression may decrease BDNF synthesis and may result in volume loss in stress-sensitive regions such as the hippocampus. The chronic activation of monoamine receptors by antidepressants appears to have the opposite effect of stress and results in an increase in BDNF transcription. In addition, activation of monoamine receptors appears to down-regulate the HPA axis and may normalize HPA function.

One of the weaknesses of the monoamine hypothesis is the fact that amine levels increase immediately with antidepressant use, but maximum beneficial effects of antidepressants are not seen for many weeks. The time required to synthesize neurotrophic factors has been proposed as an explanation for this delay of antidepres-sant effects. Appreciable protein synthesis of products such as BDNF typically takes 2 weeks or longer and coincides with the clinical course of antidepressant treatment.