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Depression: From Molecular Basis to Therapy—2nd Edition
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Depression: From Molecular Basis to Therapy—2nd Edition

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: 20 October 2025 | Viewed by 5415

Special Issue Editor

Dr. Terezia Kiskova

E-Mail Website
Guest Editor
Institute of Pathology, Faculty of Medicine, Pavol Jozef Safarik University, 040 01 Kosice, Slovakia
Interests: brain cancer; molecular mechanism; natural compounds
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Depression, often described as the “silent epidemic” of the 21st century, stands as a complex and pervasive mental health challenge that affects millions of individuals worldwide. While its clinical manifestations are readily observable in the form of persistent sadness, hopelessness, and loss of interest in daily life, the true depths of this condition lie hidden within the intricate web of the human brain. Understanding the molecular basis of depression has become a crucial endeavor in contemporary neuroscience and psychology, as it holds the potential to unravel the mysteries behind this debilitating disorder and, ultimately, pave the way for more effective therapeutic interventions.

This Special Issue welcomes original research and review papers demonstrating the molecular mechanisms of depression—from its molecular basis to therapy.

Dr. Terezia Kiskova
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.

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Keywords

  • depression
  • neurobiology
  • molecular basis
  • neurotransmitters
  • genetic factors
  • psychopharmacology
  • psychotherapy
  • genetic markers

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Published Papers (5 papers)

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Research

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16 pages, 5410 KiB  
Article
Targeted DNA Methylation Using Modified DNA Probes: A Potential Therapeutic Tool for Depression and Stress-Related Disorders
by Nishtaa Modi, Jeffrey Guo, Ryan A. Lee, Alisha Greenstein and Richard S. Lee
Int. J. Mol. Sci. 2025, 26(12), 5643; https://doi.org/10.3390/ijms26125643 - 12 Jun 2025
Viewed by 802
Abstract
Epigenetic modifications play a crucial role in gene regulation and have been implicated in various physiological processes and disease conditions. DNA methylation (DNAm) has been implicated in the etiology and progression of many stress-related psychiatric behaviors, such as depression. The ability to manipulate [...] Read more.
Epigenetic modifications play a crucial role in gene regulation and have been implicated in various physiological processes and disease conditions. DNA methylation (DNAm) has been implicated in the etiology and progression of many stress-related psychiatric behaviors, such as depression. The ability to manipulate DNAm may provide a means to reverse and treat such disorders. Although CRISPR-based technologies have enabled locus-specific DNAm editing, their clinical applicability may be limited due to immunogenicity concerns and off-target effects. In this study, we introduce a novel approach for targeted DNAm manipulation using single-stranded methylated DNA probes. The probes were designed against the GRE of FKBP5 and the promoter region of MAOA. In both human embryonic kidney HEK293 and mouse pituitary AtT-20 cells, transfection with their respective methylated probes significantly increased DNAm at targeted CpG sites in a persistent and dose-dependent manner. Importantly, the induced methylation effectively attenuated glucocorticoid-induced upregulation of FKBP5 gene expression. Alteration of methylation was specific to single-stranded probes, as double-stranded methylated probes and unmethylated probes showed no significant effects. Some limitations include the need to further characterize factors that influence probe efficiency, such as probe length and CpG density; develop an efficient in vivo probe delivery system; and perform a more extensive consideration of possible off-target effects. Despite these limitations, our findings suggest that methylated DNA probes have the potential to function as a simple tool for targeted epigenetic manipulation and serve as a safer alternative to CRISPR-based epigenome editing tools for the treatment of stress-related disorders such as depression. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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18 pages, 12271 KiB  
Article
Prolactin-Releasing Peptide System as a Potential Mechanism of Stress Coping: Studies in Male Rats
by Evelin Szabó, Viktória Kormos, Zsuzsanna E. Tóth, Dóra Zelena and Anita Kovács
Int. J. Mol. Sci. 2025, 26(9), 4155; https://doi.org/10.3390/ijms26094155 - 27 Apr 2025
Viewed by 528
Abstract
Prolactin-releasing peptide (PrRP) has a regulatory role in both acute and chronic stress, suggesting its potential contribution to stress-related disorders such as depression. However, not all individuals with depression respond equally to stressors. We aimed to determine whether the PrRP system could underlie [...] Read more.
Prolactin-releasing peptide (PrRP) has a regulatory role in both acute and chronic stress, suggesting its potential contribution to stress-related disorders such as depression. However, not all individuals with depression respond equally to stressors. We aimed to determine whether the PrRP system could underlie stress coping, an important aspect of depression. The forced swim test was used both as a stressor and as a method to assess coping strategy. Based on immobility time, active coping and passive coping subgroups were identified, and 10 brain regions were studied using qPCR to measure the mRNA expression levels of PrRP and its receptors (specific: GPR10; non-specific: NPFFR2). Passive coping animals spent more time in an immobile posture and exhibited altered mRNA expression levels in the medullary A1 region, the habenula, and the arcuate nucleus than control or active coping rats. Additionally, we identified corticotropin-releasing hormone and vesicular glutamate transporter 2 positive neurons in the A1 medullary region that contained Prrp, suggesting a modulatory role of PrRP in these excitatory neurons involved in stress regulation. Our findings reinforce the hypothesis that PrRP plays a role in stress coping, a process closely linked to depression. However its effect is brain region-specific. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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20 pages, 4155 KiB  
Article
Exploring Male-Specific Synaptic Plasticity in Major Depressive Disorder: A Single-Nucleus Transcriptomic Analysis Using Bioinformatics Methods
by Ji Chen, Xiumei Zhu, Fan Yang, Yanan Liu, Huajie Ba, Ping Huang, Hongyan Wang, Yingnan Bian, Chengtao Li and Suhua Zhang
Int. J. Mol. Sci. 2025, 26(7), 3135; https://doi.org/10.3390/ijms26073135 - 28 Mar 2025
Viewed by 591
Abstract
Major depressive disorder (MDD) is a complex psychiatric illness, with synaptic plasticity playing a key role in its pathology. Our study aims to investigate the molecular basis of MDD by analyzing synaptic plasticity-related gene expression at the single-cell level. Utilizing a published snRNA-seq [...] Read more.
Major depressive disorder (MDD) is a complex psychiatric illness, with synaptic plasticity playing a key role in its pathology. Our study aims to investigate the molecular basis of MDD by analyzing synaptic plasticity-related gene expression at the single-cell level. Utilizing a published snRNA-seq dataset (GSE144136), we identified Excitatory.neurons_1 as the cell cluster most associated with MDD and synaptic plasticity through cell clustering, gene set enrichment analysis (GSEA), and pseudotime analysis. Integrating the bulk RNA-seq data (GSE38206), we identified CASKIN1 and CSTB as hub genes via differential expression analysis and machine learning methods. Further exploration of the relevant mechanisms was performed via cell–cell communication and ligand-receptor interaction analysis, functional enrichment analysis, and the construction of molecular regulatory networks, highlighting miR-21-5p as a key biomarker. We propose that elevated miR-21-5p in MDD downregulates CASKIN1 in Excitatory.neurons_1 cells, resulting in decreased neural connectivity and altered synaptic plasticity. As our analyzed snRNA-seq dataset consists solely of male samples, these findings may be male-specific. Our findings shed light on potential mechanisms underlying synaptic plasticity in MDD, offering novel insights into the disorder’s cellular and molecular dynamics. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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Review

