The SLC6A4 gene encodes the serotonin transporter (5-HTT), which is responsible for reuptake of serotonin from the synaptic cleft back into presynaptic neurons. This transporter is the primary target of SSRIs. The 5-HTTLPR polymorphism in the gene promoter has two main alleles:

Short (S) allele: Associated with reduced transcriptional efficiency: fewer serotonin transporters expressed.

Long (L) allele: Higher expression of transporters.

Individuals with the S/S genotype have significantly reduced transporter expression compared to L/L or L/S genotypes.

This can cause:

Reduced SSRI efficacy

Increased risk of side effects (such as mood instability, agitation, anxiety, insomnia, and emotional distress or blunting) and can also be linked to bipolar symptoms with rapid mood cycling