Inadequate Homocysteine Metabolism: A Theory of Depression

Abstract

Over the past 100 years, theories regarding the etiology of major depression have appeared as the proverbial blind man’s interpretation of the elephant. It is now possible to discuss depression in terms of neuroendocrine dysregulation, differences in neuroanatomy, inflammatory response, a gene-environment interaction, or in purely psychological terms—and without any contradiction in the evidence. Indeed, a disorder as complex and variable as depression is expected to have multiple risk factors and etiologic influences. Yet, all roads eventually lead to a functional shortage of monoamines, and the monoamine hypothesis remains the basis of treatment for millions of patients. Elevated homocysteine (HCY) has long been recognized as a risk factor for major depressive disorder (MDD), and many neurologic and psychiatric conditions; however, a full understanding of HCY metabolism and monoamine synthesis indicates that perhaps HCY elevation in the central nervous system is the driving force behind MDD. The HCY theory argues that a genetically based inability to optimally metabolize HCY leads to inadequate supplies of monoamines, particularly in the presence of psychosocial stress, and results in the clinical syndrome of MDD. [ Psychiatr Ann . 2015;45(9):469–472.]