Special Issue "Molecular and Cellular Targets of Old and New Atypical Antipsychotics"

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: closed (30 November 2021) | Viewed by 20477

Special Issue Editors

Prof. Marco Scarselli
E-Mail Website
Guest Editor
Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, 56128 Pisa, Italy
Interests: GPCRs; neurodegenerative disorders; psychiatric disorders; antipsychotics; mood stabilizers; antidepressants
Special Issues, Collections and Topics in MDPI journals
Prof. Marco Andrea Riva
E-Mail Website
Guest Editor
University of Milan, Italy
Interests: atypical antipsychotics; stress; lurasidone
Prof. Filippo Caraci
E-Mail Website
Guest Editor
University of Catania, Catania, Italy
Interests: atypical antipsychotics; oxidative stress; antioxidants
Prof. Roberto Maggio
E-Mail Website
Guest Editor
Department of Biotechnological and Applied Clinical Sciences, University of L'Aquila, L'Aquila, Italy
Interests: atypical antipsychotics; dopamine receptors; allosteric drugs
Prof. Gianmarco Leggio
E-Mail Website
Guest Editor
Department of Biomedical and Biotechnological Sciences, University of Catania, Catania, Italy
Interests: atypical antipsychotics; schizophrenia; D3 receptor
Prof. Edoardo Spina
E-Mail Website
Guest Editor
Department of Clinical and Experimental Medicine, University of Messina, Messina, Italy
Interests: atypical antipsychotics; drug metabolism; cytocrome P450

Special Issue Information

Dear Colleagues,

Since the extraordinary discovery in the 70’s of clozapine, still the prototypical atypical antipsychotic, many efforts have been made in order to find better drugs, especially in terms of tolerability and side effects. In fact, unfortunately, the benefits of clozapine compared to the other drugs are somehow overshadow by the risk of severe hematological effects, weight gain and metabolic syndrome.

However, in order to find better drugs, it is imperative to determine the molecular targets that are responsible for atypical antipsychotics efficacy and undesired adverse effects. Despite a large amount of work, the hallmarks defining the ideal antipsychotic are not completely understood and new properties like antioxidant, antistress and neuroprotective have been introduced.

Moreover, besides pharmacodynamics, pharmacokinetics is another key aspect to determine the therapeutic success of atypical antipsychotics in clinical practice, and factors such as inter-individual variability in drug metabolism, drug-drug interactions and patients compliance cannot be underestimated.

With these premises, authors are invited to submit original and review articles to improve our understanding of the pharmacodynamics and pharmacokinetics characteristics of old and new atypical antipsychotics in the Special Issue of Pharmaceuticals “Molecular and cellular targets of old and new atypical antipsychotics”.

Prof. Marco Scarselli
Prof. Marco Riva
Prof. Filippo Caraci
Prof. Roberto Maggio
Prof. Gianmarco Leggio
Prof. Edoardo Spina
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. Pharmaceuticals is an international peer-reviewed open access monthly 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 2000 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

  • Atypical antipsychotics
  • G protein-coupled receptors
  • dopamine receptors
  • antistress activity
  • antioxidant activity
  • allosteric drugs
  • drug-drug interactions
  • drug metabolism

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Published Papers (9 papers)

