Pharmaceutical-mediated neuroimmune modulation in psychiatric/psychological adverse events

The therapeutic use of many pharmaceuticals, including small molecules and biological therapies, has been associated with the onset of psychiatric and psychological adverse events (PPAEs), posing substantial concerns to patients' health and safety. These events, which encompass mood (e.g., depression, schizophrenia, suicidal ideation) and cognitive changes (e.g., learning and memory impairment, dementia) often remain undetected until advanced stages of clinical trials or pharmacovigilance, mostly because the mechanisms underlying the onset of PPAEs remain poorly understood. In recent years, the role of neuroimmune modulation (comprising an intricate interplay between various cell types and signaling pathways) in PPAEs has garnered substantial interest. Indeed, understanding these complex interactions would substantially contribute to increase the ability to predict the potential onset of PPAEs during preclinical stages of a new drug's R&D. This review provides a comprehensive summary of the most recent advances in neuroimmune modulation-related mechanisms contributing to the onset of PPAEs and their association with specific pharmaceuticals. Reported data strongly support an association between neuroimmune modulation and the onset of PPAEs. Pharmaceuticals may target specific molecular pathways and pathway elements (e.g., cholinergic and serotonergic systems), which in turn may directly or indirectly impact the inflammatory status and the homeostasis of the brain, regulating inflammation and neuronal function. Also, modulation of the peripheral immune system by pharmaceuticals that do not permeate the blood-brain barrier (e.g., monoclonal antibodies) may alter the neuroimmunomodulatory status of the brain, leading to PPAEs. In summary, this review underscores the diverse pathways through which drugs can influence brain inflammation, shedding light on potential targeted interventions.