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New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies
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New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies

A special issue of Cells (ISSN 2073-4409). This special issue belongs to the section "Cellular Pathology".

Deadline for manuscript submissions: closed (31 December 2022)

Special Issue Editors

Prof. Dr. Agnieszka Basta-Kaim

E-Mail Website
Guest Editor
Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
Interests: schizophrenia; anti-psychotic drugs; neuroinflammation; neurodegeneration; immune response; resolution of inflammation; metabolic processes
Special Issues, Collections and Topics in MDPI journals
Dr. Ewa Trojan

E-Mail Website
Guest Editor
Department of Experimental Neuroendocrinology, Maj Institute of Pharmacology of the Polish Academy of Sciences, Krakow, Poland
Interests: neuroinflammation; neurodegeneration; immune response; resolution of inflammation
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Chronic and recurrent psychiatric disorders such as major depression and schizophrenia are serious social, economic, and medical problems of the contemporary world. Depression is characterized by an array of symptoms, the most prominent of which are depressed mood, recurrent thoughts of death and suicide, feelings of worthlessness, social isolation, and anhedonia. Despite multiple treatment approaches, about 30% of patients with depression do not respond to conventional antidepressants. Moreover, delayed onset of action of traditional antidepressants can result in treatment cessation and increased suicidal risk in some patients. Therefore,  there is an urgent need for designing new antidepressants with better clinical efficiency and tolerability than the already marketed drugs. Schizophrenia is a disabling mental disorder with symptoms including delusions, hallucinations, suspiciousness,  disorganized speech or behavior, and impairments in cognitive abilities, e.g. attention, working memory, or executive function. Same as in depression, circa 30% of patients with schizophrenia are resistant to pharmacotherapy.

Recent spectacular advances in understanding the pathogenesis of depression and schizophrenia beyond classical monoaminergic theories have pointed to several research directions and new molecular targets for the new generation of antidepressant and antipsychotic drugs. Some promising candidates for  antidepressants and antipsychotic drugs include but are not limited to the following  agents:

  1. Anti-inflammatory and pro-resolving agents;
  2. Modulators of brain metabolic processes;
  3. Transcription, epigenetic and trophic factors;
  4. Modulators of microbiome;
  5. Psychoplastogenes.

The aim of this Special Issue is to provide a comprehensive overview of research progress in discovering new molecular and cellular targets for innovative antidepressant and antipsychotic pharmacotherapies. The editors’ intention is to emphasize the emerging role of disturbed interaction of immune, endocrine, and CNS systems in the pathomechanisms of mental disorder beyond classical monoaminergic theories. Neurodevelopmental and neuroinflammatory aspects of chronic mental disorders, as well as co-morbidity of schizophrenia and depression with some neurodegenerative diseases, are being vigorously investigated, and the results of these studies may have a great impact on the development of new therapeutic strategies. It is expected that the holistic approach along with in-depth analysis of molecular processes which maintain brain homeostasis can open new perspectives for designing unique antidepressant and antipsychotic drugs.

In this Special Issue of Cells, we invite you to contribute in the form of original research articles, reviews, or shorter perspective articles on all aspects of the theme “New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies”. Expert articles describing functional, cellular, biochemical, or new aspects of antipsychotic and antidepressant molecular contributions in brain disorders are highly welcome.

Prof. Dr. Agnieszka Basta-Kaim
Dr. Ewa Trojan
Guest Editors

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. Cells is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2700 CHF (Swiss Francs). 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

  • Anti-inflammatory and pro-resolving agents
  • Modulators of brain metabolic processes
  • Transcription, epigenetic and trophic factors
  • Modulators of microbiome
  • Psychoplastogenes.

