Papers by Andrea de Bartolomeis
Progress in Neuro Psychopharmacology Biological Psychiatry, 2009
The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficaci... more The inducible gene Homer1a has been considered a candidate gene for schizophrenia. Drugs efficacious in schizophrenia and acting as dopamine receptor antagonists induce Homer1a expression, although the specific role of the different dopamine receptors in its induction is not completely known. In this study, we explored Homer1a expression induced by selective antagonists at dopamine receptors (SCH-23390, D 1 receptor selective antagonist, 0.5 mg/kg; L-741,626, D 2 receptor selective antagonist, 2 mg/kg; U-99194, D 3 receptor selective antagonist, 5 mg/kg; L-745,870, D 4 receptor selective antagonist, 3 mg/kg), haloperidol (0.8 mg/kg), and terguride (0.5 mg/kg), a partial agonist at D 2 receptors. Moreover, we evaluated the expression of two Homer1a-related genes which play essential roles in synaptic plasticity: mGluR5 and Homer1b. Gene expression was analyzed in brain regions relevant for schizophrenia pathophysiology and therapy, namely the striatum, the cortex, and the hippocampus. In striatum, Homer1a was induced by D 2 receptor antagonists and, with a different distribution, by SCH-23390. In the cortex, Homer1a was differentially induced by D 1 , D 2 , and D 3 receptors antagonists, while haloperidol and terguride did not affect or reduced its expression. Homer1b expression was reduced by L-741,626, L-745,870, terguride, and haloperidol in the ventral caudate-putamen, in the nucleus accumbens and in the cortex, while SCH-23390 increased the expression in the core of the accumbens. mGluR5 expression was increased by SCH-23390 in the dorsomedial putamen, the core of the accumbens, and in some hippocampal subregions. A reduction of gene expression by terguride and an increase by L-745,870 was observed in the dorsomedial putamen. The changes in expression suggest that these gene transcripts are differentially regulated by antagonism at different dopamine receptors.
Amino acids, Jan 26, 2016
D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precur... more D-Aspartate (D-Asp) is a free D-amino acid detected in multiple brain regions and putative precursor of endogenous N-methyl-D-aspartate (NMDA) acting as agonist at NMDA receptors. In this study, we investigated whether D-Asp (20 mM) in drinking solution for 1 month affects pain responses and pain-related emotional, and cognitive behaviour in a model of neuropathic pain induced by the spared nerve injury (SNI) of the sciatic nerve in mice. SNI mice developed mechanical allodynia and motor coordination impairment 30 days after SNI surgery. SNI mice showed cognitive impairment, anxiety and depression-like behaviour, reduced sociability in the three chamber sociability paradigm, increased expression of NR2B subunit of NMDA receptor and Homer 1a in the medial prefrontal cortex (mPFC). The expression of (post synaptic density) PSD-95 and Shank 1was instead unaffected in the mPFC of the SNI mice. Treatment with D-Asp drinking solution, started right after the SNI (day 0), alleviated mechan...
Expert Review of Neurotherapeutics, 2016
Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, ex... more Generalized Anxiety Disorder (GAD) is a persistent condition characterized by chronic anxiety, exaggerated worry and tension, mainly comorbid with Major Depressive Disorder (MDD). Currently, selective serotonin reuptake inhibitors and serotonin-norepinephrine reuptake inhibitors are recommended as first-line treatment of GAD. However, some patients may not respond to the treatment or discontinue due to adverse effects. Vortioxetine (VRX) is a multimodal antidepressant with a unique mechanism of action, by acting as 5-HT3A, 5-HT1D and 5-HT7 receptor antagonist, partial agonist at the 5-HT1A and 5-HT1B receptors and inhibitor at the 5-HT transporter. Preliminary clinical trials showed contrasting findings in terms of improvement of the anxiety symptomatology and/or cognitive impairment. Here, we aim to systematically review the evidence currently available on the efficacy, safety and tolerability of VRX in the treatment of GAD. The generalizability of results on the efficacy of VRX in patients with anxiety symptomatology and GAD is limited due to few and contrasting RCTs so far available. Only two studies, of which one prevention relapse trial, reported a significant improvement in anxiety symptomatology compared to three with negative findings.
