The COMT gene encodes an enzyme that breaks down dopamine in the prefrontal cortex. A common polymorphism in this gene is Val158Met (rs4680), which alters the activity of the COMT enzyme and influences dopamine levels in the brain.

Met/Met genotype: This genotype leads to low COMT enzyme activity, resulting in higher levels of dopamine in the prefrontal cortex. Individuals with this genotype may be more sensitive to serotonin and dopamine interactions, and are at increased risk of agitation, overstimulation, or emotional reactivity when treated with SSRIs.

Val/Val genotype: This genotype produces a high-activity form of the COMT enzyme, leading to lower dopamine levels in the prefrontal cortex. Individuals with this genotype experience a blunted antidepressant response, slower symptom improvement, and may be perceived as treatment resistant due to reduced emotional responsiveness during SSRI treatment.