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Novel Therapies for Schizophrenia: Beyond Dopamine

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Pathology, Diagnostics, and Therapeutics".

Deadline for manuscript submissions: closed (20 January 2025) | Viewed by 4171

Special Issue Editor


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Guest Editor
1. Paton State Hospital, 3102 Highland Ave, Patton, CA 92369, USA
2. Department of Psychiatry, University of California, Riverside 900 University Ave, Riverside, CA 92521, USA
3. School of Behavioral Health, Loma Linda University, 11139 Anderson St., Loma Linda, CA 92350, USA
Interests: neurocognitive disorders; schizophrenia; molecular biology; neurolipidomics
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Special Issue Information

Dear Colleagues,

Schizophrenia is a common multigenic and debilitating neuropsychiatric disorder characterized by chronic psychotic symptoms, psychosocial impairment, cognitive deterioration, and poor insight or anosognosia. Genetics, the environment, hormones, and cytokines “conspire” together to engender a unique pathology that has puzzled clinicians and researchers for more than a century. Uncertain pathogenesis, nonspecific medications, and variable prognosis have hindered the outcome of this disorder, contributing to a sustained recovery of less than 20% of patients and the continued existence of large public institutions for the treatment of mental illness, such as state hospitals. Indeed, more than seven decades after the discovery of first dopamine blockers, 33% of schizophrenia patients relapse during the first 12 months after an initial psychotic episode, 26% remain homeless at 2 years follow up, while 5 years after the first psychotic outbreak, only 10% are employed. Recovery at 15 and 25 years follow up is marginally better, at 16%; however, only 13.5% of patients meet the recovery criteria at any point in time after the first psychotic episode. Today, despite the poor outcome, patients with chronic schizophrenia live longer and develop neurocognitive disorders earlier than the general population, increasing medical complications and healthcare expenditures.

This Special Issue aims to collect hypotheses, original and review articles on recent advances in the pathogenesis, etiology, diagnosis, and therapy of schizophrenia. Pure clinical studies are out of the scope of this Special Issue; however, clinical submissions with biomolecular experiments are welcome.

Dr. Adonis Sfera
Guest Editor

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Keywords

  • schizophrenia
  • dopamine signaling
  • nondopaminergic pathways
  • microbial translocation
  • cognitive rehabilitation
  • delirium
  • psychopharmacology
  • novel treatment strategies

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Published Papers (3 papers)

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Research

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10 pages, 240 KiB  
Article
Impact of MAOA Gene Polymorphism on the Efficacy of Antidepressant Treatment and Craving Severity for Betel Quid Use Disorder
by Chung-Chieh Hung, Ying-Chin Ko, Ping-Ho Chen and Chia-Min Chung
Int. J. Mol. Sci. 2024, 25(17), 9221; https://doi.org/10.3390/ijms25179221 - 25 Aug 2024
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Abstract
Betel quid (BQ) use disorder (BUD) is prevalent in many Asian countries, impacting approximately 600 million people. We conducted a randomized clinical trial to analyze the impact of MAOA genetic variations on the severity of BQ craving. This was measured using DSM-5 criteria [...] Read more.
Betel quid (BQ) use disorder (BUD) is prevalent in many Asian countries, impacting approximately 600 million people. We conducted a randomized clinical trial to analyze the impact of MAOA genetic variations on the severity of BQ craving. This was measured using DSM-5 criteria and the Yale–Brown Obsessive–Compulsive Scale modified for betel quid use (Y-BOCS-BQ). Participants were grouped according to the severity of BUD and MAOA gene single-nucleotide polymorphism (SNP) rs5953210 genotypes. The Y-BOCS-BQ scores were assessed at baseline (week 0) and during follow-up at weeks 2, 4, 6, and 8. The AA genotype group showed significantly greater reductions in Y-BOCS-BQ at weeks 2 (p = 0.0194), 4 (p = 0.0078), 6 (p = 0.0277), and 8 (p = 0.0376) compared to the GG genotype group. Additionally, within the antidepressant group, the AA genotype showed significant reductions in the Y-BOCS-BQ scores at weeks 2 (p = 0.0313), 4 (p = 0.0134), 6 (p = 0.0061), and 8 (p = 0.0241) compared to the GG genotype. The statistical analysis revealed a significant interaction between the treatment and placebo groups based on MAOA genotypes, with the AA genotype in the treatment group exhibiting a more pronounced decrease in Y-BOCS-BQ score (p interaction <0.05) at week 6. Our study highlights the importance of considering genetic factors when developing personalized treatment plans for BUD. Full article
(This article belongs to the Special Issue Novel Therapies for Schizophrenia: Beyond Dopamine)

