The Emerging Role of the DDAH Proteins in Psychiatric Disorders

The heterogeneous nature of psychiatric disorders complicates their clinical management and the development of novel treatments, imposing a significant burden on both patients and health care systems. To address these challenges, it is essential to continuously identify new targets involved in their pathogenesis. In this narrative review, we propose the dimethylarginine dimethylaminohydrolase (DDAH) proteins, already known for their significant role in cardiovascular disease, as promising novel treatment targets for psychiatric conditions. The DDAH proteins exist in 2 isoforms, DDAH1 and DDAH2, which both regulate nitric oxide homeostasis. DDAH1 metabolizes the nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA), while DDAH2 acts through ADMA-independent mechanisms. We synthesize current evidence from systemic studies, genetic analyses, postmortem brain samples, and animal models to evaluate the potential roles of DDAH proteins across psychiatric conditions. Most systemic studies have revealed increased peripheral ADMA levels across several psychiatric disorders, including schizophrenia, depression, bipolar disorder, substance use disorders, and attention-deficit/hyperactivity disorder. Alterations in ADMA levels are also observed in transdiagnostic clinical domains such as cognitive deficits, sleep disturbances, white matter hyperintensities, and oxidative stress. These ADMA changes are evident from early stages of illness and respond to current treatments, suggesting diagnostic potential. Genetic and postmortem brain data further link DDAH1 and DDAH2 to psychiatric symptomatology in patient populations. Finally, fundamental studies in model systems provide insights into their role in neural proliferation, differentiation, cell death, and oxidative stress regulation-key processes in the developing and the adult brain. These data support the view that DDAH proteins may play a role in the molecular mechanisms that underlie psychiatric disorders and merit more investigation as potential therapeutic candidates.