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Special Issue "Molecular Mechanisms of Mood Stabilizers"

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

Deadline for manuscript submissions: closed (31 December 2020).

Special Issue Editor

Prof. Dr. Aleksandra Szczepankiewicz

Guest Editor
Molecular and Cellular Biology Unit, Poznań University of Medical Sciences, Poznań, Poland
Interests: cell culture; molecular biology; noncoding RNA; genetics; extracellular vesicles; allergy; pulmonology; psychiatry; adipokines; stress response

Special Issue Information

Dear Colleagues,

Mood disorders are common chronic psychiatric conditions with a high socio-economic burden, as they affect mainly young adults and present with recurrent episodes of depression or mania. Mood stabilizers encompass a heterogeneous class of drugs, including anticonvulsants, antipsychotics, and lithium, that are used to treat these psychiatric conditions. However, the efficacy of mood stabilizers differs significantly depending on age at onset, disease duration, gender, and comorbidities. The available treatment is effective in about 60% of chronically treated patients, the remaining 40% requires a switch to another drug or a combination of several normotymic agents. Despite several decades of clinical use and numerous molecular studies conducted to elucidate the molecular mechanism of mood stabilizers, the exact mechanisms are not fully identified. The discovery of molecular pathways influenced by mood stabilizers could improve the treatment response prediction as well as the identification of novel therapeutic targets for mood disorders.

In this Special Issue, we welcome your contributions, original papers, or review articles, on molecular aspects of mood stabilizer action with a particular focus on delineating the changes in gene expression regulation (including epigenome, noncoding RNAs, transcriptome, and proteome), using in vitro studies, animal models, and clinical studies, as well as works investigating the role of comorbidities on molecular action of mood stabilizers. Pure clinical studies will not be considered in this Special Issue.

Prof. Dr. Aleksandra Szczepankiewicz
Guest Editor

Manuscript Submission Information

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Keywords

  • Mood stabilizers
  • Molecular action
  • Affective disorders
  • Comorbid diseases
  • Epigenetics
  • Noncoding RNA
  • Transcriptome
  • Proteome
  • Animal models
  • In vitro models
  • Clinical studies

Published Papers (4 papers)

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Research

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Open AccessArticle
Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor
Int. J. Mol. Sci. 2021, 22(3), 1351; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031351 - 29 Jan 2021
Cited by 1
Abstract
The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R [...] Read more.
The functional suppression of serotonin (5-HT) type 7 receptor (5-HT7R) is forming a basis for scientific discussion in psychopharmacology due to its rapid-acting antidepressant-like action. A novel mood-stabilizing atypical antipsychotic agent, lurasidone, exhibits a unique receptor-binding profile, including a high affinity for 5-HT7R antagonism. A member of a novel class of antidepressants, vortioxetine, which is a serotonin partial agonist reuptake inhibitor (SPARI), also exhibits a higher affinity for serotonin transporter, serotonin receptors type 1A (5-HT1AR) and type 3 (5-HT3R), and 5-HT7R. However, the effects of chronic administration of lurasidone, vortioxetine, and the selective serotonin reuptake inhibitor (SSRI), escitalopram, on 5-HT7R function remained to be clarified. Thus, to explore the mechanisms underlying the clinical effects of vortioxetine, escitalopram, and lurasidone, the present study determined the effects of these agents on thalamocortical glutamatergic transmission, which contributes to emotional/mood perception, using multiprobe microdialysis and 5-HT7R expression using capillary immunoblotting. Acute local administration of a 5-HT7R agonist and antagonist into the mediodorsal thalamic nucleus (MDTN) enhanced and reduced thalamocortical glutamatergic transmission, induced by N-methyl-D-aspartate (NMDA)/glutamate receptor inhibition in the reticular thalamic nucleus (RTN). Acute local administration of a relevant therapeutic concentration of vortioxetine and lurasidone into the MDTN suppressed the thalamocortical glutamatergic transmission via 5-HT7R inhibition, whereas that of escitalopram activated 5-HT7R. Subchronic administration of effective doses of vortioxetine and lurasidone (for 7 days) reduced the thalamocortical glutamatergic transmission, but escitalopram did not affect it, whereas subchronic administration of these three agents attenuated the stimulatory effects of the 5-HT7R agonist on thalamocortical glutamatergic transmission. Subchronic administration of effective doses of vortioxetine, lurasidone, and escitalopram downregulated the 5-HT7R expression of the plasma membrane in the MDTN; the 5-HT7R downregulation induced by vortioxetine and lurasidone was observed at 3 days, but that induced by escitalopram required a longer duration of 7 days. These results indicate that chronic administration of vortioxetine, escitalopram, and lurasidone generate downregulation of 5-HT7R in the thalamus; however, the direct inhibition of 5-HT7R associated with vortioxetine and lurasidone generates more rapid downregulation than the indirect elevation of the extracellular serotonin level via serotonin transporter inhibition by escitalopram. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)
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Open AccessArticle
Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression
Int. J. Mol. Sci. 2021, 22(3), 1148; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22031148 - 24 Jan 2021
Cited by 1
Abstract
Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced [...] Read more.
Lithium has been the most important mood stabilizer used for the treatment of bipolar disorder and prophylaxis of manic and depressive episodes. Despite long use in clinical practice, the exact molecular mechanisms of lithium are still not well identified. Previous experimental studies produced inconsistent results due to different duration of lithium treatment and using animals without manic-like or depressive-like symptoms. Therefore, we aimed to analyze the gene expression profile in three brain regions (amygdala, frontal cortex and hippocampus) in the rat model of mania and depression during chronic lithium administration (2 and 4 weeks). Behavioral changes were verified by the forced swim test, open field test and elevated maze test. After the experiment, nucleic acid was extracted from the frontal cortex, hippocampus and amygdala. Gene expression profile was done using SurePrint G3 Rat Gene Expression whole transcriptome microarrays. Data were analyzed using Gene Spring 14.9 software. We found that chronic lithium treatment significantly influenced gene expression profile in both mania and depression models. In manic rats, chronic lithium treatment significantly influenced the expression of the genes enriched in olfactory and taste transduction pathway and long non-coding RNAs in all three brain regions. We report here for the first time that genes regulating olfactory and taste receptor pathways and long non-coding RNAs may be targeted by chronic lithium treatment in the animal model of mania. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)
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Review