Giornale Italiano di Psicopatologia
La scoperta della funzione degli autorecettori (recettori presinaptici) D2/D3 nella modulazione d... more La scoperta della funzione degli autorecettori (recettori presinaptici) D2/D3 nella modulazione della sintesi/secrezione della dopamina (29)-(31) ha condotto a tentativi di
CNS & neurological disorders drug targets, Jan 20, 2015
To review the antidepressant efficacy of S-Adenosyl-L-Methionine (SAMe) both in monotherapy and/o... more To review the antidepressant efficacy of S-Adenosyl-L-Methionine (SAMe) both in monotherapy and/or in augmentation with antidepressants to better understand its potential role in the treatment of patients with Major Depressive Disorder (MDD) and Treatment-Resistant Depression (TRD). A MEDLINE/PubMed search was carried out by using the following set of keywords: ((SAMe OR S-Adenosyl-L-Methionine) AND (major depressive disorder OR depression)). DATA SELECTION AND DATA EXTRACTION. No language or time restrictions were placed on the electronic searches. Randomized controlled trials and open trials involving humans were here included and analyzed. The references of published articles identified in the initial search process were also examined for any additional studies appropriate for the review. SAMe is an important physiologic compound, playing a central role as precursor molecule in several biochemical reactions. Numerous studies have shown that SAMe may affect the regulation of vario...
Neuron, 2015
Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several... more Major depressive disorder is among the most commonly diagnosed disabling mental diseases. Several non-pharmacological treatments of depression upregulate adenosine concentration and/or adenosine A1 receptors (A1R) in the brain. To test whether enhanced A1R signaling mediates antidepressant effects, we generated a transgenic mouse with enhanced doxycycline-regulated A1R expression, specifically in forebrain neurons. Upregulating A1R led to pronounced acute and chronic resilience toward depressive-like behavior in various tests. Conversely, A1R knockout mice displayed an increased depressive-like behavior and were resistant to the antidepressant effects of sleep deprivation (SD). Various antidepressant treatments increase homer1a expression in medial prefrontal cortex (mPFC). Specific siRNA knockdown of homer1a in mPFC enhanced depressive-like behavior and prevented the antidepressant effects of A1R upregulation, SD, imipramine, and ketamine treatment. In contrast, viral overexpression of homer1a in the mPFC had antidepressant effects. Thus, increased expression of homer1a is a final common pathway mediating the antidepressant effects of different antidepressant treatments.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2015
Homer NMDAR PSD-95 Psychosis Treatment-resistant schizophrenia N-methyl-D-aspartate receptor (NMD... more Homer NMDAR PSD-95 Psychosis Treatment-resistant schizophrenia N-methyl-D-aspartate receptor (NMDAR) hypofunction has been considered a key alteration in schizophrenia pathophysiology. Thus, several strategies aimed at enhancing glutamatergic transmission, included the introduction in therapy of D-amino acids, such as D-serine and D-cycloserine augmentation, have been proposed to counteract difficult-to-treat symptoms or treatment-resistant forms of schizophrenia. Another D-amino acid, Daspartate, has recently gained increasing interest for its role in NMDAR activation and has been found reduced in post-mortem cortex of schizophrenia patients. NMDAR is the core of the postsynaptic density (PSD), a postsynaptic site involved in glutamate signaling and responsive to antipsychotic treatment. In this study, we investigated striatal and cortical gene expression of key PSD transcripts (i.e. Homer1a, Homer1b/ c, and PSD-95) in mice with persistently elevated brain D-aspartate-levels, i.e. the D-aspartate-oxidase knockout mice (Ddo −/− ). These animal models were analyzed both in naive condition and after phencyclidine (PCP) treatment. Naive Ddo −/− mice showed decreased Homer1a expression in the prefrontal cortex, increased Homer1b/c expression in the striatum, and decreased PSD-95 expression in the striatum and in the cortex. Acute PCP treatment restored, and even potentiated, Homer1a expression in the prefrontal cortex of mutant mice, while it had limited effects on the other genes. These results suggest that persistently elevated D-aspartate, by enhancing NMDA transmission, may cause complex adaptive mechanisms affecting Homer1a, which in turn may explain the recently demonstrated protective effects of this D-amino acid against PCP-induced behavioral alterations, such as ataxic behavior.
Wiley Interdisciplinary Reviews: Membrane Transport and Signaling, 2011
Schizophrenia is a prevalent neuropsychiatric disorder associated with perturbations in medial pr... more Schizophrenia is a prevalent neuropsychiatric disorder associated with perturbations in medial prefrontal cortex (PFC) excitability and connectivity. As such, research into the neurobiology of schizophrenia and related psychotic disorders has focused on understanding the possible role played by the major excitatory neurotransmitter glutamate in mediating the cognitive and psychosocial impairments characteristic of this disease. Historically, the ionotropic NMDA glutamate receptor has received the greatest experimental attention in this regard. However, converging data point to Group 1 metabotropic glutamate receptors (mGluRs), as well as the Group 1 mGluR scaffolding protein Homer, as critical for normal psychomotor and cognitive function. Moreover, data derived primarily from behavioral pharmacological and genetic studies conducted in animal models of psychosis, suggest that dysregulation of Group 1 mGluR signaling may contribute to anomalies in neuronal excitation putatively underpinning the manifestation of cognitive abnormalities and psychotic-like behavior. These data implicate targeting Group 1 mGluRs as viable pharmacotherapeutic strategies for the treatment of schizophrenia and related disorders. proteins in Ca2+ signaling by excitable and non-excitable cells.
