Iker Bengoetxea de Tena, Farhanah Nabilah Sallie, Arvie Rodriguez Abiero, Beatrice Rizzi, Leandro Gabriel Champarini, Elisa Corti, Gianluca Masella, Ariel L. Dunn, Luisa Bandeira Binder, Tyler J. Wenzel, Agustin I. Robles, Roberta G. Anversa, Cécilia Tremblay, Aliance Romain Fokoua, Randriely Merscher Sobreira de Lima, Mateus D'Ávila, Trang T. T. Truong, Jessica C. Pierce, Rui S. Rodrigues, Luis Dinamarca‐Villarroel, Felipe Borges Almeida, Aino‐Kaisa Piironen, Andrey F. L. Aguiar, Andrés M. Jaramillo, Lucas Santos, Anja de Lange, David J. Nutt, Andrew J. Lawrence
Neuropsychiatric disorders represent a significant global health burden. Despite decades of research, current treatments typically provide only symptomatic relief, rather than addressing the underlying mechanisms of these conditions. Historically, research focused on the dopaminergic and serotonergic systems, which are deeply involved in the pathophysiology of many mental health disorders, including depression, schizophrenia, anxiety, autism spectrum disorder (ASD), and different substance use disorders, including alcohol use disorder (AUD). However, therapies targeting these systems have limitations, often only producing partial symptom relief plus compliance-limiting side effects. This highlights the need for improved treatments that may emerge from a broader understanding of the neurobiological bases of these conditions, especially neurochemical systems beyond dopamine and serotonin. Additional monoamines (e.g., histamine, acetylcholine, norepinephrine), neurolipid systems (e.g., endocannabinoids), and diverse signaling molecules such as neuropeptides, trace amines, and cytokines are increasingly recognized as key players in the dysfunction of neural circuits. In this review, which originated from the International Society for Neurochemistry (ISN)/Journal of Neurochemistry 5th Flagship School in October 2024 held in Naxos, Greece, we describe the importance of these neuromodulatory systems in the pathophysiology of select neuropsychiatric disorders, discuss their potential as targets for therapeutic intervention, exploring how they may offer more effective, mechanism-based treatments. We also highlight recent clinical trials, underscoring the progress in advancing towards clinical application, as well as sex-specific neurobiological differences, a historically overlooked, yet fundamental determinant of the pathophysiology of neuropsychiatric disorders. We propose that expanding our focus beyond traditional monoamines offers a promising avenue for the development of new, disease-modifying treatments that can more effectively address the underlying causes of neuropsychiatric disorders. By targeting these pathways, we believe it may be possible to develop therapies that restore balance to dysregulated brain circuits and improve long-term outcomes for patients.