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Research

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Article
Effects of an Atypical Antipsychotic, Zotepine, on Astroglial L-Glutamate Release through Hemichannels: Exploring the Mechanism of Mood-Stabilising Antipsychotic Actions and Antipsychotic-Induced Convulsion
Pharmaceuticals 2021, 14(11), 1116; https://doi.org/10.3390/ph14111116 - 31 Oct 2021
Cited by 5 | Viewed by 1026
Abstract
Accumulating neuropsychopharmacological evidence has suggested that functional abnormalities of astroglial transmission and protein kinase B (Akt) contribute to the pathophysiology and/or pathomechanisms of several neuropsychiatric disorders, such as epilepsy, schizophrenia, affective disorders and antipsychotic-induced convulsions. Therefore, to explore the pathophysiology of mood-stabilising antipsychotics [...] Read more.
Accumulating neuropsychopharmacological evidence has suggested that functional abnormalities of astroglial transmission and protein kinase B (Akt) contribute to the pathophysiology and/or pathomechanisms of several neuropsychiatric disorders, such as epilepsy, schizophrenia, affective disorders and antipsychotic-induced convulsions. Therefore, to explore the pathophysiology of mood-stabilising antipsychotics and the proconvulsive actions of atypical antipsychotics, the present study determined the effects of a mood-stabilising, atypical, antipsychotic agent, zotepine (ZTP), on astroglial L-glutamate release and the expression of connexin43 (Cx43) protein in cortical, primary, cultured astrocytes using ultra-high-pressure liquid chromatography and capillary immunoblotting systems. Both acute and subchronic administrations of therapeutically relevant concentrations of ZTP did not affect astroglial L-glutamate release or Cx43 expression in plasma membranes; however, chronic administration of a therapeutically relevant concentration of ZTP increased astroglial L-glutamate release and Cx43 expression in the plasma membrane. Subchronic administrations of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release and Cx43 expression in the plasma membrane, whereas acute administration of a supratherapeutic concentration of ZTP enhanced astroglial L-glutamate release without affecting Cx43 expression. These stimulatory effects of ZTP on astroglial L-glutamate release through activated hemichannels and Cx43 trafficking to the astroglial plasma membrane were suppressed by the Akt inhibitor. These results suggest that ZTP enhances astroglial L-glutamate release in a concentration-dependent and time-dependent manner due to the enhanced function of astroglial hemichannels, probably via activation of Akt signalling. Therefore, the enhanced astroglial L-glutamatergic transmission induced by ZTP is, at least partially, involved in the mood-stabilising antipsychotic and proconvulsive actions of ZTP. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Article
The Influence of Long-Term Treatment with Asenapine on Liver Cytochrome P450 Expression and Activity in the Rat. The Involvement of Different Mechanisms
Pharmaceuticals 2021, 14(7), 629; https://doi.org/10.3390/ph14070629 - 29 Jun 2021
Cited by 4 | Viewed by 1493
Abstract
Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome [...] Read more.
Therapy of schizophrenia requires long-term treatment with a relevant antipsychotic drug to achieve a therapeutic effect. The aim of the present study was to investigate the influence of prolonged treatment with the atypical neuroleptic asenapine on the expression and activity of rat cytochrome P450 (CYP) in the liver. The experiment was carried out on male Wistar rats. Asenapine (0.3 mg/kg s.c.) was administered for two weeks. The levels of CYP mRNA protein and activity were determined in the liver and hormone concentrations were measured in the pituitary gland and blood serum. Asenapine significantly decreased the activity of CYP1A (caffeine 8-hydroxylation and 3-N-demethylation), CYP2B, CYP2C11 and CYP3A (testosterone hydroxylation at positions 16β; 2α and 16α; 2β and 6β, respectively). The neuroleptic did not affect the activity of CYP2A (testosterone 7α-hydroxylation), CYP2C6 (warfarin 7-hydroxylation) and CYP2E1 (chlorzoxazone 6-hydroxylation). The mRNA and protein levels of CYP1A2, CYP2B1, CYP2C11 and CYP3A1 were decreased, while those of CYP2B2 and CYP3A2 were not changed. Simultaneously, pituitary level of growth hormone-releasing hormone and serum concentrations of growth hormone and corticosterone were reduced, while that of triiodothyronine was enhanced. In conclusion, chronic treatment with asenapine down-regulates liver cytochrome P450 enzymes, which involves neuroendocrine mechanisms. Thus, chronic asenapine treatment may slow the metabolism of CYP1A, CYP2B, CYP2C11 and CYP3A substrates (steroids and drugs). Since asenapine is metabolized by CYP1A and CYP3A, the neuroleptic may inhibit its own metabolism, therefore, the plasma concentration of asenapine in patients after prolonged treatment may be higher than expected based on a single dose. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Article
Cytokine Level Changes in Schizophrenia Patients with and without Metabolic Syndrome Treated with Atypical Antipsychotics
Pharmaceuticals 2021, 14(5), 446; https://doi.org/10.3390/ph14050446 - 09 May 2021
Cited by 8 | Viewed by 1620
Abstract
The present study aims at comparing the change in cytokine levels in schizophrenia patients treated with atypical antipsychotics, with or without metabolic syndrome (MetS). The study included 101 patients with schizophrenia, 38 with and 63 without MetS, who received risperidone, quetiapine, olanzapine or [...] Read more.
The present study aims at comparing the change in cytokine levels in schizophrenia patients treated with atypical antipsychotics, with or without metabolic syndrome (MetS). The study included 101 patients with schizophrenia, 38 with and 63 without MetS, who received risperidone, quetiapine, olanzapine or aripiprazole for six weeks. We analyzed the concentration of 21 cytokines in the serum patients. The treatment with atypical antipsychotics changed some proinflammatory cytokine levels. It led to increased IFN-α2 (p = 0.010), IL-1α (p = 0.024) and IL-7 (p = 0.017) levels in patients with MetS, whereas the same treatment led to decreased levels of IFN-γ (p = 0.011), IL-1β (p = 0.035), IL-12р40 (p = 0.011), IL-17A (p = 0.031), IL-6 (p = 0.043) and TNF-α (p = 0.012) in individuals without MetS. Our results demonstrated the effects of atypical antipsychotics on the immune–inflammatory parameters, depending on the metabolic disturbances in schizophrenia patients. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Review