Journal of Affective Disorders, 2015
To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-it... more To assess the psychometric properties of the Italian adaptation of the Hypomania-Check-List 32-item, second revision (HCL-32-R2) for the detection of bipolarity in major depressive disorder (MDD) treatment-seeking outpatients. A back-to-back Italian adaption of the "Bipolar Disorders: Improving Diagnosis, Guidance, and Education" English module of the HCL-32-R2 was administered between March 2013 and October 2014 across twelve collaborating sites in Italy. Diagnostic and Statistical Manual Fourth edition (DSM-IV) diagnoses were made adopting the mini-international neuropsychiatric interview, using bipolar disorder (BD) patients as controls. In our sample (n=441, of whom, BD-I=68; BD-II=117; MDD=256), using a cut-off of 14 allowed the HCL-32-R2 to discriminate DSM-IV-defined MDD patients between "true unipolar" (HCL-32-R2(-)) and "sub-threshold bipolar depression" (HCL-32-R2(+)) with sensitivity=89% and specificity=79%. Area under the curve was .888; positive and negative predictive values were 75.34% and 90.99% respectively. Owing to clinical interpretability considerations and consistency with previous adaptations of the HCL-32, a two-factor solution (F1="hyperactive/elated" vs.…
ISRN Pharmacology, 2014
Background. Antipsychotic polypharmacy is used in several psychiatric disorders, despite poor evi... more Background. Antipsychotic polypharmacy is used in several psychiatric disorders, despite poor evidence existing to support this practice. Aim. We evaluated whether psychotic patients in acute relapse exposed to antipsychotic polypharmacy (AP + AP) showed different demographic, clinical, or psychopathological features compared to those exposed to one antipsychotic (AP) and whether AP + AP patients showed significantly higher improvement compared to AP patients after a 4-week treatment. Methods. Inpatients were subdivided into AP + AP and AP ones. In the cross-sectional step, patients were compared according to demographics, clinical variables, and scores on rating scales. In the longitudinal step, patients remained for 4 weeks under admission medications and were compared for clinical improvement. Results. AP + AP patients were more frequently diagnosed with schizophrenia and mental retardation as a comorbid illness. AP + AP patients were more frequently under first-generation antipsychotics and had worse clinical presentation. After 4 weeks of treatment, both AP + AP and AP patients improved compared to the baseline. However, AP patients scored significantly less than AP + AP patients at the Clinical Global Impression Scale at the 4-week time point but not at the baseline, indicating a treatment-specific improvement. Conclusions. Antipsychotic polypharmacy may be offered to specific types of psychotic patients. However, efficacy of this strategy is limited at best.
Schizophrenia Research and Treatment, 2011
Excess body weight is one of the most common physical health problems among patients with schizop... more Excess body weight is one of the most common physical health problems among patients with schizophrenia that increases the risk for many medical problems, including type 2 diabetes mellitus, coronary heart disease, osteoarthritis, and hypertension, and accounts in part for 20% shorter life expectancy than in general population. Among patients with severe mental illness, obesity can be attributed to an unhealthy lifestyle, personal genetic profile, as well as the effects of psychotropic medications, above all antipsychotic drugs. Novel "atypical" antipsychotic drugs represent a substantial improvement on older "typical" drugs. However, clinical experience has shown that some, but not all, of these drugs can induce substantial weight gain. Animal models of antipsychotic-related weight gain and animal transgenic models of knockout or overexpressed genes of antipsychotic receptors have been largely evaluated by scientific community for changes in obesity-related gene expression or phenotypes. Moreover, pharmacogenomic approaches have allowed to detect more than 300 possible candidate genes for antipsychotics-induced body weight gain. In this paper, we summarize current thinking on: (1) the role of polymorphisms in several candidate genes, (2) the possible roles of various neurotransmitters and neuropeptides in this adverse drug reaction, and (3) the state of development of animal models in this matter. We also outline major areas for future research.
