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Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside

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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 (31 March 2021) | Viewed by 77062

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Dr. Felice Iasevoli

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Department of Neuroscience, University School of Naples "Federico II", Via Pansini, 80131 Naples, Italy
Interests: neurotransmitter
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Dear Colleagues,

Schizophrenia is among the most debilitating causes of morbidity worldwide, with a progressively worsening course. The WHO stated that schizophrenia should be treated by integrated therapeutic strategies, including pharmacological and non-pharmacological interventions, both considered mandatory to cure these patients efficaciously. The mainstay of pharmacological treatment of schizophrenia is the class of Antipsychotic agents, which comprises several chemically unrelated compounds. However, all antipsychotics (with the possible exception of clozapine) share a variable degree of action as dopamine D2 receptor blockers. Despite this common mechanism of action, antipsychotics exert molecular actions on multiple dopaminergic and non-dopaminergic receptors. The relevance to the therapeutic efficacy of these actions, as well as their molecular consequences, are largely unknown. Also, the molecular effects triggered by antipsychotics after their interaction with target receptors have been only limitedly characterized.

The lack of in-depth data on antipsychotic molecular action is a major cause of relevant clinical challenges since currently available antipsychotics suffer from several limitations in the treatment of schizophrenia. According to some estimations, approximately 30% of all schizophrenia patients have positive symptoms that are unresponsive or only minimally responsive to antipsychotics. The so-called negative symptoms, which include several distinct pathological phenotypes, as well as cognitive dysfunctions in schizophrenia patients are not ameliorated by current antipsychotics. Also, it has been suggested that antipsychotics may cause iatrogenic worsening and/or occurrence of negative or cognitive symptoms. Unfortunately, these symptoms are those maximally associated with long-term disability in schizophrenia patients and pharmacological therapeutic strategies addressing them are among the most relevant unmet need of schizophrenia clinics. As a further consideration, antipsychotics are burdened from multiple side effects, that in part stem from their therapeutic mechanism of action but, in many other cases, derives from the action on receptor targets that are not strictly necessary for their efficacy against psychotic symptoms.

All these considerations indicate the urge to gain more insights into the molecular mechanism of actions of currently available antipsychotics and to unravel other mechanisms of action, even including the possibility of sharp paradigmatic changes, e.g., using small molecules; gene therapy; or acting on post-receptor or non-receptor neuronal sites.

The Special Issue, “Mechanisms of Antipsychotic Action: from the researcher bench to the patient bedside” of the International Journal of Molecular Sciences will include a selection of research papers and reviews about various aspects of the molecular and cellular biology of antipsychotics. In addition, studies on molecules able to modulate various aspects of synaptic signaling, and their possible use in the treatment of psychotic diseases will also be considered.

Dr. Felice Iasevoli
Guest Editor

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Keywords

Schizophrenia
Glutamate
Dopamine
Gene expression
Synapse
Post-synaptic density
Second-messenger
Psychosis
Synaptic plasticity

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Published Papers (11 papers)

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Research

Jump to: Review

10 pages, 1397 KiB

Open AccessArticle

Clozapine Increases Nestin Concentration in the Adult Male Rat Hippocampus: A Preliminary Study

by Hakan Kayir, Bryan W. Jenkins, Begüm Alural and Jibran Y. Khokhar

Int. J. Mol. Sci. 2022, 23(7), 3436; https://doi.org/10.3390/ijms23073436 - 22 Mar 2022

Cited by 4 | Viewed by 2373

Abstract

Patients with schizophrenia, and rodent models of the disease, both exhibit suppressed neurogenesis, with antipsychotics possibly enhancing neurogenesis in pre-clinical models. Nestin, a cytoskeletal protein, is implicated in neuronal differentiation and adult neurogenesis. We hypothesized that schizophrenia pathogenesis involves nestin downregulation; however, few studies have related nestin to schizophrenia. We assessed nestin protein concentration, prepulse inhibition (PPI), and social interaction in the MK-801 model of schizophrenia, with or without antipsychotic (clozapine) treatment. Adult male Sprague–Dawley rats were intraperitoneally administered saline or MK-801 (0.1 mg/kg) to produce a schizophrenia-like phenotype, with concomitant subcutaneous injections of vehicle or clozapine (5 mg/kg). PPI was assessed on days 1, 8, and 15, and social interaction was assessed on day 4. Hippocampus tissue samples were dissected for Western blotting of nestin concentration. MK-801 alone did not alter nestin concentration, while clozapine alone enhanced hippocampal nestin concentration; this effect was not apparent in animals with MK-801 and clozapine co-administration. MK-801 also produced schizophrenia-like PPI disruptions, some of which were reversed by clozapine. Social interaction deficits were not detected in this model. This is the first report of clozapine-induced enhancements of hippocampal nestin concentration that might be mediated by NMDA receptors. Future studies will explore the impact of neurodevelopmental nestin concentration on symptom onset and antipsychotic treatment. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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19 pages, 3018 KiB