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Review
Atypical Antipsychotics and Metabolic Syndrome: From Molecular Mechanisms to Clinical Differences
Pharmaceuticals 2021, 14(3), 238; https://doi.org/10.3390/ph14030238 - 08 Mar 2021
Cited by 35 | Viewed by 4519
Abstract
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life [...] Read more.
Atypical antipsychotics (AAPs) are commonly prescribed medications to treat schizophrenia, bipolar disorders and other psychotic disorders. However, they might cause metabolic syndrome (MetS) in terms of weight gain, dyslipidemia, type 2 diabetes (T2D), and high blood pressure, which are responsible for reduced life expectancy and poor adherence. Importantly, there is clear evidence that early metabolic disturbances can precede weight gain, even if the latter still remains the hallmark of AAPs use. In fact, AAPs interfere profoundly with glucose and lipid homeostasis acting mostly on hypothalamus, liver, pancreatic β-cells, adipose tissue, and skeletal muscle. Their actions on hypothalamic centers via dopamine, serotonin, acetylcholine, and histamine receptors affect neuropeptides and 5′AMP-activated protein kinase (AMPK) activity, thus producing a supraphysiological sympathetic outflow augmenting levels of glucagon and hepatic glucose production. In addition, altered insulin secretion, dyslipidemia, fat deposition in the liver and adipose tissues, and insulin resistance become aggravating factors for MetS. In clinical practice, among AAPs, olanzapine and clozapine are associated with the highest risk of MetS, whereas quetiapine, risperidone, asenapine and amisulpride cause moderate alterations. The new AAPs such as ziprasidone, lurasidone and the partial agonist aripiprazole seem more tolerable on the metabolic profile. However, these aspects must be considered together with the differences among AAPs in terms of their efficacy, where clozapine still remains the most effective. Intriguingly, there seems to be a correlation between AAP’s higher clinical efficacy and increase risk of metabolic alterations. Finally, a multidisciplinary approach combining psychoeducation and therapeutic drug monitoring (TDM) is proposed as a first-line strategy to avoid the MetS. In addition, pharmacological treatments are discussed as well. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Review
Antioxidant Properties of Second-Generation Antipsychotics: Focus on Microglia
Pharmaceuticals 2020, 13(12), 457; https://doi.org/10.3390/ph13120457 - 12 Dec 2020
Cited by 17 | Viewed by 2662
Abstract
Recent studies suggest a primary role of oxidative stress in an early phase of the pathogenesis of schizophrenia and a strong neurobiological link has been found between dopaminergic system dysfunction, microglia overactivation, and oxidative stress. Different risk factors for schizophrenia increase oxidative stress [...] Read more.
Recent studies suggest a primary role of oxidative stress in an early phase of the pathogenesis of schizophrenia and a strong neurobiological link has been found between dopaminergic system dysfunction, microglia overactivation, and oxidative stress. Different risk factors for schizophrenia increase oxidative stress phenomena raising the risk of developing psychosis. Oxidative stress induced by first-generation antipsychotics such as haloperidol significantly contributes to the development of extrapyramidal side effects. Haloperidol also exerts neurotoxic effects by decreasing antioxidant enzyme levels then worsening pro-oxidant events. Opposite to haloperidol, second-generation antipsychotics (or atypical antipsychotics) such as risperidone, clozapine, and olanzapine exert a strong antioxidant activity in experimental models of schizophrenia by rescuing the antioxidant system, with an increase in superoxide dismutase and glutathione (GSH) serum levels. Second-generation antipsychotics also improve the antioxidant status and reduce lipid peroxidation in schizophrenic patients. Interestingly, second-generation antipsychotics, such as risperidone, paliperidone, and in particular clozapine, reduce oxidative stress induced by microglia overactivation, decreasing the production of microglia-derived free radicals, finally protecting neurons against microglia-induced oxidative stress. Further, long-term clinical studies are needed to better understand the link between oxidative stress and the clinical response to antipsychotic drugs and the therapeutic potential of antioxidants to increase the response to antipsychotics. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Review
