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Article ; Online: Present and future antipsychotic drugs: A systematic review of the putative mechanisms of action for efficacy and a critical appraisal under a translational perspective.

de Bartolomeis, Andrea / Barone, Annarita / Begni, Veronica / Riva, Marco Andrea

2022 Volume 176, Page(s) 106078

Abstract: Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture ... ...

Abstract	Antipsychotics represent the mainstay of schizophrenia pharmacological therapy, and their role has been expanded in the last years to mood disorders treatment. Although introduced in 1952, many years of research were required before an accurate picture of how antipsychotics work began to emerge. Despite the well-recognized characterization of antipsychotics in typical and atypical based on their liability to induce motor adverse events, their main action at dopamine D2R to elicit the "anti-psychotic" effect, as well as the multimodal action at other classes of receptors, their effects on intracellular mechanisms starting with receptor occupancy is still not completely understood. Significant lines of evidence converge on the impact of these compounds on multiple molecular signaling pathways implicated in the regulation of early genes and growth factors, dendritic spine shape, brain inflammation, and immune response, tuning overall the function and architecture of the synapse. Here we present, based on PRISMA approach, a comprehensive and systematic review of the above mechanisms under a translational perspective to disentangle those intracellular actions and signaling that may underline clinically relevant effects and represent potential targets for further innovative strategies in antipsychotic therapy.
MeSH term(s)	Animals ; Antipsychotic Agents/chemistry ; Antipsychotic Agents/pharmacology ; Antipsychotic Agents/therapeutic use ; Brain/drug effects ; Chromatin Assembly and Disassembly/drug effects ; Epigenesis, Genetic ; Gene Expression Regulation/drug effects ; Genes, Immediate-Early ; Humans ; Neuronal Plasticity/drug effects ; Neuroprotective Agents/chemistry ; Neuroprotective Agents/pharmacology ; Neuroprotective Agents/therapeutic use ; Neurotransmitter Transport Proteins/antagonists & inhibitors ; Neurotransmitter Transport Proteins/metabolism
Chemical Substances	Antipsychotic Agents ; Neuroprotective Agents ; Neurotransmitter Transport Proteins
Language	English
Publishing date	2022-01-10
Publishing country	Netherlands
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Systematic Review
ZDB-ID	1003347-6
ISSN	1096-1186 ; 0031-6989 ; 1043-6618
ISSN (online)	1096-1186
ISSN	0031-6989 ; 1043-6618
DOI	10.1016/j.phrs.2022.106078
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Article ; Online: Overcoming the barriers to identifying and managing treatment-resistant schizophrenia and to improving access to clozapine: A narrative review and recommendation for clinical practice.

Agid, Ofer / Crespo-Facorro, Benedicto / de Bartolomeis, Andrea / Fagiolini, Andrea / Howes, Oliver D / Seppälä, Niko / Correll, Christoph U

European neuropsychopharmacology : the journal of the European College of Neuropsychopharmacology

2024 Volume 84, Page(s) 35–47

Abstract: Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine ... ...

Abstract	Clozapine is the only approved antipsychotic for treatment-resistant schizophrenia (TRS). Although a large body of evidence supports its efficacy and favorable risk-benefit ratio in individuals who have failed two or more antipsychotics, clozapine remains underused. However, variations in clozapine utilization across geographic and clinical settings suggest that it could be possible to improve its use. In this narrative review and expert opinion, we summarized information available in the literature on the mechanisms of action, effectiveness, and potential adverse events of clozapine. We identified barriers leading to discouragement in clozapine prescription internationally, and we proposed practical solutions to overcome each barrier. One of the main obstacles identified to the use of clozapine is the lack of appropriate training for physicians: we highlighted the need to develop specific professional programs to train clinicians, both practicing and in residency, on the relevance and efficacy of clozapine in TRS treatment, initiation, maintenance, and management of potential adverse events. This approach would facilitate physicians to identify eligible patients and offer clozapine as a treatment option in the early stage of the disease. We also noted that increasing awareness of the benefits of clozapine among healthcare professionals, people with TRS, and their caregivers can help promote the use of clozapine. Educational material, such as leaflets or videos, could be developed and distributed to achieve this goal. The information provided in this article may be useful to improve disease burden and support healthcare professionals, patients, and caregivers navigating the complex pathways to TRS management.
Language	English
Publishing date	2024-04-23
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	1082947-7
ISSN	1873-7862 ; 0924-977X
ISSN (online)	1873-7862
ISSN	0924-977X
DOI	10.1016/j.euroneuro.2024.04.012
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Article: Impact of Benzodiazepines and Illness Duration on Obsessive-Compulsive Disorder during COVID-19 in Italy: Exploring Symptoms' Evolutionary Benefits.