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41 pages, 1013 KiB  
Review
Neurobiological Mechanisms of Electroconvulsive Therapy: Molecular Perspectives of Brain Stimulation
by Ermin Fetahovic, Vladimir Janjic, Maja Muric, Nemanja Jovicic, Branimir Radmanovic, Gvozden Rosic, Dragica Selakovic, Milos Filipovic and Nemanja Muric
Int. J. Mol. Sci. 2025, 26(12), 5905; https://doi.org/10.3390/ijms26125905 - 19 Jun 2025
Viewed by 510
Abstract
Electroconvulsive therapy (ECT) remains one of the most effective interventions for treatment-resistant psychiatric disorders, particularly major depressive disorder and bipolar disorder. Despite extensive clinical and preclinical investigations, the precise neurobiological mechanisms underlying ECT’s therapeutic effects are not fully understood. This review explores the [...] Read more.
Electroconvulsive therapy (ECT) remains one of the most effective interventions for treatment-resistant psychiatric disorders, particularly major depressive disorder and bipolar disorder. Despite extensive clinical and preclinical investigations, the precise neurobiological mechanisms underlying ECT’s therapeutic effects are not fully understood. This review explores the molecular and cellular pathways involved in ECT, emphasizing its impact on neurotrophic signaling, oxidative stress, apoptosis, and neuroplasticity. Evidence suggests that ECT modulates brain-derived neurotrophic factor and other neurotrophic factors, promoting synaptic plasticity and neuronal survival. Additionally, ECT influences the hypothalamic–pituitary–adrenal axis, reduces neuroinflammation, and alters neurotransmitter systems, contributing to its antidepressant effects. Recent findings also highlight the role of mitochondrial function and oxidative stress regulation in ECT-induced neural adaptation. By synthesizing current molecular insights, this review provides a comprehensive perspective on the neurobiological mechanisms of ECT, offering potential directions for future research and therapeutic advancements in brain stimulation. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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28 pages, 1169 KiB  
Review
The Potential of Selected Plants and Their Biologically Active Molecules in the Treatment of Depression and Anxiety Disorders
by Nicol Urbanska, Tolulope Joshua Ashaolu, Simona Mattova, Patrik Simko and Terezia Kiskova
Int. J. Mol. Sci. 2025, 26(5), 2368; https://doi.org/10.3390/ijms26052368 - 6 Mar 2025
Cited by 1 | Viewed by 2216
Abstract
The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third [...] Read more.
The incidence of anxiety and depression disorders is increasing worldwide. There is an increasing incidence of hard-to-treat depression with various aspects of origin. Almost 80% of people prefer to use natural remedies and supplements as their primary healthcare solution. Not surprisingly, around one-third of drugs were inspired by nature. Over the past three decades, the use of such remedies has increased significantly. Synthetic antidepressants may cause various negative side effects, whereas herbal medicines are favored because of their ability to relieve symptoms with minimal to no side effects and lower financial burden. This review provides an overview of herbs and biologically active compounds used to treat depression. Full article
(This article belongs to the Special Issue Depression: From Molecular Basis to Therapy—2nd Edition)
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