Neuropsychiatric conditions, including depression, schizophrenia, anxiety, and substance use disorders, represent a significant global health burden, contributing to substantial disability, reduced quality of life, and socioeconomic costs. Despite decades of research, current treatments are ineffective for many individuals, in part due to the complex, heterogeneous, and often poorly understood neurochemical alterations leading to these conditions. A more holistic understanding of brain circuits and molecular pathways is essential to move beyond current treatments, mostly symptomatic relief, towards mechanism‐informed therapies. Dopamine (DA) and serotonin (5‐HT) play an essential role in regulating a broad range of physiological processes involving the central nervous system (CNS) (Azizi 2022; Ng et al. 2015). As such, research on these monoamines has been central in biological psychiatry, and dysfunctions in the dopaminergic and serotonergic systems have been linked to the pathophysiology of many mental health conditions. However, we now know this is an overly simplistic viewpoint, and herein we canvass a more complex picture of how a multitude of signaling systems are implicated in various aspects of mental health conditions and may well represent novel therapeutic targets that ultimately enhance patient care.

Historically, the DA hypothesis of schizophrenia was developed in the early 1960s and stated that positive symptoms experienced by patients were due to hyperactivity of the dopaminergic system (Nayak et al. 2025), and indeed until very recently, antipsychotic drugs used to treat schizophrenia were predominantly dopamine receptor antagonists. These agents have been used despite failing to alleviate all symptoms, particularly cognitive aspects, and can in fact further exacerbate negative symptoms (Dudzik et al. 2024). For neurodevelopmental conditions such as autism spectrum disorder (ASD), the currently most prescribed drugs, such as risperidone and aripiprazole, are also based on dopamine receptor antagonism/partial agonism (Won et al. 2013). The effectiveness of these agents in the treatment of ASD suggests underlying overactive D2‐mediated pathways in the cortico‐striato‐thalamo circuit; however, the neurobiological basis of ASD remains only partially defined, and the effects of long‐term therapy are still under debate (Aman et al. 2015; Manter et al. 2025). DA neurotransmission is also a fundamental component of the brain reward system. As such, the dopaminergic system has additionally been studied in the context of addiction. As drugs of abuse are inherently rewarding (Marsden 2006; Volkow et al. 2011), many studies have (sometimes unnecessarily) focused on understanding the dynamics of DA in substance use disorders. Despite the increasing social and economic burden related to substance use disorders, current treatments such as naltrexone and buprenorphine do not guarantee high success rates. For example, more than 70% of patients who undergo treatment for alcohol use disorder (AUD) relapse within a year (Nguyen et al. 2020).

The 5‐HT link to depression was first proposed in the late 1960s by Alec Coppen's hypothesis, who linked the onset of depression to a decrease in the activity of the serotonergic system, leading to advances in 5‐HT research and pharmaceutical applications (Bremshey et al. 2024; Coppen 1967). Since then, both animal and human studies have provided evidence supporting an imbalanced serotonergic system in several other psychiatric disorders such as anxiety and schizophrenia (Bremshey et al. 2024; Pourhamzeh et al. 2022). The role of 5‐HT in psychiatric disorders is often discussed considering three main domains: (1) genetic predisposition and gene‐environmental interactions, (2) molecular mechanisms mediated by serotonin transporters and receptors, and (3) neural circuits. For instance, the most studied yet controversial genetic variants linked to depression, often through gene‐environmental interactions, include polymorphisms in the 5‐HT transporter (5‐HTT) (Kenna et al. 2012). More consistent evidence of genetic and gene‐environmental vulnerability has been reported for serotonin receptors 1A and 2A, and tryptophan hydroxylase 2 (TPH2), the brain‐specific rate‐limiting enzyme in 5‐HT synthesis (Bremshey et al. 2024). Regarding neural circuits, serotonergic abnormalities have been linked, for example, to altered activity in the prefrontal cortex (PFC)‐limbic circuit (Bremshey et al. 2024; Pourhamzeh et al. 2022). Since the 1980s, selective serotonin reuptake inhibitors (SSRIs), followed by serotonin and noradrenaline reuptake inhibitors (SNRIs), have been developed and widely used as first‐line antidepressant treatments (Bremshey et al. 2024). However, current pharmacological treatments targeting the serotonergic system show a wide range of side effects (Pillinger et al. 2023) and are not effective in properly relieving symptoms for a substantial proportion of patients (Berlim and Turecki 2007; Zugliani et al. 2019). Furthermore, sudden reduction or cessation of SSRIs can trigger a discontinuation syndrome, characterized by a range of physical and psychological symptoms, adding another clinical challenge (Davies and Read 2019).