Open AccessArticle

Sex-Specific Cannabidiol- and Iloperidone-Induced Neuronal Activity Changes in an In Vitro MAM Model System of Schizophrenia

by Rachel-Karson Thériault, Myles St-Denis, Tristen Hewitt, Jibran Y. Khokhar, Jasmin Lalonde and Melissa L. Perreault

Int. J. Mol. Sci. 2021, 22(11), 5511; https://doi.org/10.3390/ijms22115511 - 24 May 2021

Cited by 1 | Viewed by 5219

Abstract

Cortical circuit dysfunction is thought to be an underlying mechanism of schizophrenia (SZ) pathophysiology with normalization of aberrant circuit activity proposed as a biomarker for antipsychotic efficacy. Cannabidiol (CBD) shows potential as an adjunctive antipsychotic therapy; however, potential sex effects in these drug interactions remain unknown. In the present study, we sought to elucidate sex effects of CBD coadministration with the atypical antipsychotic iloperidone (ILO) on the activity of primary cortical neuron cultures derived from the rat methylazoxymethanol acetate (MAM) model used for the study of SZ. Spontaneous network activity measurements were obtained using a multielectrode array at baseline and following administration of CBD or ILO alone, or combined. At baseline, MAM male neurons displayed increased bursting activity whereas MAM female neurons exhibited no difference in bursting activity compared to sex-matched controls. CBD administered alone showed a rapid but transient increase in neuronal activity in the MAM networks, an effect more pronounced in females. Furthermore, ILO had an additive effect on CBD-induced elevations in activity in the MAM male neurons. In the MAM female neurons, CBD or ILO administration resulted in time-dependent elevations in neuronal activity, but the short-term CBD-induced increases in activity were lost when CBD and ILO were combined. Our findings indicate that CBD induces rapid increases in cortical neuronal activity, with sex-specific drug interactions upon ILO coadministration. This suggests that sex should be a consideration when implementing adjunct therapy for treatment of SZ. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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14 pages, 2134 KiB

Open AccessArticle

Effects of Haloperidol, Risperidone, and Aripiprazole on the Immunometabolic Properties of BV-2 Microglial Cells

by Valentino Racki, Marina Marcelic, Igor Stimac, Daniela Petric and Natalia Kucic

Int. J. Mol. Sci. 2021, 22(9), 4399; https://doi.org/10.3390/ijms22094399 - 22 Apr 2021

Cited by 23 | Viewed by 4847

Abstract

Microglial cells are resident macrophages in the brain that have been implicated in the pathophysiology of schizophrenia. There is a lack of studies covering the effects of antipsychotics on microglial cells. The current literature points to a possible anti-inflammatory action without clear mechanisms of action. The aim of this study is to characterize the effects of haloperidol, risperidone and aripiprazole on BV-2 microglial cells in in vitro conditions. We have used immunofluorescence and flow cytometry to analyze the classical pro and anti-inflammatory markers, while a real-time metabolic assay (Seahorse) was used to assess metabolic function. We analyzed the expression of p70S6K to evaluate the mTOR pathway activity with Western blot. In this study, we demonstrate the varying effects of haloperidol, risperidone and aripiprazole administration in BV-2 microglial cells. All three tested antipsychotics were successful in reducing the pro-inflammatory action of microglial cells, although only aripiprazole increased the expression of anti-inflammatory markers. Most significant differences in the possible mechanisms of action were seen in the real-time metabolic assays and in the mTORC1 signaling pathway activity, with aripiprazole being the only antipsychotic to reduce the mTORC1 activity. Our results shed some new light on the effects of haloperidol, risperidone and aripiprazole action in microglial cells, and reveal a novel possible mechanism of action for aripiprazole. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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20 pages, 16652 KiB

