The HTR2A gene encodes the 5-HT2A receptor which is a key serotonin receptor. It plays a role in mood regulation, sleep, anxiety, and emotional processing. SSRIs indirectly affect this receptor by increasing extracellular serotonin.

Two commonly studied HTR2A polymorphisms that affect SSRI response and sensitivity are rs6311 (−1438G/A) and rs6313 (102T/C).

The G/G genotype of rs6311 is associated with lower 5-HT2A receptor density, meaning that there are fewer serotonin 2A receptors in a specific region of the brain. This may cause blunted emotional response/apathy and lower SSRI efficiency, which can lead the individual to be labeled as treatment resistant due to their lack of emotional responsiveness.

The rs6313 (102T/C) mutation is highly similar to the rs6311 allele where (C/C) may lead to jitteriness or impulsivity.

Overall, low threshold responders with these polymorphisms may show hypersensitivity to serotonergic modulation and experience opposite reactions (worsening of anxiety or insomnia instead of helping it), which can lead to the patient discontinuing treatment.