Published Papers (6 papers)

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11 pages, 3532 KiB  
Article
The Atypical Antipsychotic Lurasidone Affects Brain but Not Liver Cytochrome P450 2D (CYP2D) Activity. A Comparison with Other Novel Neuroleptics and Significance for Drug Treatment of Schizophrenia
by Przemysław J. Danek and Władysława A. Daniel
Cells 2022, 11(21), 3513; https://doi.org/10.3390/cells11213513 - 06 Nov 2022
Cited by 3 | Viewed by 2222
Abstract
The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats [...] Read more.
The aim of this work was to study the effect of prolonged lurasidone administration on the cytochrome 2D (CYP2D) expression and activity in the rat liver and selected brain structures involved in the therapeutic or side effects of this neuroleptic. Male Wistar rats received lurasidone (1 mg/kg ip.) for two weeks. The activity of CYP2D was measured in brain and liver microsomes as the rate of bufuralol 1′-hydroxylation. The CYP2D protein level was determined in microsomes by Western blot analysis. The CYP2D gene expression was estimated in liver tissue by a qRT-PCR method. Lurasidone decreased the activity and protein level of CYP2D in the frontal cortex but increased them in the striatum, nucleus accumbens, brain stem, substantia nigra, and the remainder of the brain. The neuroleptic did not affect CYP2D in the hippocampus, hypothalamus, and cerebellum. In the liver, lurasidone did not affect the CYP2D activity and protein level, though it enhanced the mRNA of CYP2D1 without affecting that of CYP2D2, CYP2D3, CYP2D4, and CYP2D5. In conclusion, lurasidone regulates brain (but not liver) CYP2D activity/protein level in a region-dependent manner, which is similar to that of other atypical neuroleptics (iloperidone and asenapine) as concerns the frontal cortex (down-regulation) and nigrostriatal pathway (up-regulation) and may be of pharmacological significance. However, further molecular studies with selective receptor agonists are necessary to find out which individual monoaminergic receptors/signaling pathways are involved in the regulation of the rat CYP2D4 and human CYP2D6 enzyme in particular brain structures. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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22 pages, 2362 KiB  
Article
Quetiapine Ameliorates MIA-Induced Impairment of Sensorimotor Gating: Focus on Neuron-Microglia Communication and the Inflammatory Response in the Frontal Cortex of Adult Offspring of Wistar Rats
by Katarzyna Chamera, Katarzyna Curzytek, Kinga Kamińska, Ewa Trojan and Agnieszka Basta-Kaim
Cells 2022, 11(18), 2788; https://doi.org/10.3390/cells11182788 - 07 Sep 2022
Cited by 3 | Viewed by 1969
Abstract
The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the [...] Read more.
The maternal immune activation produced by the systemic administration of lipopolysaccharide (LPS) in rats provides valuable insights into the basis of behavioural schizophrenia-like disturbances and biochemical changes in the brains of the offspring, such as microglial activation. Regarding therapy, antipsychotics continually constitute the cornerstone of schizophrenia treatment. To their various efficacy and side effects, as well as not fully recognised mechanisms of action, further characteristics have been suggested, including an anti-inflammatory action via the impact on neuron–microglia axes responsible for inhibition of microglial activation. Therefore, in the present study, we sought to determine whether chronic treatment with chlorpromazine, quetiapine or aripiprazole could influence schizophrenia-like behavioural disturbances at the level of sensorimotor gating in male offspring prenatally exposed to LPS. Simultaneously, we wanted to explore if the chosen antipsychotics display a positive impact on the neuroimmunological parameters in the brains of these adult animals with a special focus on the ligand-receptor axes controlling neuron–microglia communication as well as pro- and anti-inflammatory factors related to the microglial activity. The results of our research revealed the beneficial effect of quetiapine on deficits in sensorimotor gating observed in prenatally LPS-exposed offspring. In terms of axes controlling neuron–microglia communication and markers of microglial reactivity, we observed a subtle impact of quetiapine on hippocampal Cx3cl1 and Cx3cr1 levels, as well as cortical Cd68 expression. Hence, further research is required to fully define and explain the involvement of quetiapine and other antipsychotics in Cx3cl1-Cx3cr1 and/or Cd200-Cd200r axes modulation and inflammatory processes in the LPS-based model of schizophrenia-like disturbances. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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23 pages, 3041 KiB  