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Open AccessReview
Inflammation-Related Changes in Mood Disorders and the Immunomodulatory Role of Lithium
Int. J. Mol. Sci. 2021, 22(4), 1532; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22041532 - 03 Feb 2021
Abstract
Mood disorders are chronic, recurrent diseases characterized by changes in mood and emotions. The most common are major depressive disorder (MDD) and bipolar disorder (BD). Molecular biology studies have indicated an involvement of the immune system in the pathogenesis of mood disorders, and [...] Read more.
Mood disorders are chronic, recurrent diseases characterized by changes in mood and emotions. The most common are major depressive disorder (MDD) and bipolar disorder (BD). Molecular biology studies have indicated an involvement of the immune system in the pathogenesis of mood disorders, and showed their correlation with altered levels of inflammatory markers and energy metabolism. Previous reports, including meta-analyses, also suggested the role of microglia activation in the M1 polarized macrophages, reflecting the pro-inflammatory phenotype. Lithium is an effective mood stabilizer used to treat both manic and depressive episodes in bipolar disorder, and as an augmentation of the antidepressant treatment of depression with a multidimensional mode of action. This review aims to summarize the molecular studies regarding inflammation, microglia activation and energy metabolism changes in mood disorders. We also aimed to outline the impact of lithium on these changes and discuss its immunomodulatory effect in mood disorders. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)
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Open AccessReview
Astroglial Connexin43 as a Potential Target for a Mood Stabiliser
Int. J. Mol. Sci. 2021, 22(1), 339; https://0-doi-org.brum.beds.ac.uk/10.3390/ijms22010339 - 30 Dec 2020
Cited by 1
Abstract
Mood disorders remain a major public health concern worldwide. Monoaminergic hypotheses of pathophysiology of bipolar and major depressive disorders have led to the development of monoamine transporter-inhibiting antidepressants for the treatment of major depression and have contributed to the expanded indications of atypical [...] Read more.
Mood disorders remain a major public health concern worldwide. Monoaminergic hypotheses of pathophysiology of bipolar and major depressive disorders have led to the development of monoamine transporter-inhibiting antidepressants for the treatment of major depression and have contributed to the expanded indications of atypical antipsychotics for the treatment of bipolar disorders. In spite of psychopharmacological progress, current pharmacotherapy according to the monoaminergic hypothesis alone is insufficient to improve or prevent mood disorders. Recent approval of esketamine for treatment of treatment-resistant depression has attracted attention in psychopharmacology as a glutamatergic hypothesis of the pathophysiology of mood disorders. On the other hand, in the last decade, accumulated findings regarding the pathomechanisms of mood disorders emphasised that functional abnormalities of tripartite synaptic transmission play important roles in the pathophysiology of mood disorders. At first glance, the enhancement of astroglial connexin seems to contribute to antidepressant and mood-stabilising effects, but in reality, antidepressive and mood-stabilising actions are mediated by more complicated interactions associated with the astroglial gap junction and hemichannel. Indeed, several depressive mood-inducing stress stimulations suppress connexin43 expression and astroglial gap junction function, but enhance astroglial hemichannel activity. On the other hand, monoamine transporter-inhibiting antidepressants suppress astroglial hemichannel activity and enhance astroglial gap junction function, whereas several non-antidepressant mood stabilisers activate astroglial hemichannel activity. Based on preclinical findings, in this review, we summarise the effects of antidepressants, mood-stabilising antipsychotics, and anticonvulsants on astroglial connexin, and then, to establish a novel strategy for treatment of mood disorders, we reveal the current progress in psychopharmacology, changing the question from “what has been revealed?” to “what should be clarified?”. Full article
(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)
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