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1. Prevalence and correlates of QTc prolongation in Italian psychiatric care: cross-sectional multicentre study

Author

Nosè, M., Bighelli, I., Castellazzi, M., Martinotti, G., Carrà, G., Lucii, C., Ostuzzi, G., Sozzi, F., Barbui, C., Acciavatti, T., Adamo, A., Aguglia, A., Albanese, C., Baccaglini, S., Bardicchia, F., Barone, R., Barone, Y., Bartoli, F., Bergamini, C., Bertolini, F., Bolognesi, S., Bordone, A., Bortolaso, P., Bugliani, M., Calandra, C., Calò, S., Cardamone, G., Caroleo, M., Carra, E., Carretta, D., Chiocchi, L., Clerici, M., Corbo, M., Corsi, E., Costanzo, R., Costoloni, G., D'Arienzo, F., Debolini, S., De Capua, A., Di Napoli, W. A., Dinelli, M., Facchi, E., Fargnoli, F., Fiori, F., Franchi, A., Gardellin, F., Gazzoletti, E., Ghio, L., Giacomin, M., Gregis, M., Iovieno, N., Koukouna, D., Lax, A., Lintas, C., Luca, A., Luca, M., Lussetti, M., Madrucci, M., Magnani, N., Magni, L., Manca, E., Martorelli, C., Mattafirri, R., Percudani, M., Perini, G., Petrosemolo, P., Pezzullo, M., Piantanida, S., Pinna, F., Prato, K., Prestia, D., Quattrone, D., Reggianini, C., Restaino, F., Ribolsi, M., Rinosi, G., Rizzo, C., Rizzo, R., Roggi, M., Rossi, G., Rossi, S., Ruberto, S., Santoro, R., Santi, M., Signorelli, M. S., Soscia, F., Staffa, P., Stilo, M., Strizzolo, S., Suraniti, F., Tavian, N., Tortelli, L., Tosoni, F., Valdagno, M., Zanobini, V., Nosè, M, Bighelli, I, Castellazzi, M, Martinotti, G, Carra', G, Lucii, C, Ostuzzi, G, Sozzi, F, Barbui, C, Acciavatti, T, Adamo, A, Aguglia, A, Albanese, C, Baccaglini, S, Bardicchia, F, Barone, R, Barone, Y, Bartoli, F, Bergamini, C, Bertolini, F, Bolognesi, S, Bordone, A, Bortolaso, P, Bugliani, M, Calandra, C, Calò, S, Cardamone, G, Caroleo, M, Carra, E, Carretta, D, Chiocchi, L, Clerici, M, Corbo, M, Corsi, E, Costanzo, R, Costoloni, G, D'Arienzo, F, Debolini, S, De Capua, A, Di Napoli, W, Dinelli, M, Facchi, E, Fargnoli, F, Fiori, F, Franchi, A, Gardellin, F, Gazzoletti, E, Ghio, L, Giacomin, M, Gregis, M, Iovieno, N, Koukouna, D, Lax, A, Lintas, C, Luca, A, Luca, M, Lussetti, M, Madrucci, M, Magnani, N, Magni, L, Manca, E, Martorelli, C, Mattafirri, R, Percudani, M, Perini, G, Petrosemolo, P, Pezzullo, M, Piantanida, S, Pinna, F, Prato, K, Prestia, D, Quattrone, D, Reggianini, C, Restaino, F, Ribolsi, M, Rinosi, G, Rizzo, C, Rizzo, R, Roggi, M, Rossi, G, Rossi, S, Ruberto, S, Santoro, R, Santi, M, Signorelli, M, Soscia, F, Staffa, P, Stilo, M, Strizzolo, S, Suraniti, F, Tavian, N, Tortelli, L, Tosoni, F, Valdagno, M, and Zanobini, V

Subjects
Adult, Male, medicine.medical_specialty, Psychotropic drugs, Epidemiology, medicine.medical_treatment, Long QT syndrome, Antidepressant, Drug overdose, Adverse effect, QT interval, Antipsychotic, 03 medical and health sciences, Electrocardiography, 0302 clinical medicine, Risk Factors, Psychotropic drug, medicine, Prevalence, Humans, cardiovascular diseases, Psychiatry, Settore MED/25 - Psichiatria, Polypharmacy, business.industry, Environmental and Occupational Health, Public Health, Environmental and Occupational Health, Public Health, Psychiatry and Mental Health, Original Articles, medicine.disease, 030227 psychiatry, Substance abuse, Long QT Syndrome, Cross-Sectional Studies, Italy, Aripiprazole, Female, business, adverse effect, antipsychotic, psychotropic drugs, Antipsychotic Agents, 030217 neurology & neurosurgery, medicine.drug
Abstract