Article
The Immune Profile of Major Dysmood Disorder: Proof of Concept and Mechanism Using the Precision Nomothetic Psychiatry Approach
by Michael Maes, Muanpetch Rachayon, Ketsupar Jirakran, Pimpayao Sodsai, Siriwan Klinchanhom, Piotr Gałecki, Atapol Sughondhabirom and Agnieszka Basta-Kaim
Cells 2022, 11(7), 1183; https://doi.org/10.3390/cells11071183 - 31 Mar 2022
Cited by 25 | Viewed by 2717
Abstract
Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a [...] Read more.
Major depressive disorder and a major depressive episode (MDD/MDE) are characterized by activation of the immune-inflammatory response system (IRS) and the compensatory immune-regulatory system (CIRS). In MDD/MDE, recent precision nomothetic psychiatry studies discovered a new endophenotype class, namely major dysmood disorder (MDMD), a new pathway phenotype, namely reoccurrence of illness (ROI), and a new model of the phenome of depression. The aim of the present study is to examine the association between ROI, the phenome of depression, and MDMD’s features and IRS, CIRS, macrophages (M1), T helper (Th)1, Th2, Th17, T regulatory, and growth factor (GF) profiles. Culture supernatants of unstimulated and stimulated (5 μg/mL of PHA and 25 μg/mL of LPS) diluted whole blood of 30 MDD/MDE patients and 20 controls were assayed for cytokines/GF using the LUMINEX assay. MDMD was characterized by increased M1, Th1, Th2, Th17, Treg, IRS, CIRS, neurotoxicity, and GF profiles. Factor analysis shows that ROI features and immune-GF profiles may be combined into a new pathway phenotype (an extracted latent vector). ROI, lifetime and recent suicidal behaviors, and severity of depression are significantly associated with immunotoxicity and GF profiles. Around 80.0% of the variance in the phenome is predicted by ROI and neurotoxicity or the IRS/CIRS ratio. The molecular pathways underpinning ROI-associated sensitization of immune/growth networks are transmembrane receptor protein kinase-triggered STAT protein phosphorylation, TLR/NF-κB, JAK-STAT, and the main proliferation/survival PI3K/Akt/RAS/MAPK pathway. In conclusion, MDMD’s heightened immune responses are the consequence of ROI-associated sensitization combined with immunostimulatory triggers. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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21 pages, 15683 KiB  
Article
Phenotypical Screening on Neuronal Plasticity in Hippocampal-Prefrontal Cortex Connectivity Reveals an Antipsychotic with a Novel Profile
by Michael Spedding, Claude Sebban, Thérèse M. Jay, Cyril Rocher, Brigitte Tesolin-Decros, Paul Chazot, Esther Schenker, Gabor Szénási, György I. Lévay, Katalin Megyeri, Jozsef Barkóczy, Laszlo G. Hársing, Jr., Ian Thomson, Mark O. Cunningham, Miles A. Whittington, Lori-An Etherington, Jeremy J. Lambert, Ferenc A. Antoni and Istvan Gacsályi
Cells 2022, 11(7), 1181; https://doi.org/10.3390/cells11071181 - 31 Mar 2022
Cited by 1 | Viewed by 2568
Abstract
Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which [...] Read more.
Dysfunction in the hippocampus-prefrontal cortex (H-PFC) circuit is a critical determinant of schizophrenia. Screening of pyridazinone-risperidone hybrids on this circuit revealed EGIS 11150 (S 36549). EGIS 11150 induced theta rhythm in hippocampal slice preparations in the stratum lacunosum molecular area of CA1, which was resistant to atropine and prazosin. EGIS 11150 enhanced H-PFC coherence, and increased the 8–9 Hz theta band of the EEG power spectrum (from 0.002 mg/kg i.p, at >30× lower doses than clozapine, and >100× for olanzapine, risperidone, or haloperidol). EGIS 11150 fully blocked the effects of phencyclidine (PCP) or ketamine on EEG. Inhibition of long-term potentiation (LTP) in H-PFC was blocked by platform stress, but was fully restored by EGIS 11150 (0.01 mg/kg i.p.), whereas clozapine (0.3 mg/kg ip) only partially restored LTP. EGIS 11150 has a unique electrophysiological profile, so phenotypical screening on H-PFC connectivity can reveal novel antipsychotics. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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14 pages, 2018 KiB  
Article
Long-Term Treatment with Atypical Antipsychotic Iloperidone Modulates Cytochrome P450 2D (CYP2D) Expression and Activity in the Liver and Brain via Different Mechanisms
by Przemysław J. Danek and Władysława A. Daniel
Cells 2021, 10(12), 3472; https://doi.org/10.3390/cells10123472 - 09 Dec 2021
Cited by 5 | Viewed by 2517
Abstract
CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory [...] Read more.
