Neuroinflammation as a Pharmacological Target in Psychiatric Disorders.

Neuroinflammation in major depressive disorder: Mechanisms, biomarkers, and emerging therapeutic targets

Major depressive disorder (MDD) affects an estimated 280 million people worldwide and remains a leading cause of disability. The monoamine hypothesis, and later the neuroplasticity hypothesis, transformed treatment but leave a substantial share of patients with delayed response, partial remission, or outright treatment resistance. Over the past two decades, evidence has accumulated that a subset of MDD is driven by chronic, low-grade neuroinflammation rather than, or in addition to, monoaminergic deficits. This review synthesizes current evidence on the neuroimmune mechanisms involved in MDD microglial activation, pro-inflammatory cytokine signaling, blood–brain barrier disruption, oxidative stress, kynurenine pathway dysregulation, and impaired neuroplasticity and examines how these mechanisms are captured by peripheral, central, neuroimaging, and emerging molecular biomarkers. It then reviews therapeutic strategies that target inflammation directly (minocycline, celecoxib, TNF-α antagonists), indirectly (selective serotonin reuptake inhibitors (SSRIs), serotonin-norepinephrine reuptake inhibitors (SNRIs), ketamine), or through lifestyle modification (exercise, diet, sleep), with attention to why inflammation-stratified trials have outperformed unstratified ones. Across mechanisms, biomarkers, and treatment response, a consistent pattern emerges: neuroinflammation does not simply co-occur with depression, it may mark a biologically distinct, identifiable subtype roughly a quarter to a third of patients with elevated high-sensitivity C-reactive protein (hsCRP) or IL-6 for whom anti-inflammatory or immune-modulating strategies produce disproportionate benefit. Overall, the findings suggest that neuroinflammation represents a promising and increasingly actionable target for biomarker-guided, personalized psychiatric care.

Microglial advances in psychiatric disorders.

Targeting RIPK1 for the treatment of depression: From neuroinflammation to synaptic plasticity.

This review discusses the mechanisms by which RIPK1 participates in the pathological process of depression, including its role in neuroinflammation and synaptic plasticity, and outlines the effects of RIPK1 inhibitors in animal models.

Molecular and Cellular Mechanisms Linking Mood Disorders, HPA Axis Dysregulation, and Neurocognitive Inflammation to Perioperative Neurocognitive Disorders

Perioperative neurocognitive disorders (PND) encompass a spectrum of cognitive impairments occurring across the surgical period and are associated with significant morbidity, delayed recovery, and reduced quality of life. Although established risk factors include advanced age, cardiovascular disease, and preexisting cognitive impairment, the contribution of mood disorders to PND susceptibility remains incompletely understood. This review systematically examines the neurobiological overlap between mood disorders, particularly major depressive disorder (MDD) and bipolar disorder, and PND, with emphasis on shared biomolecular mechanisms. We identify convergent pathophysiologic pathways including hypothalamic–pituitary–adrenal (HPA) axis dysregulation, chronic neuroinflammation, NF-κB-mediated cytokine signaling, microglial priming, tryptophan–kynurenine pathway dysregulation, and brain-derived neurotrophic factor (BDNF) suppression. These mechanisms collectively suggest that patients with preexisting mood disorders may enter surgery in a biologically sensitized neuroimmune state, lowering the threshold for exaggerated neuroinflammatory responses and postoperative cognitive dysfunction. Recognition of mood disorders as modifiable perioperative vulnerability states may inform preoperative risk stratification, guide anesthetic and analgesic management, and support the development of targeted interventions to reduce postoperative cognitive complications and improve surgical outcomes.

Astroglial dysregulation and gliotransmitter imbalance in schizophrenia.

From Xenobiotic Exposure to Neuroinflammation: Mechanisms Linking Lipopolysaccharide Signaling to Depressive-like Behavior

Depression is increasingly recognized as a multifactorial disorder involving immune, metabolic, and neurobiological disturbances that extend beyond classical monoaminergic hypotheses. Among xenobiotic-based experimental approaches, lipopolysaccharide (LPS) has become a valuable tool for investigating how peripheral inflammatory stimuli are translated into central neurobiological dysfunction. This narrative review aimed to integrate current evidence regarding the mechanisms by which LPS-induced neuroimmune activation contributes to depression-related phenotypes and to discuss the translational relevance of these findings. Literature searches were performed in PubMed, ScienceDirect, and Google Scholar, focusing on studies addressing inflammatory signaling, oxidative imbalance, inflammasome activation, neurotransmitter dysfunction, and experimental modeling strategies. Current evidence suggests that LPS-induced neuroinflammation involves a dynamic interaction between peripheral immune signaling, mitochondrial dysfunction, redox imbalance, and glial activation, establishing self-amplifying mechanisms capable of sustaining chronic inflammatory states. Such alterations profoundly affect kynurenine metabolism, glutamatergic homeostasis, and reward-related neurotransmission, thereby contributing to synaptic dysfunction and behavioral impairment. Experimental findings obtained from animal, cellular, and computational platforms further support the emergence of integrated therapeutic strategies targeting multiple neuroimmune pathways. Collectively, these observations reinforce the concept that neuroinflammation represents a central biological interface linking xenobiotic exposure to depressive-like behavior.