Aims.In recent years several warnings have been issued by regulatory authorities on the risk of electrocardiogram abnormalities in individuals exposed to psychotropic drugs. As a consequence of these warnings, monitoring of the QT interval corrected for heart rate (QTc) has become increasingly common. This study was conducted to measure the frequency of QTc prolongation in unselected psychiatric patients, and to document the associated factors using a cross-sectional approach.Method.The study was carried out in 35 Italian psychiatric services that are part of the STAR (Servizi Territoriali Associati per la Ricerca) Network, a research group established to produce scientific knowledge by collecting data under ordinary circumstances. During a three-month period, a consecutive unselected series of both in- and out-patients were enrolled if they performed an ECG during the recruitment period and were receiving psychotropic drugs on the day ECG was recorded.Results.During the recruitment period a total of 2411 patients were included in the study. The prevalence of QTc prolongation ranged from 14.7% (men) and 18.6% (women) for the cut-off of 450 ms, to 1.26% (men) and 1.01% (women) for the cut-off of 500 ms. In the multivariate model conducted in the whole sample of patients exposed to psychotropic drugs, female sex, age, heart rate, alcohol and/or substance abuse, cardiovascular diseases and cardiovascular drug treatment, and drug overdose were significantly associated with QTc prolongation. In patients exposed to antipsychotic drugs, polypharmacy was positively associated with QTc prolongation, whereas use of aripiprazole decreased the risk. In patients exposed to antidepressant drugs, use of citalopram, citalopram dose and use of haloperidol in addition to antidepressant drugs, were all positively associated with QTc prolongation.Conclusions.The confirmation of a link between antipsychotic polypharmacy and QTc prolongation supports the current guidelines that recommend avoiding the concurrent use of two or more antipsychotic drugs, and the confirmation of a link between citalopram and QTc prolongation supports the need for routine QTc monitoring. The relatively low proportion of patients with QTc prolongation not only suggests compliance with current safety warnings issued by regulatory authorities, but also casts some doubts on the clinical relevance of QTc prolongation related to some psychotropic drugs.

Published
2016

2. Recessive gene disruptions in autism spectrum disorder

Author

Doan, R. N., Lim, E. T., De Rubeis, S., Betancur, C., Cutler, D. J., Chiocchetti, A. G., Overman, L. M., Soucy, A., Goetze, S., Asc, Consortium, Brusco, A., Curró, A., Fallerini, C., Lopergolo, D., Lintas, C., Domenici, E., Dalla Bernardina, B., Ferrero, G. B., Giorgio, E., Trabetti, E., Renieri, A., Riberi, E., Freitag, C. M., Daly, M. J., Walsh, C. A., Buxbaum, J. D., T. W., Yu, Dupuis, Christine, Boston Children's Hospital, Harvard Medical School [Boston] (HMS), Icahn School of Medicine at Mount Sinai [New York] (MSSM), Neuroscience Paris Seine (NPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut de Biologie Paris Seine (IBPS), Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS), Emory University School of Medicine, Emory University [Atlanta, GA], Universitätsklinikum Frankfurt, Goethe-University Frankfurt am Main, Newcastle University [Newcastle], Broad Institute [Cambridge], Harvard University [Cambridge]-Massachusetts Institute of Technology (MIT), Massachusetts General Hospital [Boston], Howard Hughes Medical Institute [Boston] (HHMI), Howard Hughes Medical Institute (HHMI)-Harvard Medical School [Boston] (HMS), Autism Sequencing Consortium, Neurosciences Paris Seine (NPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Sorbonne Université (SU)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), Génétique de l'autisme = Genetics of Autism (NPS-01), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut de Biologie Paris Seine (IBPS), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Centre National de la Recherche Scientifique (CNRS), and Massachusetts Institute of Technology (MIT)-Harvard University [Cambridge]