Review

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20 pages, 530 KiB  
Review
Glutamate-Based Therapeutic Strategies for Schizophrenia: Emerging Approaches Beyond Dopamine
by Mihaela Fadgyas-Stanculete and Octavia Oana Capatina
Int. J. Mol. Sci. 2025, 26(9), 4331; https://doi.org/10.3390/ijms26094331 - 2 May 2025
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Abstract
Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly [...] Read more.
Schizophrenia is a complex neuropsychiatric disorder composed of primary cluster-positive symptoms, negative symptoms, disorganization, neurocognitive deficits, and social cognitive impairments. While traditional antipsychotics primarily target dopamine pathways, they provide limited efficacy against cognitive deficits and negative symptoms. Growing evidence implicates glutamatergic dysregulation, particularly N-methyl-D-aspartate receptor (NMDA-R) hypofunction, in the pathophysiology of schizophrenia, making glutamate modulation a promising therapeutic approach. This review explores emerging glutamate-based treatment strategies, including NMDA receptor modulators, metabotropic glutamate receptor (mGluR) agents, glutamate transporter regulators, and kynurenine pathway inhibitors. We summarize preclinical and clinical findings on NMDA co-agonists (D-serine and glycine), glycine transporter inhibitors, D-amino acid oxidase inhibitors, and mGluR-targeted therapies, highlighting their mechanisms, efficacy, and limitations. In addition, we discuss novel interventions aimed at restoring glutamate homeostasis, including neuroinflammatory modulation and synaptic plasticity enhancers. Despite promising results, many glutamate-targeting therapies have yielded inconsistent clinical outcomes, underscoring the need for biomarker-driven patient selection and optimized treatment protocols. We propose that integrating glutamate modulators with existing antipsychotic regimens may enhance therapeutic response while minimizing side effects. Future research should focus on refining glutamate-based interventions, identifying predictive biomarkers, and addressing the heterogeneity in schizophrenia pathology. With continued advancements, glutamate modulation has the potential to transform schizophrenia treatment, particularly for cognitive and negative symptoms that remain largely unaddressed by current therapies. Full article
(This article belongs to the Special Issue Novel Therapies for Schizophrenia: Beyond Dopamine)
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Other

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21 pages, 2556 KiB  
Hypothesis
Receptor-Independent Therapies for Forensic Detainees with Schizophrenia–Dementia Comorbidity
by Adonis Sfera, Luminita Andronescu, William G. Britt, Kiera Himsl, Carolina Klein, Leah Rahman and Zisis Kozlakidis
Int. J. Mol. Sci. 2023, 24(21), 15797; https://doi.org/10.3390/ijms242115797 - 31 Oct 2023
Viewed by 2049
Abstract
Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than [...] Read more.
Forensic institutions throughout the world house patients with severe psychiatric illness and history of criminal violations. Improved medical care, hygiene, psychiatric treatment, and nutrition led to an unmatched longevity in this population, which previously lived, on average, 15 to 20 years shorter than the public at large. On the other hand, longevity has contributed to increased prevalence of age-related diseases, including neurodegenerative disorders, which complicate clinical management, increasing healthcare expenditures. Forensic institutions, originally intended for the treatment of younger individuals, are ill-equipped for the growing number of older offenders. Moreover, as antipsychotic drugs became available in 1950s and 1960s, we are observing the first generation of forensic detainees who have aged on dopamine-blocking agents. Although the consequences of long-term treatment with these agents are unclear, schizophrenia-associated gray matter loss may contribute to the development of early dementia. Taken together, increased lifespan and the subsequent cognitive deficit observed in long-term forensic institutions raise questions and dilemmas unencountered by the previous generations of clinicians. These include: does the presence of neurocognitive dysfunction justify antipsychotic dose reduction or discontinuation despite a lifelong history of schizophrenia and violent behavior? Should neurolipidomic interventions become the standard of care in elderly individuals with lifelong schizophrenia and dementia? Can patients with schizophrenia and dementia meet the Dusky standard to stand trial? Should neurocognitive disorders in the elderly with lifelong schizophrenia be treated differently than age-related neurodegeneration? In this article, we hypothesize that gray matter loss is the core symptom of schizophrenia which leads to dementia. We hypothesize further that strategies to delay or stop gray matter depletion would not only improve the schizophrenia sustained recovery, but also avert the development of major neurocognitive disorders in people living with schizophrenia. Based on this hypothesis, we suggest utilization of both receptor-dependent and independent therapeutics for chronic psychosis. Full article
(This article belongs to the Special Issue Novel Therapies for Schizophrenia: Beyond Dopamine)
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