Targeting neurotransmitter-mediated inflammatory mechanisms of psychiatric drugs to mitigate the double burden of multimorbidity and polypharmacy

Abstract

The increased incidence of multimorbidities and polypharmacy is a major concern, particularly in the growing aging population. While polypharmacy can be beneficial, in many cases it can be more harmful than no treatment, especially in individuals suffering from psychiatric disorders, who have elevated risks of multimorbidity and polypharmacy. Age-related chronic inflammation and immunopathologies might contribute to these increased risks in this population, but the optimal clinical management of drug-drug interactions and the neuro-immune mechanisms that are involved warrants further investigation. Given that neurotransmitter systems, which psychiatric medications predominantly act on, can influence the development of inflammation and the regulation of immune function, it is important to better understand these interactions to develop more successful strategies to manage these comorbidities and complicated polypharmacy. I propose that expanding upon research in translationally relevant human in vitro models, in tandem with other preclinical models, is critical to defining the neurotransmitter-mediated mechanisms by which psychiatric drugs alter immune function. This will define more precisely the interactions of psychiatric drugs and other immunomodulatory drugs, used in combination, enabling identification of novel targets to be translated into more efficacious diagnostic, preventive, and therapeutic interventions. This interdisciplinary approach will aid in better precision polypharmacy for combating adverse events associated with multimorbidity and polypharmacy in the future.

Dopamine-driven Increase in IL-1β in Myeloid Cells is Mediated by Differential Dopamine Receptor Expression and Exacerbated by HIV

“…Many of these effects could be exacerbated in the presence of diseases, substances of misuse and therapeutics that dysregulate the dopaminergic system (Gaskill and Khoshbouei 2022). For example, a number of neuropsychiatric diseases associated with altered dopaminergic neurotransmission are also associated with inflammation, and a number of neurotransmitter-altering therapeutics used to treat these diseases also impact inflammation (Kubera, Kenis et al 2004, Buttarelli, Fanciulli et al 2011, Hannestad, DellaGioia et al 2011, Hiles, Baker et al 2012, Nazimek, Strobel et al 2017, Kohler, Freitas et al 2018, Wiedlocha, Marcinowicz et al 2018, Matt and Gaskill 2019, Matt 2021, Channer, Matt et al 2022). It is possible that the changes in the dopaminergic system resulting from either the disease or the treatment could create a vicious cycle, altering myeloid activity to exacerbate disease, reducing or counteracting the effectiveness of treatment, and promoting further dysregulation that drives the cycle forward.…”

“…Careful regulation of dopamine concentrations and bioavailability is crucial for normal CNS function and protection against the development of neurological diseases, such as Parkinson's disease (hypodopaminergic) or schizophrenia (hyperdopaminergic). However, dopamine is not only found in the CNS, but also has a unique distribution pattern throughout the circulatory system and in many peripheral tissues, where it is important to both neuronal and nonneuronal processes (Matt andGaskill 2019, Channer, Matt et al 2022). For example, changes in peripheral dopamine can regulate metabolism, gastrointestinal motility, kidney function, blood pressure maintenance, and many other functions (Eisenhofer, Aneman et al 1997, Fitzgerald and Dinan 2008, Armando, Villar et al 2011, Harris and Zhang 2012, Blum, Thanos et al 2014).…”

Dopamine, Immunity, and Disease

“…Research that further defines and validates the crosstalk between the immune system and CNS in the development of disease is also needed. Development of this research will require collaborative efforts using a broad array of research modalities: from human trials, imaging studies, and in vivo animal systems to multiple preclinical models, including human in vitro models such as induced pluripotent stem cell mono- and coculture systems and organoids, ex vivo primary cells/tissues, and postmortem human samples, as we recently suggested in the context of neuroHIV and neuropsychiatric diseases ( Nickoloff-Bybel et al, 2020 ; Matt, 2021 ). The integration of these strategies with pharmacogenetic testing, predictive modeling, and the mining of other high-dimensional proteomic and metabolomic analyses can be leveraged to help identify new candidate biomarkers, as well as develop and repurpose dopaminergic therapeutics.…”

Editorial commentary on the special issue emerging psychoneuroimmunology research: Future leaders in focus

“…In addition, UDCA is able to induce apoptosis of brain blastoma cells in homeostatic conditions. Matt (2021) proposes that it is critical to define the neurotransmitter-mediated mechanisms by which psychiatric drugs alter immune function to allow the interactions of psychiatric drugs and other immunomodulatory drugs, which are often used in combination. Having this information will enable the identification of novel targets that may be translated into more efficacious diagnostic, preventive, and therapeutic interventions.…”