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Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies
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Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Neurobiology".

Deadline for manuscript submissions: 25 July 2025 | Viewed by 15290

Special Issue Editor

Dr. Blerida Banushi

E-Mail Website
Guest Editor
School of Indigenous Studies, The University of Western Australia, 35 Stirling Highway, Perth 6009, Australia
Interests: neurobiology; mental health; molecular and cellular biolog; intergenerational trauma; Indigenous mental health; psychedelic research; psychiatric disorders

Special Issue Information

Dear Colleagues,

This Special Issue aims to explore cutting-edge research on the molecular underpinnings of mental health disorders and novel therapeutic approaches. Advances in genetics, epigenetics, and neurobiology have transformed our understanding of psychiatric illnesses, revealing the intricate roles of genes, epigenetic modifications, and disrupted neural circuits in conditions such as depression, schizophrenia, and anxiety disorders.

We welcome submissions investigating molecular mechanisms, including gene expression changes, epigenetic alterations, neurotransmitter system dysregulation, and neuroplasticity deficits. Of particular interest are studies examining the interplay between genetic susceptibility and environmental factors in mental illness onset and progression.

In addition, we encourage the submission of papers presenting novel treatment approaches targeting recently identified molecular pathways. This includes pharmacological approaches like rapid-acting antidepressants, as well as emerging therapies such as psychedelics, neuromodulation techniques, and personalized medicine informed by genetic profiles.

Additionally, we seek the submission of research on the role of inflammation, oxidative stress, and mitochondrial dysfunction in mental illness. Investigations into the gut–brain axis, circadian rhythm disruptions, and the impact of diet on mental health and diseases are also of interest. We welcome studies utilizing innovative approaches such as neuroimaging, proteomics, and single-cell sequencing to elucidate disease mechanisms.

By bringing together diverse perspectives on molecular mechanisms and novel interventions, this Special Issue aims to advance our understanding of mental health disorders and accelerate the development of effective therapies.

Dr. Blerida Banushi
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • molecular psychiatry
  • epigenetics
  • neurobiology
  • gene–environment interactions
  • neuroplasticity
  • psychopharmacology
  • neuromodulation
  • personalized medicine
  • neuroinflammation

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Further information on MDPI's Special Issue policies can be found here.

Published Papers (5 papers)

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Research

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22 pages, 688 KiB  
Article
The Effects of Psychotherapy on Single and Repeated Ketamine Infusion(s) Therapy for Treatment-Resistant Depression: The Convergence of Molecular and Psychological Treatment
by Sofia Sakopoulos and McWelling Todman
Int. J. Mol. Sci. 2025, 26(14), 6673; https://doi.org/10.3390/ijms26146673 - 11 Jul 2025
Viewed by 208
Abstract
Ketamine infusion therapy has gained recognition as an innovative treatment for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects. Its therapeutic promise is increasingly understood to involve molecular and neurobiological processes that promote neural plasticity and cognitive flexibility. These changes may create [...] Read more.
Ketamine infusion therapy has gained recognition as an innovative treatment for treatment-resistant depression (TRD), demonstrating rapid and robust antidepressant effects. Its therapeutic promise is increasingly understood to involve molecular and neurobiological processes that promote neural plasticity and cognitive flexibility. These changes may create a unique window for psychotherapeutic interventions to take deeper effect. This retrospective chart review examined the clinical outcomes of individuals with TRD who received either single or repeated ketamine infusion(s), with or without weekly psychotherapy. Depression severity, measured by Beck Depression Inventory scores, was assessed pre-treatment and 30 days post-infusion(s). The results showed significant symptom reduction across all groups, with the most pronounced effects observed in those who received concurrent psychotherapy. While infusion number did not significantly alter outcomes, the integration of ketamine with psychotherapy appeared to enhance treatment response. Full article
(This article belongs to the Special Issue Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies)
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18 pages, 1224 KiB  
Article
Reduced Gene Dosage of the Psychiatric Risk Gene Cacna1c Is Associated with Impairments in Hypothalamic–Pituitary–Adrenal Axis Activity in Rats
by Anna L. Moon, Eleanor R. Mawson, Patricia Gasalla, Lawrence S. Wilkinson, Dominic M. Dwyer, Jeremy Hall and Kerrie L. Thomas
Int. J. Mol. Sci. 2025, 26(12), 5547; https://doi.org/10.3390/ijms26125547 - 10 Jun 2025
Viewed by 396
Abstract
Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. However, the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present [...] Read more.
Common and rare variation in CACNA1C gene expression has been consistently associated with neuropsychiatric disorders such as schizophrenia, bipolar disorder, and major depression. However, the underlying biological pathways that cause this association have yet to be fully determined. In this study, we present evidence that rats with a reduced gene dosage of Cacna1c have increased basal corticosterone levels in the periphery and reduced the expression of Nr3c1 encoding the glucocorticoid receptor in the hippocampus and hypothalamus. These results are consistent, with an effect of Cacna1c dosage on hypothalamus–pituitary–adrenal (HPA) axis function. Heterozygous Cacna1c rats had lower levels of the histone markers H3K4me3 and H3K27acat exon 17 of the Nr3c1 gene. These histone modifications are typically linked to increased gene expression, but here were not associated with changes in the expression of exon 17 variants under non-stress conditions. Heterozygous Cacna1c rats additionally show increased anxiety behaviours. These results support an association of Cacna1c heterozygosity with the altered activity of the HPA axis and function in the resting state, and this may be a predisposing mechanism that contributes to the increased risk of psychiatric disorders with stress. Full article
(This article belongs to the Special Issue Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies)
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Review