Subjects
Male, genetic structures, Autism Spectrum Disorder, [SDV]Life Sciences [q-bio], Allelic Imbalance, medicine.disease_cause, Whole Exome Sequencing, Cohort Studies, 0302 clinical medicine, Missense mutation, MESH: Cohort Studies, Exome sequencing, MESH: Autism Spectrum Disorder, Genetics, 0303 health sciences, Mutation, Genome, biology, SLC1A1, MESH: Genetic Predisposition to Disease, MESH: Case-Control Studies, [SDV] Life Sciences [q-bio], Case-Control Studies, Female, Genes, Recessive, Genome, Human, Humans, Genetic Predisposition to Disease, Mutation, Missense, Autism spectrum disorder, Human, Article, 03 medical and health sciences, MESH: Whole Exome Sequencing, mental disorders, Exome Sequencing, medicine, Recessive, Gene, MESH: Genes, Recessive, MESH: Genome, Human, 030304 developmental biology, MESH: Mutation, Missense, MESH: Humans, MESH: Allelic Imbalance, Case-control study, medicine.disease, MESH: Male, Genes, biology.protein, Missense, MESH: Female, 030217 neurology & neurosurgery
Abstract

Autism spectrum disorder (ASD) affects up to 1 in 59 individuals1. Genome-wide association and large-scale sequencing studies strongly implicate both common variants2–4 and rare de novo variants5–10 in ASD. Recessive mutations have also been implicated11–14 but their contribution remains less well defined. Here we demonstrate an excess of biallelic loss-of-function and damaging missense mutations in a large ASD cohort, corresponding to ~5% of total cases, including 10% of females, consistent with a female protective effect. We document biallelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) as well as other genes not previously implicated in ASD including the transcription factor FEV, a key regulator of the serotonergic circuitry. Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating novel biological pathways responsible for this condition., Editorial Summary: Analysis of whole exome sequencing data from 2,343 individuals with autism spectrum disorder (ASD) compared to 5,852 unaffected individuals demonstrates an excess of biallelic, autosomal mutations for both loss-of-function and damaging missense variants.

Published
2018

3. Antipsychotic dose mediates the association between polypharmacy and corrected QT interval

Author

Barbui, Corrado, Bighelli, Irene, Carrà, Giuseppe, Castellazzi, Mariasole, Lucii, Claudio, Martinotti, Giovanni, Nosè, Michela, Ostuzzi, Giovanni, Acciavatti, T., Adamo, A., Aguglia, A., Albanese, C., Baccaglini, S., Bardicchia, F., Barone, R., Barone, Y., Bartoli, F., Bergamini, C., Bertolini, F., Bolognesi, S., Bordone, A., Bortolaso, P., Bugliani, M., Calandra, C., Calò, S., Cardamone, G., Caroleo, M., Carra, E., Car-Retta, D., Chiocchi, L., Cinosi, E., Clerici, M., Corbo, M., Corsi, E., Costanzo, R., Costoloni, G., D'Arienzo, F., Debolini, S., De Capua, A., Di Napoli, W. A., Dinelli, M., Facchi, E., Fargnoli, F., Fiori, F., Franchi, A., Gardellin, F., Gastaldon, C., Gazzoletti, E., Ghio, L., Giacomin, M., Gregis, M., Iovieno, N., Koukouna, D., Lax, A., Lintas, C., Luca, A., Luca, M., Lussetti, M., Madrucci, M., Magnani, N., Magni, L., Manca, E., Martorelli, C., Mattafirri, R., Paladini, C., Papola, D., Percudani, M., Perini, G., Petrosemolo, P., Pezzullo, M., Piantanida, S., Pinna, F., Prato, K., Prestia, D., Quattrone, D., Reggianini, C., Restaino, F., Ribolsi, M., Rinosi, G., Rizzo, C., Rizzo, R., Roggi, M., Rossi, G., Rossi, S., Ruberto, S., Santi, M., Santoro, R., Sepede, G., Signorelli, M. S., Soscia, F., Sozzi, F., Staffa, P., Stilo, M., Strizzolo, S., Suraniti, F., Tavian, N., Tortelli, L., Tosoni, F., Valdagno, M., Zanobini, V., Barbui, C, Bighelli, I, Carrà, G, Castellazzi, M, Lucii, C, Martinotti, G, Nosè, M, Ostuzzi, G, Acciavatti, T, Adamo, A, Aguglia, A, Albanese, C, Baccaglini, S, Bardicchia, F, Barone, R, Barone, Y, Bartoli, F, Bergamini, C, Bertolini, F, Bolognesi, S, Bordone, A, Bortolaso, P, Bugliani, M, Calandra, C, Calò, S, Cardamone, G, Caroleo, M, Carra, E, Carretta, D, Chiocchi, L, Cinosi, E, Clerici, M, Corbo, M, Corsi, E, Costanzo, R, Costoloni, G, D'Arienzo, F, Debolini, S, De Capua, A, Di Napoli, W, Dinelli, M, Facchi, E, Fargnoli, F, Fiori, F, Franchi, A, Gardellin, F, Gastaldon, C, Gazzoletti, E, Ghio, L, Giacomin, M, Gregis, M, Iovieno, N, Koukouna, D, Lax, A, Lintas, C, Luca, A, Luca, M, Lussetti, M, Madrucci, M, Magnani, N, Magni, L, Manca, E, Martorelli, C, Mattafirri, R, Paladini, C, Papola, D, Percudani, M, Perini, G, Petrosemolo, P, Pezzullo, M, Piantanida, S, Pinna, F, Prato, K, Prestia, D, Quattrone, D, Reggianini, C, Restaino, F, Ribolsi, M, Rinosi, G, Rizzo, C, Rizzo, R, Roggi, M, Rossi, G, Rossi, S, Ruberto, S, Santi, M, Santoro, R, Sepede, G, Signorelli, M, Soscia, F, Sozzi, F, Staffa, P, Stilo, M, Strizzolo, S, Suraniti, F, Tavian, N, Tortelli, L, Tosoni, F, Valdagno, M, and Zanobini, V