Current evidence supports a heterogenous, multisystems nature of neuropsychiatric disorders. While DA and 5‐HT provided a starting point into early neurobiology in psychiatric drug development, traditional monoamine hypotheses fail to capture the full complexity of neuropsychiatric conditions. Thus, therapies directed at other neurotransmitter and neuromodulator systems have received increasing attention.

Neuromodulators are a class of signaling molecules that regulate the activity and synaptic transmission of diverse neuronal populations (Alcedo and Prahlad 2020). A neuromodulator can be defined as a neurotransmitter‐like molecule that is neither rapidly reabsorbed by the presynaptic neuron, nor immediately degraded into metabolites. Instead, they typically act by volume transmission, diffusing beyond synaptic clefts to influence multiple neurons within a given region, and sometimes persist in the cerebrospinal fluid for extended periods (Özçete et al. 2024). Neuromodulators exert broader and often longer‐lasting effects by altering the excitability and responsiveness of neurons, generally binding to specific G protein‐coupled receptors (GPCRs), leading to second messenger signaling cascades which modulate neurotransmitter release, receptor sensitivity, and/or neuronal structure (Gonzalez‐Hernandez et al. 2024). Based on their chemical structure and functional properties, neuromodulators can be divided into several classes. These include monoamines (Ng et al. 2015), neurolipids (Veloso et al. 2011) and a diverse class of other molecules, including cytokines, traces amines, neurotrophins, and purines, among others (see Figure 1). Dysregulated neuromodulatory systems are implicated in a wide range of neurodevelopmental and psychiatric disorders, underscoring their significance in physiological and pathological brain function (Gilani et al. 2024; Maehashi et al. 2024). Although neuromodulatory signaling also involves interactions with non‐neuronal cell types, including glial and immune cells (e.g., endocannabinoid signaling through cannabinoid receptors expressed in astrocytes and microglia, noradrenergic modulation of microglia through β‐adrenergic signaling), we primarily focus on neuronal mechanisms. This scope reflects the substantial complexity inherent to neuromodulatory signaling already within neuronal circuits.

Hence, in this review, we synthesize emerging evidence of neuromodulator systems, beyond DA and 5‐HT, that may contribute to the pathophysiology of various neuropsychiatric disorders, focusing on mechanisms of action that have recently led to clinical trials at different phases, particularly interventional ones and those focusing on both sexes (see Tables S1–S5), and we offer directions for future research in the field. One of the principal challenges for the field at present is the shift from symptomatic relief towards disease‐modifying approaches. Although some of the available treatments offer a solution for certain behavioral manifestations of neuropsychiatric disorders, they often fail to address the cause. Notably, even some recent and novel strategies explicitly designed to target proposed disease mechanisms have yielded modest or heterogeneous clinical outcomes, resulting in some clinical trials being terminated at phase 2/3 (see Tables S1–S5). This highlights a persistent challenge in converting mechanistic advances into robust therapeutic gains and can result in undesirable outcomes, such as diminished efficacy over long‐term treatment and the emergence of side effects. Hence, understanding the underlying mechanisms of these disorders is crucial for the development of effective molecular‐based treatments, but that alone is not enough. In this sense, translationally relevant models are necessary to first elucidate the neurobiology of neuropsychiatric conditions and then test different approaches for treating them.

Importantly, across the neuromodulatory systems and disorders discussed in this review, we consider sex as a critical biological variable influencing neuropsychiatric vulnerability, symptom presentation, and treatment response. Historically, both preclinical and clinical neuropsychiatric research has relied on male subjects, often excluding females due to concerns about hormonal variability, thereby reducing the translational relevance of mechanistic discoveries and clinical interventions. This male bias has contributed to an incomplete understanding of disease biology and may partly underlie inconsistencies in treatment efficacy and side effects observed between sexes. Consistent evidence now demonstrates that sex impacts disease prevalence and clinical trajectories of several neuropsychiatric disorders. These differences are not merely modulatory but often fundamentally shape circuit function. A systematic and mechanistic integration of sex‐specific biology is therefore essential for advancing precision psychiatry and for developing biologically informed interventions.

The authors of this work participated in the 5^th Flagship School hosted by the International Society for Neurochemistry (ISN) and the Journal of Neurochemistry (JNC), under the title “Neurochemistry of Mental Illness”, in October 2024 in Naxos, Greece.