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Molecular Mechanisms of Mood Stabilizers

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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 (30 September 2021) | Viewed by 44506

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Prof. Dr. Aleksandra Szczepankiewicz

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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

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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

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Published Papers (7 papers)

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Research

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20 pages, 37698 KiB

Open AccessArticle

Assessment of Paroxetine Molecular Interactions with Selected Monoamine and γ-Aminobutyric Acid Transporters

by Magdalena Kowalska, Łukasz Fijałkowski and Alicja Nowaczyk

Int. J. Mol. Sci. 2021, 22(12), 6293; https://doi.org/10.3390/ijms22126293 - 11 Jun 2021

Cited by 3 | Viewed by 3212

Abstract

Thus far, many hypotheses have been proposed explaining the cause of depression. Among the most popular of these are: monoamine, neurogenesis, neurobiology, inflammation and stress hypotheses. Many studies have proven that neurogenesis in the brains of adult mammals occurs throughout life. The generation of new neurons persists throughout adulthood in the mammalian brain due to the proliferation and differentiation of adult neural stem cells. For this reason, the search for drugs acting in this mechanism seems to be a priority for modern pharmacotherapy. Paroxetine is one of the most commonly used antidepressants. However, the exact mechanism of its action is not fully understood. The fact that the therapeutic effect after the administration of paroxetine occurs after a few weeks, even if the levels of monoamine are rapidly increased (within a few minutes), allows us to assume a neurogenic mechanism of action. Due to the confirmed dependence of depression on serotonin, norepinephrine, dopamine and γ-aminobutyric acid levels, studies have been undertaken into paroxetine interactions with these primary neurotransmitters using in silico and in vitro methods. We confirmed that paroxetine interacts most strongly with monoamine transporters and shows some interaction with γ-aminobutyric acid transporters. However, studies of the potency inhibitors and binding affinity values indicate that the neurogenic mechanism of paroxetine’s action may be determined mainly by its interactions with serotonin transporters. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)

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19 pages, 2081 KiB

Open AccessArticle

Effects of Subchronic Administrations of Vortioxetine, Lurasidone, and Escitalopram on Thalamocortical Glutamatergic Transmission Associated with Serotonin 5-HT7 Receptor

by Motohiro Okada, Ryusuke Matsumoto, Yoshimasa Yamamoto and Kouji Fukuyama

Int. J. Mol. Sci. 2021, 22(3), 1351; https://doi.org/10.3390/ijms22031351 - 29 Jan 2021

Cited by 25 | Viewed by 4295

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 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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26 pages, 3791 KiB

Open AccessArticle

Transcriptome Changes in Three Brain Regions during Chronic Lithium Administration in the Rat Models of Mania and Depression

by Dawid Szczepankiewicz, Piotr Celichowski, Paweł A. Kołodziejski, Ewa Pruszyńska-Oszmałek, Maciej Sassek, Przemysław Zakowicz, Ewa Banach, Wojciech Langwiński, Kosma Sakrajda, Joanna Nowakowska, Magdalena Socha, Ewelina Bukowska-Olech, Joanna Pawlak, Joanna Twarowska-Hauser, Leszek Nogowski, Janusz K. Rybakowski and Aleksandra Szczepankiewicz

Int. J. Mol. Sci. 2021, 22(3), 1148; https://doi.org/10.3390/ijms22031148 - 24 Jan 2021

Cited by 6 | Viewed by 3433

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 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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27 pages, 1566 KiB

Open AccessReview

Mood Stabilizers in Psychiatric Disorders and Mechanisms Learnt from In Vitro Model Systems

by Ritu Nayak, Idan Rosh, Irina Kustanovich and Shani Stern

Int. J. Mol. Sci. 2021, 22(17), 9315; https://doi.org/10.3390/ijms22179315 - 27 Aug 2021

