Integration of Hypotheses
Regarding the Pathophysiology of Depression
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.