Open AccessArticle

Understanding Mechanisms Underlying Non-Alcoholic Fatty Liver Disease (NAFLD) in Mental Illness: Risperidone and Olanzapine Alter the Hepatic Proteomic Signature in Mice

by Bahman Rostama, Megan Beauchemin, Celeste Bouchard, Elizabeth Bernier, Calvin P. H. Vary, Meghan May and Karen L. Houseknecht

Int. J. Mol. Sci. 2020, 21(24), 9362; https://doi.org/10.3390/ijms21249362 - 8 Dec 2020

Cited by 18 | Viewed by 5418

Abstract

Patients with severe mental illness have increased mortality, often linked to cardio-metabolic disease. Non-alcoholic fatty liver disease (NAFLD) incidence is higher in patients with schizophrenia and is exacerbated with antipsychotic treatment. NAFLD is associated with obesity and insulin resistance, both of which are induced by several antipsychotic medications. NAFLD is considered an independent risk factor for cardiovascular disease, the leading cause of death for patients with severe mental illness. Although the clinical literature clearly defines increased risk of NAFLD with antipsychotic therapy, the underlying mechanisms are not understood. Given the complexity of the disorder as well as the complex pharmacology associated with atypical antipsychotic (AA) medications, we chose to use a proteomic approach in healthy mice treated with a low dose of risperidone (RIS) or olanzapine (OLAN) for 28 days to determine effects on development of NAFLD and to identify pathways impacted by AA medications, while removing confounding intrinsic effects of mental illness. Both AA drugs caused development of steatosis in comparison with vehicle controls (p < 0.01) and affected multiple pathways relating to energy metabolism, NAFLD, and immune function. AA-associated alteration in autonomic function appears to be a unifying theme in the regulation of hepatic pathology. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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7 pages, 1127 KiB

Open AccessCommunication

Enhancement in Phospholipase D Activity as a New Proposed Molecular Mechanism of Haloperidol-Induced Neurotoxicity

by Marek Krzystanek, Ewa Krzystanek, Katarzyna Skałacka and Artur Pałasz

Int. J. Mol. Sci. 2020, 21(23), 9265; https://doi.org/10.3390/ijms21239265 - 4 Dec 2020

Cited by 7 | Viewed by 2711

Abstract

Membrane phospholipase D (PLD) is associated with numerous neuronal functions, such as axonal growth, synaptogenesis, formation of secretory vesicles, neurodegeneration, and apoptosis. PLD acts mainly on phosphatidylcholine, from which phosphatidic acid (PA) and choline are formed. In turn, PA is a key element of the PLD-dependent secondary messenger system. Changes in PLD activity are associated with the mechanism of action of olanzapine, an atypical antipsychotic. The aim of the present study was to assess the effect of short-term administration of the first-generation antipsychotic drugs haloperidol, chlorpromazine, and fluphenazine on membrane PLD activity in the rat brain. Animals were sacrificed for a time equal to the half-life of the antipsychotic drug in the brain, then the membranes in which PLD activity was determined were isolated from the tissue. The results indicate that only haloperidol in a higher dose increases the activity of phospholipase D. Such a mechanism of action of haloperidol has not been described previously. Induction of PLD activity by haloperidol may be related to its mechanism of cytotoxicity. The finding could justify the use of PLD inhibitors as protective drugs against the cytotoxicity of first-generation antipsychotic drugs like haloperidol. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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22 pages, 3761 KiB

Open AccessArticle

The Effects of Antipsychotics on the Synaptic Plasticity Gene Homer1a Depend on a Combination of Their Receptor Profile, Dose, Duration of Treatment, and Brain Regions Targeted

by Felice Iasevoli, Elisabetta Filomena Buonaguro, Camilla Avagliano, Annarita Barone, Anna Eramo, Licia Vellucci and Andrea de Bartolomeis

Int. J. Mol. Sci. 2020, 21(15), 5555; https://doi.org/10.3390/ijms21155555 - 3 Aug 2020

Cited by 8 | Viewed by 3071

Abstract

Background: Antipsychotic agents modulate key molecules of the postsynaptic density (PSD), including the Homer1a gene, implicated in dendritic spine architecture. How the antipsychotic receptor profile, dose, and duration of administration may influence synaptic plasticity and the Homer1a pattern of expression is yet to be determined. Methods: In situ hybridization for Homer1a was performed on rat tissue sections from cortical and striatal regions of interest (ROI) after acute or chronic administration of three antipsychotics with divergent receptor profile: Haloperidol, asenapine, and olanzapine. Univariate and multivariate analyses of the effects of topography, treatment, dose, and duration of antipsychotic administration were performed. Results: All acute treatment regimens were found to induce a consistently higher expression of Homer1a compared to chronic ones. Haloperidol increased Homer1a expression compared to olanzapine in striatum at the acute time-point. A dose effect was also observed for acute administration of haloperidol. Conclusions: Biological effects of antipsychotics on Homer1a varied strongly depending on the combination of their receptor profile, dose, duration of administration, and throughout the different brain regions. These molecular data may have translational valence and may reflect behavioral sensitization/tolerance phenomena observed with prolonged antipsychotics. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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Review

