Dopaminergic Epistases in Schizophrenia

Background: The dopaminergic theory, the oldest and most comprehensively analyzed neurotransmitter theory of schizophrenia, remains a focal point of research. Methods: This systematic review examines the association between combinations of 14 dopaminergic genes and the risk of schizophrenia. The selected genes include dopamine receptors (DRD1-5), metabolizing enzymes (COMT, MAOA, MAOB, DBH), synthesizing enzymes (TH, DDC), and dopamine transporters (DAT, VMAT1, and VMAT2). Results: Recurring functional patterns show combinations with either hyperdopaminergic effects in limbic and striatal regions or high striatal and low prefrontal dopamine levels. The protective statuses of certain alleles or genotypes are often maintained in epistatic effects; however, exceptions exist. This complexity could explain the inconsistent results in previous genetic studies. Investigating individual alleles may be insufficient due to the heterozygous advantage observed in some studies. Conclusions: Schizophrenia may not be a monolithic disease, but rather a sum of different phenotypes which respond uniquely to different treatment and prevention approaches.