Cited by 15 | Viewed by 7486

Abstract

Bipolar disorder (BD) and schizophrenia are psychiatric disorders that manifest unusual mental, behavioral, and emotional patterns leading to suffering and disability. These disorders span heterogeneous conditions with variable heredity and elusive pathophysiology. Mood stabilizers such as lithium and valproic acid (VPA) have been shown to be effective in BD and, to some extent in schizophrenia. This review highlights the efficacy of lithium and VPA treatment in several randomized, controlled human trials conducted in patients suffering from BD and schizophrenia. Furthermore, we also address the importance of using induced pluripotent stem cells (iPSCs) as a disease model for mirroring the disease’s phenotypes. In BD, iPSC-derived neurons enabled finding an endophenotype of hyperexcitability with increased hyperpolarizations. Some of the disease phenotypes were significantly alleviated by lithium treatment. VPA studies have also reported rescuing the Wnt/β-catenin pathway and reducing activity. Another significant contribution of iPSC models can be attributed to studying the molecular etiologies of schizophrenia such as abnormal differentiation of patient-derived neural stem cells, decreased neuronal connectivity and neurite number, impaired synaptic function, and altered gene expression patterns. Overall, despite significant advances using these novel models, much more work remains to fully understand the mechanisms by which these disorders affect the patients’ brains. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)

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17 pages, 8903 KiB

Open AccessReview

Therapeutic Effect and Mechanisms of Essential Oils in Mood Disorders: Interaction between the Nervous and Respiratory Systems

by Timothy K. H. Fung, Benson W. M. Lau, Shirley P. C. Ngai and Hector W. H. Tsang

Int. J. Mol. Sci. 2021, 22(9), 4844; https://doi.org/10.3390/ijms22094844 - 3 May 2021

Cited by 48 | Viewed by 16682

Abstract

Essential oils (EOs) are extracted from plants and contain active components with therapeutic effects. Evidence shows that various types of EOs have a wide range of health benefits. In our previous studies, the potential of lavender EO for prevention and even treatment of depression and anxiety symptoms was demonstrated. The favourable outcomes may be due to multiple mechanisms, including the regulation of monoamine level, the induction of neurotrophic factor expression, the regulation of the endocrine system and the promotion of neurogenesis. The molecules of EOs may reach the brain and exert an effect through two distinctive pathways, namely, the olfactory system and the respiratory system. After inhalation, the molecules of the EOs would either act directly on the olfactory mucosa or pass into the respiratory tract. These two delivery pathways suggest different underlying mechanisms of action. Different sets of responses would be triggered, such as increased neurogenesis, regulation of hormonal levels, activation of different brain regions, and alteration in blood biochemistry, which would ultimately affect both mood and emotion. In this review, we will discuss the clinical effects of EOs on mood regulation and emotional disturbances as well as the cellular and molecular mechanisms of action. Emphasis will be put on the interaction between the respiratory and central nervous system and the involved potential mechanisms. Further evidence is needed to support the use of EOs in the clinical treatment of mood disturbances. Exploration of the underlying mechanisms may provide insight into the future therapeutic use of EO components treatment of psychiatric and physical symptoms. Full article

(This article belongs to the Special Issue Molecular Mechanisms of Mood Stabilizers)

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14 pages, 621 KiB

Open AccessReview

by Kosma Sakrajda and Aleksandra Szczepankiewicz

Int. J. Mol. Sci. 2021, 22(4), 1532; https://doi.org/10.3390/ijms22041532 - 3 Feb 2021

Cited by 32 | Viewed by 4415

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 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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19 pages, 676 KiB

Open AccessReview

Astroglial Connexin43 as a Potential Target for a Mood Stabiliser

by Motohiro Okada, Tomoka Oka, Misaki Nakamoto, Kouji Fukuyama and Takashi Shiroyama

Int. J. Mol. Sci. 2021, 22(1), 339; https://doi.org/10.3390/ijms22010339 - 30 Dec 2020

Cited by 26 | Viewed by 4046

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 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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