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21 pages, 847 KiB

Open AccessReview

Pharmacological Treatment for Social Cognition: Current Evidence

by Cecilia Riccardi, Cristiana Montemagni, Elisa Del Favero, Silvio Bellino, Claudio Brasso and Paola Rocca

Int. J. Mol. Sci. 2021, 22(14), 7457; https://doi.org/10.3390/ijms22147457 - 12 Jul 2021

Cited by 5 | Viewed by 3187

Abstract

Cognitive impairment is currently considered a core feature of schizophrenia (SZ) and is gaining attention as a fundamental therapeutic target. Standard treatment for SZ involves the use of antipsychotics that are successfully used to control positive symptoms and disorganized behaviour. However, it is still unclear whether they are effective on social cognition (SC) impairment. Furthermore, different medications are currently being studied to improve SC in patients with SZ. A literature search on this topic was conducted using the PubMed database. All kinds of publications (i.e., reviews, original contributions and case reports) written in English and published in the last 15 years were included. The aim of our literature review is to draw a picture of the current state of the pharmacological treatment of SC impairment in SZ. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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20 pages, 1043 KiB

Open AccessReview

Shared Biological Pathways between Antipsychotics and Omega-3 Fatty Acids: A Key Feature for Schizophrenia Preventive Treatment?

by Ariel Frajerman, Linda Scoriels, Oussama Kebir and Boris Chaumette

Int. J. Mol. Sci. 2021, 22(13), 6881; https://doi.org/10.3390/ijms22136881 - 26 Jun 2021

Cited by 14 | Viewed by 6701

Abstract

Schizophrenia typically emerges during adolescence, with progression from an ultra-high risk state (UHR) to the first episode of psychosis (FEP) followed by a chronic phase. The detailed pathophysiology of schizophrenia and the factors leading to progression across these stages remain relatively unknown. The current treatment relies on antipsychotics, which are effective for FEP and chronic schizophrenia but ineffective for UHR patients. Antipsychotics modulate dopaminergic and glutamatergic neurotransmission, inflammation, oxidative stress, and membrane lipids pathways. Many of these biological pathways intercommunicate and play a role in schizophrenia pathophysiology. In this context, research of preventive treatment in early stages has explored the antipsychotic effects of omega-3 supplementation in UHR and FEP patients. This review summarizes the action of omega-3 in various biological systems involved in schizophrenia. Similar to antipsychotics, omega-3 supplementation reduces inflammation and oxidative stress, improves myelination, modifies the properties of cell membranes, and influences dopamine and glutamate pathways. Omega-3 supplementation also modulates one-carbon metabolism, the endocannabinoid system, and appears to present neuroprotective properties. Omega-3 has little side effects compared to antipsychotics and may be safely prescribed for UHR patients and as an add-on for FEP patients. This could to lead to more efficacious individualised treatments, thus contributing to precision medicine in psychiatry. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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18 pages, 1135 KiB

Open AccessReview

Beyond Dopamine Receptor Antagonism: New Targets for Schizophrenia Treatment and Prevention

by Felipe V. Gomes and Anthony A. Grace

Int. J. Mol. Sci. 2021, 22(9), 4467; https://doi.org/10.3390/ijms22094467 - 25 Apr 2021

