The COMT gene encodes catechol-O-methyltransferase which is an enzyme that plays a part in dopamine degradation in the prefrontal cortex, where dopamine transporters are scarce. The Val158Met (rs4680) polymorphism can alter COMT activity, which influences dopamine availability and antipsychotic response.

Met/Met (A/A at rs4680, low-activity COMT): Linked with higher prefrontal dopamine due to reduced enzyme activity. Met/Met individuals may have elevated dopamine tone that can enhance cognitive function but may reduce the tolerability to dopaminergic agents like antipsychotics. Additionally, some studies show that Met allele carriers have significantly improved antipsychotic responses.

Val/Val (G/G at rs4680, high-activity COMT): This genotype is associated with lower dopamine levels due to higher enzyme activity. Val/Val individuals often show better cognitive improvement with dopaminergic agents but may have less benefit from antipsychotics targeting the dopamine system. Some research (Huang et al., 2016) shows reduced treatment efficacy for Val/Val carriers when compared to Met/Met, especially with atypical antipsychotics.

Val/Met (A/G heterozygotes): Shows intermediate COMT activity and dopamine levels: clinically non-actionable, individuals have typical medication tolerability.