Neuroinflammation as a Pharmacological Target in Psychiatric Disorders

Abstract:

Neuroinflammation is increasingly recognized as a pivotal mechanism linking immune dysregulation with the onset, progression, and treatment resistance of major psychiatric disorders. Once considered distinct from classical neurodegenerative diseases, psychiatric conditions such as Major Depressive Disorder (MDD), schizophrenia, bipolar disorder, and anxiety disorders are now known to involve chronic, low-grade inflammation within the Central Nervous System (CNS). Persistent activation of microglia and astrocytes, together with disruption of Blood–Brain Barrier (BBB) integrity, initiates neurotoxic cascades that alter the balance between pro-inflammatory and anti-inflammatory cytokines. These alterations impair neurotransmission, reduce neuroplasticity, increase oxidative stress, and ultimately contribute to neuronal dysfunction. Several molecular pathways, including Nuclear Factor Kappa B (NF-κB), the NLRP3 inflammasome, and the kynurenine pathway (KP), play central roles in mediating these inflammatory responses. Activation of the KP diverts tryptophan metabolism away from serotonin synthesis toward the production of neuroactive metabolites such as quinolinic acid, thereby promoting excitotoxicity and neurodegeneration. Elevated circulating inflammatory biomarkers, including C-Reactive Protein (CRP), interleukin-6 (IL-6), and Tumor Necrosis Factor- alpha (TNF-α), have been consistently associated with increased disease severity and poor response to conventional monoaminergic therapies. Consequently, pharmacological modulation of neuroinflammation has emerged as a promising therapeutic strategy. Current and emerging approaches include cyclooxygenase-2 (COX-2) inhibitors, cytokine-targeted therapies, modulators of microglial activation, antioxidant agents such as N-acetylcysteine and omega-3 fatty acids, as well as novel therapeutics targeting the NLRP3 inflammasome, P2X7 receptors, and microglial polarization. Furthermore, integrating inflammatory biomarker profiling with advanced neuroimaging techniques, including Translocator Protein Positron Emission Tomography (TSPO-PET), may facilitate patient stratification and enable precision psychiatry. A comprehensive understanding of neuroinflammatory mechanisms may therefore provide new opportunities for developing targeted therapeutic interventions and improving clinical outcomes in psychiatric disorders.