Pharmacological Insights in to Schizophrenia: Neurochemical Dysregulation, Disease Mechanisms and Future Therapeutic Strategies

Toward a Pluralistic Model for the Schizophrenia Spectrum-Dopamine and Beyond.

Importance Dopaminergic dysregulation has been considered the final common pathway for pathophysiology of schizophrenia and related disorders (SRD). However, this model does not adequately explain treatment resistance, cognitive impairment, negative symptoms, and marked biological heterogeneity across patients. Objective To examine whether SRD are best conceptualized as resulting from a final common dopaminergic pathway or from several partially independent neurochemical mechanisms and to evaluate the implications of these models for treatment development. Evidence Review Neuroimaging, postmortem and genetic investigations, pharmacologic challenge paradigms, clinical trials, and animal models published between 1980 and 2025 were synthesized. Studies were identified through expert knowledge and targeted searches of PubMed and related databases. Systematic reviews, meta-analyses, and multimodal convergent findings were emphasized. Evidence was appraised qualitatively with attention to consistency, specificity, and translational relevance. Findings Positive psychotic symptoms are strongly linked to increased presynaptic dopaminergic activity in the associative striatum, which predicts response to dopamine D2 receptor antagonists. However, approximately one-third of patients exhibit treatment resistance and show no increase in striatal dopamine synthesis capacity. Increasing evidence implicates glutamatergic, gamma-aminobutyric acid (GABA)ergic, serotonergic, cholinergic, endocannabinoid, and opioidergic systems, as well as nonneurotransmitter processes including oxidative stress, mitochondrial dysfunction, and neuroinflammation. The efficacy of the muscarinic M1/M4-preferring agonist xanomeline-trospium, which lacks direct D2 receptor antagonism, suggests that nondopaminergic mechanisms can reduce psychotic symptoms. Neurochemically distinct subgroups within SRD may cut across overlapping clinical phenotypes. Conclusions and Relevance Dopaminergic hyperactivity may be a key mechanism for core psychotic symptoms in many patients, but it is unlikely that dopamine dysregulation is a universal final common pathway across symptom domains. A pluralistic model-recognizing multiple interacting neurochemical and cellular processes-may better account for heterogeneity and translational failures. Future development of novel treatments may depend on biomarker-informed stratification, mechanism-based clinical trials, and integration of molecular, circuit-level, and clinical phenotypes.

Neuroinflammatory pathways linking pain and rehabilitation outcomes in schizophrenia: a narrative review.

INTRODUCTION Schizophrenia is a chronic and disabling neuropsychiatric disorder traditionally defined by psychotic and cognitive symptoms. Increasing evidence suggests that neuroinflammatory mechanisms contribute to its pathophysiology and may also underlie common but underrecognized somatic manifestations. These include altered pain perception, characterized by both diminished sensitivity and chronic pain, with important implications for functional outcomes and rehabilitation. AREAS COVERED This narrative review examines clinical, preclinical, and translational studies addressing the role of neuroinflammation in schizophrenia, with a specific focus on microglial and astrocytic activation, cytokine signaling, oxidative stress pathways, and their interactions with central pain processing circuits. The review was informed by targeted searches of PubMed, Scopus, Web of Science, and Google Scholar, covering articles published from database inception to January 2026, with emphasis on studies relevant to pain modulation, symptom expression, and neurobiological heterogeneity in schizophrenia. EXPERT OPINION Neuroinflammation represents a biologically plausible link between core schizophrenia pathology and altered pain perception. Recognition of pain as an integrated component of disease biology, rather than a secondary complaint, may improve clinical assessment and treatment planning. Investigating and targeting neuroinflammatory pathways holds promise for personalized interventions that address neuropsychiatric symptoms and pain, potentially enhancing rehabilitation outcomes and quality of life.

Exercise and brain health in long COVID: mechanisms and therapeutic implications for neuropsychiatric disorders

Psychiatric and neurological disorders represent a major global health burden, often characterized by chronic disability and incomplete response to pharmacological treatments. The emergence of long COVID has further contributed to this challenge, introducing persistent neuropsychiatric and neurological sequelae, including cognitive impairment, fatigue, mood disturbances, and autonomic dysfunction, that overlap with mechanisms observed in established brain disorders. This narrative review synthesizes current evidence on exercise as a multimodal therapeutic strategy for individuals with long COVID and pre-existing or COVID-related psychiatric and neurological conditions. Exercise may exert broad effects across interconnected biological systems, potentially enhancing neuroplasticity and neurotrophic signaling, modulating neuroinflammation and immune responses, improving mitochondrial function and energy metabolism, supporting cerebrovascular health, regulating stress physiology and autonomic balance, and influencing the gut–brain axis. These mechanisms are thought to converge on shared pathophysiological pathways implicated in depression, anxiety, bipolar disorder, schizophrenia, post-traumatic stress disorder, neurodegenerative diseases, stroke, epilepsy, and post-viral syndromes. Clinical evidence suggests that structured, individualized, and supervised exercise programs may improve mood, cognition, mobility, fatigue, and quality of life. However, careful pacing and symptom-contingent adaptation are essential in long COVID to avoid post-exertional symptom exacerbation. Although high-quality randomized trials remain limited, exercise appears to be a promising, low-risk, and potentially scalable component of multidisciplinary rehabilitation in long COVID-related brain disorders.

Advances in the Treatment of Cognitive Impairment in Major Depressive Disorder: Innovations and Research Challenges

The Unbalanced Brain: From Normal Behavior to Schizophrenia

Thalamic Reticular Nucleus Dysfunction as a Stage-Dependent Integrative Circuit Mechanism in Psychosis.

Psychosis is increasingly conceptualized as a disorder of distributed neural circuits rather than focal brain pathology, with thalamocortical dysconnectivity emerging as one of its most consistent neurobiological features. This review argues that (TRN) dysfunction may help explain how cellular abnormalities, sleep-spindle deficits, thalamocortical dysconnectivity, and clinical symptoms become linked across the psychosis spectrum We synthesize evidence from postmortem studies, genetics, sleep spindle physiology, neuroimaging, and preclinical models to argue that TRN dysfunction may contribute to impaired sensory gating, altered thalamocortical connectivity, disrupted sleep spindles, and downstream dopaminergic dysregulation. Recent identification of molecularly and functionally distinct TRN subnetworks offers a potential framework for explaining the bidirectional connectivity pattern observed in psychosis, including reduced thalamic coupling with prefrontal/associative regions and increased coupling with sensorimotor cortex. We further propose a stage-dependent model in which early TRN dysfunction contributes to subtle sensory and cognitive disturbances in clinical high-risk states, unstable gating during first-episode psychosis supports the emergence of positive symptoms, and persistent network-level dysfunction contributes to chronic cognitive and negative symptoms. While current evidence remains largely indirect and causal relationships in humans require further testing, the TRN represents a biologically plausible and clinically underexplored convergence point for mechanistic studies of psychosis and for future biomarker and treatment development.