D'Urso, Giordano / Magliacano, Alfonso / Manzo, Marco / Pomes, Mattia Vittorio / Iuliano, Carla / Iasevoli, Felice / Dell'Osso, Bernardo / de Bartolomeis, Andrea

Brain sciences

2024 Volume 14, Issue 4

Abstract: Obsessive-compulsive disorder (OCD) is believed to follow a waxing and waning course, often according to environmental stressors. During the COVID-19 pandemic, pre-existing OCD symptoms were reported to increase and to change from checking to washing ... ...

Abstract	Obsessive-compulsive disorder (OCD) is believed to follow a waxing and waning course, often according to environmental stressors. During the COVID-19 pandemic, pre-existing OCD symptoms were reported to increase and to change from checking to washing behaviors, while new-onset symptoms were predominantly of the hoarding type. In the present study, we followed the evolution of OCD symptoms, anxiety, depression, and insights of illness in forty-six OCD patients throughout the pandemic. Clinical measures were collected at four different time points before and during the COVID-19 pandemic in Italy. Within-subject comparisons were used to compare clinical scale scores across time, and correlations were examined between patients' baseline characteristics and changes in clinical scores. We found that all clinical measures increased during the first Italian lockdown with respect to the pre-pandemic values. Anxiety decreased during the temporary elimination of restriction provisions, whereas the severity of OCD symptoms and insight returned to pre-pandemic values during the second mandatory lockdown. These results were observed only in two sub-groups of patients: those taking benzodiazepines and those with shorter illness duration. Our findings suggest the need for additional clinical attention to these specific sub-groups of OCD patients in case of particularly distressing circumstances while pointing to a possible adaptive role of their OCD symptoms when the environment requires a higher care of hygiene and an extraordinary supply of essential resources.
Language	English
Publishing date	2024-03-30
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2651993-8
ISSN	2076-3425
ISSN	2076-3425
DOI	10.3390/brainsci14040338
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Article: Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment.

De Simone, Giuseppe / Mazza, Benedetta / Vellucci, Licia / Barone, Annarita / Ciccarelli, Mariateresa / de Bartolomeis, Andrea

Antioxidants (Basel, Switzerland)

2023 Volume 12, Issue 4

Abstract: Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, ... ...

Abstract	Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants' mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.
Language	English
Publishing date	2023-04-21
Publishing country	Switzerland
Document type	Journal Article ; Review
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12040975
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Article ; Online: Dysregulated Signaling at Postsynaptic Density: A Systematic Review and Translational Appraisal for the Pathophysiology, Clinics, and Antipsychotics' Treatment of Schizophrenia.

de Bartolomeis, Andrea / Vellucci, Licia / De Simone, Giuseppe / Mazza, Benedetta / Barone, Annarita / Ciccarelli, Mariateresa

Cells

2023 Volume 12, Issue 4

Abstract: Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a ...