International Review of Neurobiology, 2004
Excitatory synapses are characterized by an electron-dense thickening at the cytoplasmic surface ... more Excitatory synapses are characterized by an electron-dense thickening at the cytoplasmic surface of the postsynaptic membrane, called the postsynaptic density (PSD). The PSD is a fibrous specialization of the submembrane cytoskeleton approximately 30-40 nm thick and about 100 nm wide. Hundreds of molecules have been identified in the PSD: ion-gated and G-protein-coupled receptors, association, adaptors, and scaffolding proteins, key enzymes involved in phosphorylation-dephosphorylation mechanisms, and cytoskeletal proteins. Each of these proteins may have a pivotal function in setting the molecular scenario for the development of synaptic plasticity. Scaffolding proteins are major players in the organization of the postsynaptic signal transduction machinery,they regulate receptor trafficking and clustering, modulate axon pathfinding,and drive the correct targeting of neuronal proteins to their appropriate cytoplasmic compartment. Emerging findings suggest a relevant involvement of PSD scaffolding/adaptor proteins in behavior modulation in animal models of synaptic plasticity disorders and pharmacological isomorphisms.
The international journal of neuropsychopharmacology / official scientific journal of the Collegium Internationale Neuropsychopharmacologicum (CINP), 2007
The 5-HT2C receptor has been hypothesized to represent an important modulator in feeding behaviou... more The 5-HT2C receptor has been hypothesized to represent an important modulator in feeding behaviour. Evidence was based on the observation that knock-out mice for the 5-HT2C receptor gene (HTR2C) develop obesity and that many atypical antipsychotics with potent 5-HT2C antagonism may induce weight gain in susceptible individuals. Pharmacogenetic studies focusing mainly on the -759C/T promoter polymorphism (rs3813929) of the X-linked HTR2C gene revealed controversial results. We investigated the association of the HTR2C gene and weight gain using meta-analytical techniques, combining all published data while restricting our analysis to studies investigating the 759C/T. We also investigated whether ancestry (Caucasian vs. Asian) and clinical factors moderated any association. We found evidence for a slight association of -759C/T with weight gain and significance between studies for heterogeneity. Our meta-analysis provides support for the association of HTR2C in weight gain but indicate...
BioMed Research International, 2014
Approximately 30% of schizophrenia patients do not respond adequately to the therapy. Previous MR... more Approximately 30% of schizophrenia patients do not respond adequately to the therapy. Previous MRI studies have suggested that drug treatment resistance is associated with brain morphological abnormalities, although region-of-interest analysis of MR studies from nonresponder and responder patients failed to demonstrate a statistically significant difference between these two schizophrenia subgroups. We have used a voxel-based analysis of segmented MR studies to assess structural cerebral differences in 20 nonresponder and 15 responder patients and 16 age-matched normal volunteers. Differences between the three groups emerged bilaterally mainly at the level of the superior and middle frontal gyri, primarily due to reduced grey matter volumes in nonresponders, as compared to both normal volunteers and responder patients. Post hoc direct comparison between the two schizophrenia subgroups demonstrated significantly reduced grey matter volumes in middle frontal gyrus bilaterally, in the dorsolateral aspects of left superior frontal gyrus extending into postcentral gyrus and in the right medial temporal cortex. Our results extend and integrate previous findings suggesting a more severe atrophy in nonresponder schizophrenia patients, compared to responder patients, mainly at the level of the superior and middle frontal gyri. Longitudinal studies in drug-naïve patients are needed to assess the role of these associations.
European Neuropsychopharmacology, 2015
International Journal of Molecular Sciences, 2015
Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recen... more Agomelatine, a melatonergic antidepressant with a rapid onset of action, is one of the most recent drugs in the antidepressant category. Agomelatine's antidepressant actions are attributed to its sleep-promoting and chronobiotic actions mediated by MT1 and MT2 receptors present in the suprachiasmatic nucleus, as well as to its effects on the blockade of 5-HT2c receptors. Blockade of 5-HT2c receptors causes release of both noradrenaline and dopamine at the fronto-cortical dopaminergic and noradrenergic pathways. The combined actions of agomelatine on MT1/MT2 and 5-HT2c receptors facilitate the resynchronization of altered circadian rhythms and abnormal sleep patterns. Agomelatine appeared to be effective in treating major depression. Moreover, evidence exists that points out a possible efficacy of such drug in the treatment of bipolar depression, anxiety disorders, alcohol dependence, migraines etc. Thus, the aim of this narrative review was to elucidate current evidences on the role of agomelatine in disorders other than major depression.
