The COMT gene encodes catechol-O-methyltransferase, an enzyme responsible for dopamine degradation in the prefrontal cortex, where dopamine transporters are scarce. The Val158Met (rs4680) polymorphism alters COMT activity, influencing dopamine availability and antipsychotic response:

• Met/Met (A/A, low-activity COMT): Results in reduced enzyme activity and higher prefrontal dopamine. While this can enhance cognitive function, it may reduce tolerability to dopaminergic agents like antipsychotics. However, some studies indicate Met allele carriers exhibit significantly improved antipsychotic responses.
• Val/Val (G/G, high-activity COMT): Results in higher enzyme activity and lower dopamine levels. These individuals often show better cognitive improvement with dopaminergic agents but may experience reduced treatment efficacy from antipsychotics (especially atypical antipsychotics) compared to Met/Met carriers (Huang et al., 2016).
• Val/Met (A/G heterozygotes): Results in intermediate COMT activity and dopamine levels. Individuals typically experience standard medication tolerability.