CYP2D enzymes engage in the synthesis of endogenous neuroactive substances (dopamine, serotonin) and in the metabolism of neurosteroids. The present work investigates the effect of iloperidone on CYP2D enzyme expression and activity in rat brains and livers. Iloperidone exerted a weak direct inhibitory effect on CYP2D activity in vitro in the liver and brain microsomes (Ki = 11.5 μM and Ki = 462 μM, respectively). However, a two-week treatment with iloperidone (1 mg/kg ip.) produced a significant decrease in the activity of liver CYP2D, which correlated positively with the reduced CYP2D1, CYP2D2 and CYP2D4 protein and mRNA levels. Like in the liver, iloperidone reduced CYP2D activity and protein levels in the frontal cortex and cerebellum but enhanced these levels in the nucleus accumbens, striatum and substantia nigra. Chronic iloperidone did not change the brain CYP2D4 mRNA levels, except in the striatum, where they were significantly increased. In conclusion, by affecting CYP2D activity in the brain, iloperidone may modify its pharmacological effect, via influencing the rate of dopamine and serotonin synthesis or the metabolism of neurosteroids. By elevating the CYP2D expression/activity in the substantia nigra and striatum (i.e., in the dopaminergic nigrostriatal pathway), iloperidone may attenuate extrapyramidal symptoms, while by decreasing the CYP2D activity and metabolism of neurosteroiods in the frontal cortex and cerebellum, iloperidone can have beneficial effects in the treatment of schizophrenia. In the liver, pharmacokinetic interactions involving chronic iloperidone and CYP2D substrates are likely to occur. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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18 pages, 590 KiB  
Systematic Review
Ketamine and Lamotrigine Combination in Psychopharmacology: Systematic Review
by Alina Wilkowska, Mariusz S. Wiglusz, Katarzyna Jakuszkowiak-Wojten and Wiesław J. Cubała
Cells 2022, 11(4), 645; https://doi.org/10.3390/cells11040645 - 12 Feb 2022
Cited by 9 | Viewed by 8875
Abstract
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. [...] Read more.
Background and Objectives: Ketamine is a rapid-acting antidepressant with proven efficacy as an add-on agent in unipolar and bipolar treatment-resistant depression. Although many studies have been published, there is still not enough data on the effect of ketamine in combination with other medications. Particularly interesting is the combination of ketamine and lamotrigine, and its potential role in bipolar depression. The aim of this review was to identify animal and human studies in which ketamine and lamotrigine were used together in order to find out if there is scientific ground for combining ketamine and lamotrigine in the treatment of mood disorders. Directions for future studies are presented. Materials and Methods: PubMed and Web of Science were searched. Preferred Reporting Items for Systematic Reviews and Meta-Analyses PRISMA 2020 methodology was applied. Results: Seventeen studies were included for review. Animal studies using models of depression suggested a synergistic effect of ketamine and lamotrigine in combination. Studies on healthy humans showed a reduction in ketamine-induced dissociative symptoms with lamotrigine pretreatment. In a study on patients with depression, ketamine and lamotrigine did not have a stronger antidepressant effect than ketamine alone, but in this study only one ketamine infusion was administered. One case series described the antidepressant and anti-suicidal effect of the combination in two bipolar patients. Available clinical studies on patients with mood disorders did not support the hypothesis that lamotrigine reduces ketamine-induced dissociative symptoms. Conclusions: The results of the analyzed studies were not sufficient to answer any of the stated questions; however, they allowed us to delineate future research directions. The identified animal studies suggested a possible synergistic antidepressant effect of ketamine and lamotrigine. The available clinical studies were not conclusive. No controlled studies on large groups of bipolar patients with multiple ketamine infusions combined with lamotrigine treatment have been published so far. There is some evidence for the reduction of ketamine’s side effects by lamotrigine, and there are reports suggesting that lamotrigine can reduce ketamine craving. More studies with follow-up are needed in order to investigate the ketamine–lamotrigine combination in bipolar patients. Full article
(This article belongs to the Special Issue New Molecular Targets for Antipsychotic and Antidepressant Pharmacotherapies)
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