Theory Into Practice-Addressing the Homocysteine Basis of Depression

The success of antidepressant medications has been cited as evidence for the monoamine hypothesis of depression. Yet, this hypothesis simply elaborates that monoamines are lower than optimal in major depressive disorder, not why they are low in genetically vulnerable individuals. The homocysteine (HCY) theory argues the cause of low monoamines can be traced to low levels of coenzymes and cofactors that are necessary for their production. We can now prescribe agents generally recognized as safe, and designed to provide neurons with every coenzyme necessary for optimal HCY metabolism and monoamine synthesis. The coenzyme l-methylfolate is not only necessary for HCY reduction, but is instrumental in the production of the cofactor BH4, which aids tyrosine hydroxylase and tryptophan hydroxylase. Thus, using metabolized B vitamins enhances monoamine production at all levels. The literature regarding the use of B vitamins for depression is daunting, but this article elaborates key principles that will guide clinicians, and argues that this approach deserves first-line consideration.