Accepted

The kynurenine pathway (KP) plays a critical role in generating cellular energy in the form of nicotinamide adenine dinucleotide (NAD+). Because energy requirements are substantially increased during an immune response, the KP is a key regulator of the immune system. Perhaps more importantly in the context of psychiatry, many kynurenines are neuroactive, modulating neuroplasticity and/or exerting neurotoxic effects in part through their effects on NMDA receptor signaling and glutamatergic neurotransmission. As such, it is not surprising that the kynurenines have been implicated in psychiatric illness in the context of inflammation. However, because of their neuromodulatory properties, the kynurenines are not just additional members of a list of inflammatory mediators linked with psychiatric illness, but in preclinical studies have been shown to be necessary components of the behavioral analogs of depression and schizophrenia-like cognitive deficits. Further, as the title suggests, the KP is regulated by, and in turn regulates multiple other physiological systems that are commonly disrupted in psychiatric disorders, including endocrine, metabolic, and hormonal systems. This review provides a broad overview of the mechanistic pathways through which the kynurenines interact with these systems, thus impacting emotion, cognition, pain, metabolic function, and aging, and in so doing potentially increasing the risk of developing psychiatric disorders. Novel therapeutic approaches targeting the KP are discussed. Moreover, electroconvulsive therapy, ketamine, physical exercise, and certain non-steroidal anti-inflammatories have been shown to alter kynurenine metabolism, raising the possibility that kynurenine metabolites may have utility as treatment response or therapeutic monitoring biomarkers.

The relatively high efficacy of opioids, which have associated risks of addiction, tolerance, and dependence, for the management of acute and terminal pain has been a major driver of the opioid crisis, together with the availability, overprescription, and diversion of these drugs. Eliminating opioids without an effective replacement is, however, no solution, as it substitutes one major problem with another. To deal successfully with the opioid crisis, we need to discover novel analgesics whose mechanisms do not involve the mu opioid receptor but that have high analgesic potency and low risk of adverse effects, particularly no abuse liability. The question is how to achieve this. There are several necessary elements; first, we need to understand the nature of pain and the mechanisms responsible for it, and second, we need to adopt novel and unbiased approaches to the identification and validation of pain targets.