Clinically Relevant Interactions between Atypical Antipsychotics and Anti-Infective Agents
Pharmaceuticals 2020, 13(12), 439; https://doi.org/10.3390/ph13120439 - 02 Dec 2020
Cited by 7 | Viewed by 2017
Abstract
This is a comprehensive review of the literature on drug interactions (DIs) between atypical antipsychotics and anti-infective agents that focuses on those DIs with the potential to be clinically relevant and classifies them as pharmacokinetic (PK) or pharmacodynamic (PD) DIs. PubMed searches were [...] Read more.
This is a comprehensive review of the literature on drug interactions (DIs) between atypical antipsychotics and anti-infective agents that focuses on those DIs with the potential to be clinically relevant and classifies them as pharmacokinetic (PK) or pharmacodynamic (PD) DIs. PubMed searches were conducted for each of the atypical antipsychotics and most commonly used anti-infective agents (13 atypical antipsychotics by 61 anti-infective agents/classes leading to 793 individual searches). Additional relevant articles were obtained from citations and from prior review articles written by the authors. Based on prior DI articles and our current understanding of PK and PD mechanism, we developed tables with practical recommendations for clinicians for: antibiotic DIs, antitubercular DIs, antifungal DIs, antiviral DIs, and other anti-infective DIs. Another table reflects that in clinical practice, DIs between atypical antipsychotics and anti-infective agents occur in patients also suffering an infection that may also influence the PK and PD mechanisms of both drugs (the atypical antipsychotic and the anti-infective agent(s)). These tables reflect the currently available literature and our current knowledge of the field and will need to be updated as new DI information becomes available. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
Review
Allosteric Modulators of G Protein-Coupled Dopamine and Serotonin Receptors: A New Class of Atypical Antipsychotics
Pharmaceuticals 2020, 13(11), 388; https://doi.org/10.3390/ph13110388 - 14 Nov 2020
Cited by 7 | Viewed by 2258
Abstract
Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for [...] Read more.
Schizophrenia was first described by Emil Krapelin in the 19th century as one of the major mental illnesses causing disability worldwide. Since the introduction of chlorpromazine in 1952, strategies aimed at modifying the activity of dopamine receptors have played a major role for the treatment of schizophrenia. The introduction of atypical antipsychotics with clozapine broadened the range of potential targets for the treatment of this psychiatric disease, as they also modify the activity of the serotoninergic receptors. Interestingly, all marketed drugs for schizophrenia bind to the orthosteric binding pocket of the receptor as competitive antagonists or partial agonists. In recent years, a strong effort to develop allosteric modulators as potential therapeutic agents for schizophrenia was made, mainly for the several advantages in their use. In particular, the allosteric binding sites are topographically distinct from the orthosteric pockets, and thus drugs targeting these sites have a higher degree of receptor subunit specificity. Moreover, “pure” allosteric modulators maintain the temporal and spatial fidelity of native orthosteric ligand. Furthermore, allosteric modulators have a “ceiling effect”, and their modulatory effect is saturated above certain concentrations. In this review, we summarize the progresses made in the identification of allosteric drugs for dopamine and serotonin receptors, which could lead to a new generation of atypical antipsychotics with a better profile, especially in terms of reduced side effects. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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Review
