Molecular and cellular mechanisms of depression

Over the past three decades, considerable progress has been made in our understanding of the biology of depressive disorders. Still, there are a great number of unanswered questions regarding the relative roles specific biological sys-tems may play in pathogenesis. This debate in part reflects a number of methodologic factors: a possibly over broad definition of the clinical syndrome of major depression; lim-itations inherent in studies using indirect measurement of brain neuronal activity; problems inherent in postmortem studies; and an overemphasis on cross-sectional rather than longitudinal studies. In this chapter, we review the current status of the neurochemical and cellular features of depres-sive disorders. BACKGROUND Although Freud put forth a hypothesis for understanding the psychological causes of depression in his classic paper, ‘‘Mourning and Melancholia,’ ’ he noted that some depres-sions were clearly biological in etiology. Research over the past 40 years has done much to point to likely ‘‘culprits’’ that are involved in the etiology of the disorder as well as in the mediation of treatment response; these have been reviewed several times recently (1,2). Early research revolved around monoaminergic theories with particular emphasis first on norepinephrine and later serotonin. The basis for invoking these systems rested largely on a number of pharmacologic observations that have been termed ‘‘the psychopharmacologic bridge.’ ’ These observa-tions included: reserpine, an early antihypertensive, caused depression in some patients and depleted monoamine stores in rat brain; iproniazid, a drug studied as an antitubercula