Abstract	Emerging evidence from genomics, post-mortem, and preclinical studies point to a potential dysregulation of molecular signaling at postsynaptic density (PSD) in schizophrenia pathophysiology. The PSD that identifies the archetypal asymmetric synapse is a structure of approximately 300 nm in diameter, localized behind the neuronal membrane in the glutamatergic synapse, and constituted by more than 1000 proteins, including receptors, adaptors, kinases, and scaffold proteins. Furthermore, using FASS (fluorescence-activated synaptosome sorting) techniques, glutamatergic synaptosomes were isolated at around 70 nm, where the receptors anchored to the PSD proteins can diffuse laterally along the PSD and were stabilized by scaffold proteins in nanodomains of 50-80 nm at a distance of 20-40 nm creating "nanocolumns" within the synaptic button. In this context, PSD was envisioned as a multimodal hub integrating multiple signaling-related intracellular functions. Dysfunctions of glutamate signaling have been postulated in schizophrenia, starting from the glutamate receptor's interaction with scaffolding proteins involved in the N-methyl-D-aspartate receptor (NMDAR). Despite the emerging role of PSD proteins in behavioral disorders, there is currently no systematic review that integrates preclinical and clinical findings addressing dysregulated PSD signaling and translational implications for antipsychotic treatment in the aberrant postsynaptic function context. Here we reviewed a critical appraisal of the role of dysregulated PSD proteins signaling in the pathophysiology of schizophrenia, discussing how antipsychotics may affect PSD structures and synaptic plasticity in brain regions relevant to psychosis.
MeSH term(s)	Humans ; Antipsychotic Agents/therapeutic use ; Schizophrenia/metabolism ; Post-Synaptic Density/metabolism ; Psychotic Disorders ; Receptors, N-Methyl-D-Aspartate
Chemical Substances	Antipsychotic Agents ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2023-02-10
Publishing country	Switzerland
Document type	Systematic Review ; Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	2661518-6
ISSN	2073-4409 ; 2073-4409
ISSN (online)	2073-4409
ISSN	2073-4409
DOI	10.3390/cells12040574
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Article ; Online: Canonical and Non-Canonical Antipsychotics' Dopamine-Related Mechanisms of Present and Next Generation Molecules: A Systematic Review on Translational Highlights for Treatment Response and Treatment-Resistant Schizophrenia.

de Bartolomeis, Andrea / Ciccarelli, Mariateresa / De Simone, Giuseppe / Mazza, Benedetta / Barone, Annarita / Vellucci, Licia

International journal of molecular sciences

2023 Volume 24, Issue 6

Abstract: Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty ... ...

Abstract	Schizophrenia is a severe psychiatric illness affecting almost 25 million people worldwide and is conceptualized as a disorder of synaptic plasticity and brain connectivity. Antipsychotics are the primary pharmacological treatment after more than sixty years after their introduction in therapy. Two findings hold true for all presently available antipsychotics. First, all antipsychotics occupy the dopamine D2 receptor (D2R) as an antagonist or partial agonist, even if with different affinity; second, D2R occupancy is the necessary and probably the sufficient mechanism for antipsychotic effect despite the complexity of antipsychotics' receptor profile. D2R occupancy is followed by coincident or divergent intracellular mechanisms, implying the contribution of cAMP regulation, β-arrestin recruitment, and phospholipase A activation, to quote some of the mechanisms considered canonical. However, in recent years, novel mechanisms related to dopamine function beyond or together with D2R occupancy have emerged. Among these potentially non-canonical mechanisms, the role of Na
MeSH term(s)	Humans ; Antipsychotic Agents/pharmacology ; Antipsychotic Agents/therapeutic use ; Dopamine/therapeutic use ; Schizophrenia/drug therapy ; Schizophrenia, Treatment-Resistant ; beta-Arrestins
Chemical Substances	Antipsychotic Agents ; Dopamine (VTD58H1Z2X) ; beta-Arrestins
Language	English
Publishing date	2023-03-21
Publishing country	Switzerland
Document type	Systematic Review ; Journal Article ; Review
ZDB-ID	2019364-6
ISSN	1422-0067 ; 1422-0067 ; 1661-6596
ISSN (online)	1422-0067
ISSN	1422-0067 ; 1661-6596
DOI	10.3390/ijms24065945
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Article ; Online: Insomnia and related mental health conditions: Essential neurobiological underpinnings towards reduced polypharmacy utilization rates.

Fornaro, Michele / Caiazza, Claudio / De Simone, Giuseppe / Rossano, Flavia / de Bartolomeis, Andrea

Sleep medicine

2023 Volume 113, Page(s) 198–214

Abstract: Insomnia represents a significant public health burden, with a 10% prevalence in the general population. Reduced sleep affects social and working functioning, productivity, and patient's quality of life, leading to a total of $100 billion per year in ... ...

