HTR4 and major depressive disorder: As shown in a mixed male-female cohort of MDD patients, only those responding to treatment had a lower baseline (unmedicated) 5-HT4R level compared to healthy controls, so it has been speculated whether they have a serotonergic subtype of MDD, in which the lower binding is due to a compensatory upregulation of the serotonergic tonus as an attempt to maintain euthymia (26).