The current generation of antidepressant drugs acts predominantly by targeting 
the serotonin transporter (SERT). The original trend to do this selectively 
(e.g., with SSRIs or selective serotonin reuptake inhibitors) has given way to 
combining various additional pharmacologic mechanisms with SERT inhibition, 
including dual actions by single drugs (e.g., SNRIs or serotonin norepinephrine 
reuptake inhibitors), or by augmenting SSRIs with a second drug of a different 
mechanism (e.g., bupropion with dopamine and norepinephrine reuptake inhibition; 
trazodone with 5HT2A antagonism; mirtazapine with 5HT2A/5HT2C/5HT3/alpha2 
antagonism; buspirone or some atypical antipsychotics with 5HT1A partial 
agonism; other atypical antipsychotics with 5HT2C/5HT7 antagonism and other 
mechanisms). Novel drugs in development include those that combine multiple 
simultaneous pharmacologic mechanisms in addition to SERT inhibition within the 
same molecule, such as vilazodone (combining 5HT1A partial agonism with SERT 
inhibition), triple reuptake inhibitors (combining norepinephrine and dopamine 
reuptake inhibition with SERT inhibition), and vortioxetine, a multimodal 
antidepressant combining actions at the G protein receptor mode (5HT1A and 5HT1B 
partial agonism and 5HT7 antagonism), at the ion channel mode (5HT3 antagonism) 
as well as the neurotransmitter transporter mode (SERT inhibition). These 
various strategies that build upon SERT inhibition provide promise for novel 
therapeutic approaches to depression, including the possibility of targeting 
residual symptoms not well treated by SERT inhibition alone, and reducing side 
effects, such as sexual dysfunction.