Dopamine, Cognitive Impairments and Second-Generation Antipsychotics: From Mechanistic Advances to More Personalized Treatments
Pharmaceuticals 2020, 13(11), 365; https://doi.org/10.3390/ph13110365 - 05 Nov 2020
Cited by 19 | Viewed by 2058
Abstract
The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive [...] Read more.
The pharmacological treatment of cognitive impairments associated with schizophrenia is still a major unmet clinical need. Indeed, treatments with available antipsychotics generate highly variable cognitive responses among patients with schizophrenia. This has led to the general assumption that antipsychotics are ineffective on cognitive impairment, although personalized medicine and drug repurposing approaches might scale down this clinical issue. In this scenario, evidence suggests that cognitive improvement exerted by old and new atypical antipsychotics depends on dopaminergic mechanisms. Moreover, the newer antipsychotics brexpiprazole and cariprazine, which might have superior clinical efficacy on cognitive deficits over older antipsychotics, mainly target dopamine receptors. It is thus reasonable to assume that despite more than 50 years of elusive efforts to develop novel non-dopaminergic antipsychotics, dopamine receptors remain the most attractive and promising pharmacological targets in this field. In the present review, we discuss preclinical and clinical findings showing dopaminergic mechanisms as key players in the cognitive improvement induced by both atypical antipsychotics and potential antipsychotics. We also emphasize the concept that these mechanistic advances, which help to understand the heterogeneity of cognitive responses to antipsychotics, may properly guide treatment decisions and address the unmet medical need for the management of cognitive impairment associated with schizophrenia. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
Review
Anti-stress Properties of Atypical Antipsychotics
Pharmaceuticals 2020, 13(10), 322; https://doi.org/10.3390/ph13100322 - 20 Oct 2020
Cited by 7 | Viewed by 1812
Abstract
Stress exposure represents a major environmental risk factor for schizophrenia and other psychiatric disorders, as it plays a pivotal role in the etiology as well as in the manifestation of disease symptomatology. It may be inferred that pharmacological treatments must be able to [...] Read more.
Stress exposure represents a major environmental risk factor for schizophrenia and other psychiatric disorders, as it plays a pivotal role in the etiology as well as in the manifestation of disease symptomatology. It may be inferred that pharmacological treatments must be able to modulate the behavioral, functional, and molecular alterations produced by stress exposure to achieve significant clinical outcomes. This review aims at examining existing clinical and preclinical evidence that supports the ability of atypical antipsychotic drugs (AAPDs) to modulate stress-related alterations. Indeed, while the pharmacodynamic differences between AAPDs have been extensively characterized, less is known on their ability to regulate downstream mechanisms that are critical for functional recovery and patient stabilization. We will discuss stress-related mechanisms, spanning from neuroendocrine function to inflammation and neuronal plasticity, which are relevant for the manifestation of schizophrenic symptomatology, and we will discuss if and how AAPDs may interfere with such mechanisms. Considering the impact of stress in everyday life, we believe that a better understanding of the potential effects of AAPDs on stress-related mechanisms may provide novel and important insights for improving therapeutic strategies aimed at promoting coping mechanisms and enhancing the quality of life of patients affected by psychiatric disorders. Full article
(This article belongs to the Special Issue Molecular and Cellular Targets of Old and New Atypical Antipsychotics)
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