Toward a Rapidly Acting Antidepressant: The Normetanephrine and Extraneuronal Monoamine Transporter (Uptake 2) Hypothesis

OBJECTIVE: The authors considered the possible role of the extraneuronal monoamine transporter (uptake 2) in accounting for the delay in clinical action of norepinephrine reuptake inhibitor antidepressant drugs. METHOD: Literature searches were performed by means of the MEDLINE and Current Contents databases with search terms such as “extraneuronal uptake,” “uptake 2,” “extraneuronal monoamine transporter,” and “organic cation transporter type-3.” RESULTS: The findings in this literature indicate that inhibition of glial uptake 2 by normetanephrine or other inhibitors of uptake 2 would enhance the accumulation of norepinephrine in the synapse. CONCLUSIONS: The authors propose the hypothesis that drugs or other agents that increase levels of normetanephrine or otherwise inhibit the extraneuronal monoamine transporter, uptake 2, in the brain will speed up the clinical effects of norepinephrine reuptake inhibitor antidepressant drugs.