Peripheral Immune-Inflammatory Pathways in Major Depressive Disorder, Bipolar Disorder, and Schizophrenia: Exploring Their Potential as Treatment Targets

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Abstract
Major depressive disorder (MDD), bipolar disorder (BD), and schizophrenia (SCZ) are major mental disorders linked to substantial morbidity. Traditional monoamine-based pharmacotherapies frequently produce inadequate outcomes for many patients. The elevated levels of treatment resistance require the exploration of new pharmacological targets. Evidence indicates that peripheral immune-inflammatory dysregulation, characterized by an imbalance between immunological responses and compensatory immune-regulatory systems (IRS/CIRS), together with increased oxidative and nitrosative stress (O&NS), significantly contributes to the pathogenesis of these disorders. This review examines IRS/CIRS/O&NS pathways as new drug targets and highlights novel pharmacological trials. Antiinflammatory drugs have been repurposed as augmentation strategies for the treatment of MDD/BD and SCZ, including nonsteroidal antiinflammatory medications, such as cyclooxygenase-2 (COX-2) inhibitors; cytokine-targeting biologics, such as tumor necrosis factor-α monoclonal antibodies; and minocycline, an antibiotic that attenuates neuroinflammation. N-acetylcysteine, curcumin, and omega-3 polyunsaturated fatty acids demonstrate some efficacy as augmentation therapies in MDD, likely by diminishing IRS activation and O&NS. Strategies aimed at the gut–brain axis and gut dysbiosis, including fecal microbiota transplantation, are under investigation for their capacity to restore immunological homeostasis by improving gut barrier integrity and microbiome composition. This review examines new potential therapeutic targets arising from recent discoveries in neuro-immune interactions and oxidative stress, including particular lymphocyte surface markers, the CIRS, and intracellular network molecules in both affective and psychotic disorders. The evidence underscores the clinical importance of immune-targeted augmentation treatments in psychiatric disorders and supports the ongoing development of these novel pharmacotherapies within a precision medicine paradigm.

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