Abstract	Insomnia represents a significant public health burden, with a 10% prevalence in the general population. Reduced sleep affects social and working functioning, productivity, and patient's quality of life, leading to a total of $100 billion per year in direct and indirect healthcare costs. Primary insomnia is unrelated to any other mental or medical illness; secondary insomnia co-occurs with other underlying medical, iatrogenic, or mental conditions. Epidemiological studies found a 40-50% comorbidity prevalence between insomnia and psychiatric disorders, suggesting a high relevance of mental health in insomniacs. Sleep disturbances also worsen the outcomes of several psychiatric disorders, leading to more severe psychopathology and incomplete remission, plausibly contributing to treatment-resistant conditions. Insomnia and psychiatric disorder coexistence can lead to polypharmacy, namely, the concurrent use of two or more medications in the same patient, regardless of their purpose or rationale. Polypharmacy increases the risk of using unnecessary drugs, the likelihood of drug interactions and adverse events, and reduces the patient's compliance due to regimen complexity. The workup of insomnia must consider the patient's sleep habits and inquire about any medical and mental concurrent conditions that must be handled to allow insomnia to be remitted adequately. Monotherapy or limited polypharmacy should be preferred, especially in case of multiple comorbidities, promoting multipurpose molecules with sedative properties and with bedtime administration. Also, non-pharmacological interventions for insomnia, such as sleep hygiene, relaxation training and Cognitive Behavioral Therapy may be useful in secondary insomnia to confront behaviors and thoughts contributing to insomnia and help optimizing the pharmacotherapy. However, insomnia therapy should always be patient-tailored, considering drug indications, contraindications, and pharmacokinetics, besides insomnia phenotype, clinical picture, patient preferences, and side effect profile.
MeSH term(s)	Humans ; Sleep Initiation and Maintenance Disorders/drug therapy ; Sleep Initiation and Maintenance Disorders/epidemiology ; Sleep Initiation and Maintenance Disorders/complications ; Mental Health ; Quality of Life ; Polypharmacy ; Mental Disorders/complications ; Mental Disorders/drug therapy ; Mental Disorders/epidemiology ; Sleep
Language	English
Publishing date	2023-11-29
Publishing country	Netherlands
Document type	Journal Article ; Review
ZDB-ID	2012041-2
ISSN	1878-5506 ; 1389-9457
ISSN (online)	1878-5506
ISSN	1389-9457
DOI	10.1016/j.sleep.2023.11.033
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Zs.MO 635: Show issues

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Article ; Online: Schizophrenia Synaptic Pathology and Antipsychotic Treatment in the Framework of Oxidative and Mitochondrial Dysfunction: Translational Highlights for the Clinics and Treatment

De Simone, Giuseppe / Mazza, Benedetta / Vellucci, Licia / Barone, Annarita / Ciccarelli, Mariateresa / de Bartolomeis, Andrea

Antioxidants. 2023 Apr. 21, v. 12, no. 4

2023

Abstract	Schizophrenia is a worldwide mental illness characterized by alterations at dopaminergic and glutamatergic synapses resulting in global dysconnectivity within and between brain networks. Impairments in inflammatory processes, mitochondrial functions, energy expenditure, and oxidative stress have been extensively associated with schizophrenia pathophysiology. Antipsychotics, the mainstay of schizophrenia pharmacological treatment and all sharing the common feature of dopamine D2 receptor occupancy, may affect antioxidant pathways as well as mitochondrial protein levels and gene expression. Here, we systematically reviewed the available evidence on antioxidants’ mechanisms in antipsychotic action and the impact of first- and second-generation compounds on mitochondrial functions and oxidative stress. We further focused on clinical trials addressing the efficacy and tolerability of antioxidants as an augmentation strategy of antipsychotic treatment. EMBASE, Scopus, and Medline/PubMed databases were interrogated. The selection process was conducted in respect of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) criteria. Several mitochondrial proteins involved in cell viability, energy metabolism, and regulation of oxidative systems were reported to be significantly modified by antipsychotic treatment with differences between first- and second-generation drugs. Finally, antioxidants may affect cognitive and psychotic symptoms in patients with schizophrenia, and although the evidence is only preliminary, the results indicate that further studies are warranted.
Keywords	antioxidants ; antipsychotics ; brain ; cell viability ; cognition ; dopamine receptors ; energy expenditure ; energy metabolism ; gene expression ; meta-analysis ; mitochondria ; mitochondrial proteins ; oxidative stress ; pathophysiology ; schizophrenia
Language	English
Dates of publication	2023-0421
Publishing place	Multidisciplinary Digital Publishing Institute
Document type	Article ; Online
ZDB-ID	2704216-9
ISSN	2076-3921
ISSN	2076-3921
DOI	10.3390/antiox12040975
Database	NAL-Catalogue (AGRICOLA)

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Article: Predicting the Severity of Lockdown-Induced Psychiatric Symptoms with Machine Learning.