Progress in Neuro-Psychopharmacology and Biological Psychiatry, 2011
The detection of changes in postsynaptic gene expression after the administration of mood stabili... more The detection of changes in postsynaptic gene expression after the administration of mood stabilizers, alone or in combination with antipsychotics, and antidepressants in animal models of drug treatment, may represent a valuable strategy to explore the molecular targets of the mainstay treatments for bipolar disorder. In this study we investigated, in both acute and chronic paradigms, the expression of specific postsynaptic density genes (Homer1a, Homer1b/c, and PSD95) and genes putatively implicated in mood stabilizers mechanism of action (GSK3b, ERK) after administration of first (haloperidol) or second generation antipsychotics (quetiapine 30 mg/kg), alone or in combination with valproate. Moreover, we compared the effects of an antidepressant agent widely used in bipolar depression (citalopram) with a low dose of quetiapine (15 mg/kg), which has been demonstrated to display antidepressant action in bipolar depression. In striatal regions, Homer1a expression was strongly induced by haloperidol compared to all the other treatments. Haloperidol plus valproate also markedly induced Homer1a, but to a significant lesser extent than haloperidol alone. Also in the chronic paradigm haloperidol, but not haloperidol plus valproate, induced Homer1a expression in all the subregions of the caudate-putamen and in the nucleus accumbens core. The high dose of quetiapine significantly induced Homer1a in anterior cingulated, premotor and motor subregions of the cortex, and the extent of induction was significantly higher as compared to the lower dose. Oppositely, Homer1a expression was decreased in the cortex by citalopram acute administration. ERK gene was upregulated in cortex and striatum by the acute treatment with valproate and with the combination of haloperidol or quetiapine plus valproate, whereas no significant differences were noticed in GSK3b expression among treatments. PSD95 showed a significant upregulation by acute citalopram and by haloperidol plus valproate in both cortical and subcortical regions. Haloperidol and quetiapine 30 mg/kg, oppositely, significantly reduced the expression of the gene in the cortex. In conclusion, these results suggest that the combined treatment with a typical or an atypical antipsychotic plus valproate may induce differential modulation of postsynaptic genes expression when compared to the effects of these drugs individually administered.
Current Molecular Pharmacology, 2014
In humans, glucocorticoid excess may cause neuropsychiatric symptoms, including psychosis and cog... more In humans, glucocorticoid excess may cause neuropsychiatric symptoms, including psychosis and cognitive impairment, and glucocorticoid signaling hyperactivation may sensitize to substance of abuse. The aim of this work was to evaluate whether exposure to glucocorticoid excess triggers molecular changes in dopaminergic and opioidergic systems within relevant forebrain areas. We acutely exposed Sprague-Dawley rats to dexamethasone, a glucocorticoid analog, or vehicle and evaluated the mRNA expression of dopamine D1 and D2 receptors and enkephalin within the cortex, the striatum, and the midbrain.
Molecular Neurobiology, 2014
Despite dopamine-glutamate aberrant interaction that has long been considered a relevant landmark... more Despite dopamine-glutamate aberrant interaction that has long been considered a relevant landmark of psychosis pathophysiology, several aspects of these two neurotransmitters reciprocal interaction remain to be defined. The emerging role of postsynaptic density (PSD) proteins at glutamate synapse as a molecular "lego" making a functional hub where different signals converge may add a new piece of information to understand how dopamine-glutamate interaction may work with regard to schizophrenia pathophysiology and treatment. More recently, compelling evidence suggests a relevant role for microRNA (miRNA) as a new class of dopamine and glutamate modulators with regulatory functions in the reciprocal interaction of these two neurotransmitters. Here, we aimed at addressing the following issues: (i) Do miRNAs have a role in schizophrenia pathophysiology in the context of dopamine-glutamate aberrant interaction? (ii) If miRNAs are relevant for dopamine-glutamate interaction, at what level this modulation takes place? (iii) Finally, will this knowledge open the door to innovative diagnostic and therapeutic tools? The biogenesis of miRNAs and their role in synaptic plasticity with relevance to schizophrenia will be considered in the context of dopamine-glutamate interaction, with special focus on miRNA interaction with PSD elements. From this framework, implications both for biomarkers identification and potential innovative interventions will be considered.
Current Neuropharmacology, 2014
Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of ... more Schizophrenia is one of the most debilitating psychiatric diseases with a lifetime prevalence of approximately 1%. Although the specific molecular underpinnings of schizophrenia are still unknown, evidence has long linked its pathophysiology to postsynaptic abnormalities.
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Papers by Andrea de Bartolomeis