This hypothesis, initially based on the unintentional findings that chemical compounds inhibiting reuptake (imipramine) or metabolism (iproniazid) of monoamine neurotransmitters (5-HT and NE) would demonstrate antidepressant efficacy (Hirschfeld, 2000; Mulinari, 2012), claims that MDD is derived from deficiency of 5-HT and/or NE in the synaptic cleft, and antidepressant efficacy would be achieved by increasing 5-HT and/or NE in synaptic cleft through inhibiting clearance or promoting synthesis and release of these monoamines. The gene discussed is HTR5A; the disease is major depressive disorder.