Cited by 36 | Viewed by 13179

Abstract

Treatment of schizophrenia (SCZ) historically relies on the use of antipsychotic drugs to treat psychosis, with all of the currently available antipsychotics acting through the antagonism of dopamine D2 receptors. Although antipsychotics reduce psychotic symptoms in many patients, they induce numerous undesirable effects and are not effective against negative and cognitive symptoms. These highlight the need to develop new drugs to treat SCZ. An advanced understanding of the circuitry of SCZ has pointed to pathological origins in the excitation/inhibition balance in regions such as the hippocampus, and restoring function in this region, particularly as a means to compensate for parvalbumin (PV) interneuron loss and resultant hippocampal hyperactivity, may be a more efficacious approach to relieve a broad range of SCZ symptoms. Other targets, such as cholinergic receptors and the trace amine-associated receptor 1 (TAAR1), have also shown some promise for the treatment of SCZ. Importantly, assessing efficacy of novel compounds must take into consideration treatment history of the patient, as preclinical studies suggest prior antipsychotic treatment may interfere with the efficacy of these novel agents. However, while novel therapeutic targets may be more effective in treating SCZ, a more effective approach would be to prevent the transition to SCZ in susceptible individuals. A focus on stress, which has been shown to be a predisposing factor in risk for SCZ, is a possible avenue that has shown promise in preclinical studies. Therefore, therapeutic approaches based on our current understanding of the circuitry of SCZ and its etiology are likely to enable development of more effective therapeutic interventions for this complex disorder. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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15 pages, 1404 KiB

Open AccessReview

Mechanism of Action of Atypical Antipsychotic Drugs in Mood Disorders

by Daniil Grinchii and Eliyahu Dremencov

Int. J. Mol. Sci. 2020, 21(24), 9532; https://doi.org/10.3390/ijms21249532 - 15 Dec 2020

Cited by 64 | Viewed by 25210

Abstract

Atypical antipsychotic drugs were introduced in the early 1990s. Unlike typical antipsychotics, which are effective only against positive symptoms of schizophrenia, atypical antipsychotics are effective against negative and cognitive symptoms as well. Furthermore, they are effective not only in psychotic but also in affective disorders, on their own or as adjuncts to antidepressant drugs. This review presents the neural mechanisms of currently existing atypical antipsychotics and putative antipsychotics currently being investigated in preclinical and clinical studies and how these relate to their effectiveness in mood disorders such as depression, anxiety, and post-traumatic stress disorder (PTSD). Typical antipsychotics act almost exclusively on the dopamine system. Atypical drugs, however, modulate serotonin (5-HT), norepinephrine, and/or histamine neurotransmission as well. This multimodal mechanism of action putatively underlies the beneficial effect of atypical antipsychotics in mood and anxiety disorders. Interestingly, novel experimental drugs having dual antipsychotic and antidepressant therapeutic potential, such as histamine, adenosine, and trace amine-associated receptors (TAAR) ligand, are also characterized by a multimodal stimulatory effect on central 5-HT, norepinephrine, and/or histamine transmission. The multimodal stimulatory effect on central monoamine neurotransmission may be thus primarily responsible for the combined antidepressant and antipsychotic therapeutic potential of certain central nervous system (CNS) drugs. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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21 pages, 1508 KiB

Open AccessReview

A Working Hypothesis Regarding Identical Pathomechanisms between Clinical Efficacy and Adverse Reaction of Clozapine via the Activation of Connexin43

by Motohiro Okada, Kouji Fukuyama, Takashi Shiroyama and Masahiko Murata

Int. J. Mol. Sci. 2020, 21(19), 7019; https://doi.org/10.3390/ijms21197019 - 24 Sep 2020

Cited by 31 | Viewed by 3757

Abstract

Clozapine (CLZ) is an approved antipsychotic agent for the medication of treatment-resistant schizophrenia but is also well known as one of the most toxic antipsychotics. Recently, the World Health Organization’s (WHO) global database (VigiBase) reported the relative lethality of severe adverse reactions of CLZ. Agranulocytosis is the most famous adverse CLZ reaction but is of lesser lethality compared with the other adverse drug reactions of CLZ. Unexpectedly, VigiBase indicated that the prevalence and relative lethality of pneumonia, cardiotoxicity, and seizures associated with CLZ were more serious than that of agranulocytosis. Therefore, haematological monitoring in CLZ patients monitoring system provided success in the prevention of lethal adverse events from CLZ-induced agranulocytosis. Hereafter, psychiatrists must amend the CLZ patients monitoring system to protect patients with treatment-resistant schizophrenia from severe adverse CLZ reactions, such as pneumonia, cardiotoxicity, and seizures, according to the clinical evidence and pathophysiology. In this review, we discuss the mechanisms of clinical efficacy and the adverse reactions of CLZ based on the accumulating pharmacodynamic findings of CLZ, including tripartite synaptic transmission, and we propose suggestions for amending the monitoring and medication of adverse CLZ reactions associated with pneumonia, cardiotoxicity, and seizures. Full article

(This article belongs to the Special Issue Mechanisms of Antipsychotic Action: From the Researcher Bench to the Patient Bedside)

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