Subjects
Male, Genetics and Molecular Biology (all), medicine.medical_treatment, Aripiprazole, lcsh:Medicine, Pharmacology, Cardiovascular Medicine, dose-dependent risk, Biochemistry, Electrocardiography, 0302 clinical medicine, Heart Rate, Medicine and Health Sciences, 80 and over, Antipsychotics, lcsh:Science, Aged, 80 and over, Multidisciplinary, Pharmaceutics, Medicine (all), Mental Disorders, Confounding, Drug Information, Drugs, Middle Aged, Long QT Syndrome, Bioassays and Physiological Analysis, Italy, Cardiovascular Diseases, Cardiology, Female, QT interval corrected for heart rate, Adult, Aged, Antipsychotic Agents, Cross-Sectional Studies, Dose-Response Relationship, Drug, Haloperidol, Humans, Young Adult, Polypharmacy, Agricultural and Biological Sciences (all), medicine.drug, Research Article, medicine.medical_specialty, Patients, QTc lenghtening, therapy risk, Long QT syndrome, antipsychotic drugs, Research and Analysis Methods, polypharmacy, QT interval, 03 medical and health sciences, Dose Prediction Methods, Drug Therapy, Internal medicine, Dose-Response Relationship, Drug, Biochemistry, Genetics and Molecular Biology (all), Heart rate, medicine, Antipsychotic, Inpatients, business.industry, lcsh:R, Electrophysiological Techniques, medicine.disease, 030227 psychiatry, Health Care, Defined daily dose, Settore MED/25, lcsh:Q, Cardiac Electrophysiology, business, 030217 neurology & neurosurgery
Abstract

Antipsychotic (AP) drugs have the potential to cause prolongation of the QT interval corrected for heart rate (QTc). As this risk is dose-dependent, it may be associated with the number of AP drugs concurrently prescribed, which is known to be associated with increased cumulative equivalent AP dosage. This study analysed whether AP dose mediates the relationship between polypharmacy and QTc interval. We used data from a cross-sectional survey that investigated the prevalence of QTc lengthening among people with psychiatric illnesses in Italy. AP polypharmacy was tested for evidence of association with AP dose and QTc interval using the Baron and Kenny mediational model. A total of 725 patients were included in this analysis. Of these, 186 (26%) were treated with two or more AP drugs (AP polypharmacy). The mean cumulative AP dose was significantly higher in those receiving AP polypharmacy (prescribed daily dose/defined daily dose = 2.93, standard deviation 1.31) than monotherapy (prescribed daily dose/defined daily dose = 0.82, standard deviation 0.77) (z = -12.62, p < 0.001). Similarly, the mean QTc interval was significantly longer in those receiving AP polypharmacy (mean = 420.86 milliseconds, standard deviation 27.16) than monotherapy (mean = 413.42 milliseconds, standard deviation 31.54) (z = -2.70, p = 0.006). The Baron and Kenny mediational analysis showed that, after adjustment for confounding variables, AP dose mediates the association between polypharmacy and QTc interval. The present study found that AP polypharmacy is associated with QTc interval, and this effect is mediated by AP dose. Given the high prevalence of AP polypharmacy in real-world clinical practice, clinicians should consider not only the myriad risk factors for QTc prolongation in their patients, but also that adding a second AP drug may further increase risk as compared with monotherapy.