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16 pages, 1068 KiB  
Review
Novel Roles for Urokinase- and Tissue-Type Plasminogen Activators in the Pathogenesis of Mood Disorders
by Amine Bahi and Sinclair Steele
Int. J. Mol. Sci. 2025, 26(14), 6899; https://doi.org/10.3390/ijms26146899 - 18 Jul 2025
Viewed by 163
Abstract
This narrative review explores the intricate relationship between the plasminogen activator system (PAS), comprising urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and a range of neuropsychiatric disorders, including depression and anxiety. By synthesizing existing preclinical and clinical evidence, we clarify the [...] Read more.
This narrative review explores the intricate relationship between the plasminogen activator system (PAS), comprising urokinase-type plasminogen activator (uPA) and tissue-type plasminogen activator (tPA), and a range of neuropsychiatric disorders, including depression and anxiety. By synthesizing existing preclinical and clinical evidence, we clarify the roles of uPA and tPA in the pathogenesis and potential treatments of these conditions. This narrative review emphasizes their involvement in modulating neuronal plasticity, synaptic remodeling, and neurotransmitter systems, which are pivotal in maintaining brain function and behavior. Additionally, this review highlights key mechanisms by which these activators influence the neurobiological processes underlying mood and cognitive dysfunction. Critical analysis identifies areas of consensus, such as the role of plasminogen activators in neuroinflammation and stress responses, while also addressing gaps and controversies in the literature. The findings underscore the therapeutic potential of targeting the uPA/tPA system for innovative interventions. By offering a nuanced understanding of their contributions to mood disorders, this review aims to inspire future research toward developing novel, mechanism-based treatment strategies that harness the PAS’ capacity to restore neural homeostasis and improve patient outcomes. Full article
(This article belongs to the Special Issue Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies)
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31 pages, 1338 KiB  
Review
Epigenetic Echoes: Bridging Nature, Nurture, and Healing Across Generations
by Blerida Banushi, Jemma Collova and Helen Milroy
Int. J. Mol. Sci. 2025, 26(7), 3075; https://doi.org/10.3390/ijms26073075 - 27 Mar 2025
Cited by 2 | Viewed by 4620
Abstract
Trauma can impact individuals within a generation (intragenerational) and future generations (transgenerational) through a complex interplay of biological and environmental factors. This review explores the epigenetic mechanisms that have been correlated with the effects of trauma across generations, including DNA methylation, histone modifications, [...] Read more.
Trauma can impact individuals within a generation (intragenerational) and future generations (transgenerational) through a complex interplay of biological and environmental factors. This review explores the epigenetic mechanisms that have been correlated with the effects of trauma across generations, including DNA methylation, histone modifications, and non-coding RNAs. These mechanisms can regulate the expression of stress-related genes (such as the glucocorticoid receptor (NR3C1) and FK506 binding protein 5 (FKBP5) gene), linking trauma to biological pathways that may affect long-term stress regulation and health outcomes. Although research using model organisms has elucidated potential epigenetic mechanisms underlying the intergenerational effects of trauma, applying these findings to human populations remains challenging due to confounding variables, methodological limitations, and ethical considerations. This complexity is compounded by difficulties in establishing causality and in disentangling epigenetic influences from shared environmental factors. Emerging therapies, such as psychedelic-assisted treatments and mind–body interventions, offer promising avenues to address both the psychological and potential epigenetic aspects of trauma. However, translating these findings into effective interventions will require interdisciplinary methods and culturally sensitive approaches. Enriched environments, cultural reconnection, and psychosocial interventions have shown the potential to mitigate trauma’s impacts within and across generations. By integrating biological, social, and cultural perspectives, this review highlights the critical importance of interdisciplinary frameworks in breaking cycles of trauma, fostering resilience, and advancing comprehensive healing across generations. Full article
(This article belongs to the Special Issue Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies)
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15 pages, 8090 KiB  
Review
Interaction of the Vagus Nerve and Serotonin in the Gut–Brain Axis
by Young Keun Hwang and Jae Sang Oh
Int. J. Mol. Sci. 2025, 26(3), 1160; https://doi.org/10.3390/ijms26031160 - 29 Jan 2025
Cited by 8 | Viewed by 9109
Abstract
The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells [...] Read more.
The gut–brain axis represents an important bidirectional communication network, with the vagus nerve acting as a central conduit for peripheral signals from the various gut organs to the central nervous system. Among the molecular mediators involved, serotonin (5-HT), synthesized predominantly by enterochromaffin cells in the gut, plays a pivotal role. Gut-derived serotonin activates vagal afferent fibers, transmitting signals to the nucleus tractus solitarius (NTS) and modulating serotonergic neurons in the dorsal raphe nucleus (DRN) as well as the norepinephrinergic neurons in the locus coeruleus (LC). This interaction influences emotional regulation, stress responses, and immune modulation. Emerging evidence also highlights the role of microbial metabolites, particularly short-chain fatty acids (SCFAs), in enhancing serotonin synthesis and vagal activity, thereby shaping gut–brain communication. This review synthesizes the current knowledge on serotonin signaling, vagal nerve pathways, and central autonomic regulation, with an emphasis on their implications for neuropsychiatric and gastrointestinal disorders. By elucidating these pathways, novel therapeutic strategies targeting the gut–brain axis may be developed to improve mental and physical health outcomes. Full article
(This article belongs to the Special Issue Unveiling Mental Disorders: Molecular Mechanisms and Innovative Therapies)
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