D'Urso, Giordano / Magliacano, Alfonso / Rotbei, Sayna / Iasevoli, Felice / de Bartolomeis, Andrea / Botta, Alessio

Diagnostics (Basel, Switzerland)

2022 Volume 12, Issue 4

Abstract: During the COVID-19 pandemic, an increase in the incidence of psychiatric disorders in the general population and an increase in the severity of symptoms in psychiatric patients have been reported. Anxiety and depression symptoms are the most commonly ... ...

Abstract	During the COVID-19 pandemic, an increase in the incidence of psychiatric disorders in the general population and an increase in the severity of symptoms in psychiatric patients have been reported. Anxiety and depression symptoms are the most commonly observed during large-scale dramatic events such as pandemics and wars, especially when these implicate an extended lockdown. The early detection of higher risk clinical and non-clinical individuals would help prevent the new onset and/or deterioration of these symptoms. This in turn would lead to the implementation of public policies aimed at protecting vulnerable populations during these dramatic contingencies, therefore optimising the effectiveness of interventions and saving the resources of national healthcare systems. We used a supervised machine learning method to identify the predictors of the severity of psychiatric symptoms during the Italian lockdown due to the COVID-19 pandemic. Via a case study, we applied this methodology to a small sample of healthy individuals, obsessive-compulsive disorder patients, and adjustment disorder patients. Our preliminary results show that our models were able to predict depression, anxiety, and obsessive-compulsive symptoms during the lockdown with up to 92% accuracy based on demographic and clinical characteristics collected before the pandemic. The presented methodology may be used to predict the psychiatric prognosis of individuals under a large-scale lockdown and thus supporting the related clinical decisions.
Language	English
Publishing date	2022-04-12
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	2662336-5
ISSN	2075-4418
ISSN	2075-4418
DOI	10.3390/diagnostics12040957
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Article ; Online: Rational and Translational Implications of D-Amino Acids for Treatment-Resistant Schizophrenia: From Neurobiology to the Clinics.

de Bartolomeis, Andrea / Vellucci, Licia / Austin, Mark C / De Simone, Giuseppe / Barone, Annarita

Biomolecules

2022 Volume 12, Issue 7

Abstract: Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine ...

Abstract	Schizophrenia has been conceptualized as a neurodevelopmental disorder with synaptic alterations and aberrant cortical-subcortical connections. Antipsychotics are the mainstay of schizophrenia treatment and nearly all share the common feature of dopamine D2 receptor occupancy, whereas glutamatergic abnormalities are not targeted by the presently available therapies. D-amino acids, acting as N-methyl-D-aspartate receptor (NMDAR) modulators, have emerged in the last few years as a potential augmentation strategy in those cases of schizophrenia that do not respond well to antipsychotics, a condition defined as treatment-resistant schizophrenia (TRS), affecting almost 30-40% of patients, and characterized by serious cognitive deficits and functional impairment. In the present systematic review, we address with a direct and reverse translational perspective the efficacy of D-amino acids, including D-serine, D-aspartate, and D-alanine, in poor responders. The impact of these molecules on the synaptic architecture is also considered in the light of dendritic spine changes reported in schizophrenia and antipsychotics' effect on postsynaptic density proteins. Moreover, we describe compounds targeting D-amino acid oxidase and D-aspartate oxidase enzymes. Finally, other drugs acting at NMDAR and proxy of D-amino acids function, such as D-cycloserine, sarcosine, and glycine, are considered in the light of the clinical burden of TRS, together with other emerging molecules.
MeSH term(s)	Amino Acids ; Antipsychotic Agents/pharmacology ; Antipsychotic Agents/therapeutic use ; Humans ; Neurobiology ; Receptors, N-Methyl-D-Aspartate/physiology ; Schizophrenia/drug therapy ; Schizophrenia, Treatment-Resistant
Chemical Substances	Amino Acids ; Antipsychotic Agents ; Receptors, N-Methyl-D-Aspartate
Language	English
Publishing date	2022-06-29
Publishing country	Switzerland
Document type	Journal Article ; Review ; Systematic Review
ZDB-ID	2701262-1
ISSN	2218-273X ; 2218-273X
ISSN (online)	2218-273X
ISSN	2218-273X
DOI	10.3390/biom12070909
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