Published
2016

4. Aripiprazole Versus Haloperidol in Combination With Clozapine for Treatment-Resistant Schizophrenia in Routine Clinical Care A Randomized, Controlled Trial

Author

Barbui, C, Accordini, S, Nosè, M, Stroup, S, Purgato, M, Girlanda, F, Esposito, E, Veronese, A, Tansella, M, Cipriani, A, CHAT Clozapine Haloperidol Aripiprazole Trial, Study Group, Losavio, T, Percudani, M, Aldini, F, Appino, Mg, Artioli, P, Barale, F, Beneduce, R, Berardi, D, Bertolazzi, G, Biancosino, B, Bisogno, A, Bivi, R, Bogetto, F, Boso, M, Bozzani, A, Bucolo, P, Casale, M, Cascone, L, Ciammella, L, Cicolini, A, Cipresso, G, Colombo, P, Dal Santo, B, De Francesco, M, Di Lorenzo, G, Di Munzio, W, Erlicher, A, Ferrannini, L, Ferrato, F, Ferro, A, Fragomeno, N, Fricchione Parise, V, Frova, M, Gardellin, F, Garzotto, N, Giambartolomei, A, Giupponi, G, Grassi, L, Grazian, N, Grecu, L, Guerrini, G, Laddomada, F, Lazzarin, E, Lintas, C, Malchiodi, F, Malvini, L, Marchiaro, L, Marsilio, A, Mauri, Mc, Mautone, A, Menchetti, M, Migliorini, G, Mollica, M, Moretti, D, Mulè, S, Nicholau, S, Nosè, F, Occhionero, G, Pacilli, Am, Pecchioli, S, Petrosemolo, P, Piantato, E, Piazza, C, Pontarollo, F, Pycha, R, Quartesan, Roberto, Rillosi, L, Risso, F, Rizzo, R, Rocca, P, Roma, S, Rossattini, M, Rossi, G, Sala, A, Santilli, C, Saraò, G, Sarnicola, A, Sartore, F, Scarone, S, Sciarma, Tiziana, Siracusano, A, Strizzolo, S, Targa, G, Tasser, A, Tomasi, R, Travaglini, R, Valentini, C, Ziero, S., Barbui C., Accordini S., Nosè M., Stroup S., Purgato M., Girlanda F., Esposito E., Veronese A., Tansella M., Cipriani A., CHAT (Clozapine Haloperidol Aripiprazole Trial) Study Group […, Losavio T., Percudani M., Aldini F., Appino M.G., Artioli P., Barale F., Beneduce R., Berardi D., Bertolazzi G., Biancosino B., Bisogno A., Bivi R., Bogetto F., Boso M., Bozzani A., Bucolo P., Casale M., Cascone L., Ciammella L., Cicolini A., Cipresso G., Colombo P., Dal Santo B., De Francesco M., Di Lorenzo G., Di Munzio W., Erlicher A., Ferrannini L., Ferrato F., Ferro A., Fragomeno N., Fricchione Parise V., Frova M., Gardellin F., Garzotto N., Giambartolomei A., Giupponi G., Grassi L., Grazian N., Grecu L., Guerrini G., Laddomada F., Lazzarin E., Lintas C., Malchiodi F., Malvini L., Marchiaro L., Marsilio A., Mauri M.C., Mautone A., Menchetti M., Migliorini G., Mollica M., Moretti D., Mulè S., Nicholau S., Nosè F., Occhionero G., Pacilli A.M., Pecchioli S., Petrosemolo P., Piantato E., Piazza C., Pontarollo F., Pycha R., Quartesan R., Rillosi L., Risso F., Rizzo R., Rocca P., Roma S., Rossattini M., Rossi G., Sala A., Santilli C., Saraò G., Sarnicola A., Sartore F., Scarone S., Sciarma T., Siracusano A., Strizzolo S., Targa G., Tasser A., Tomasi R., Travaglini R., Valentini C., and Ziero S. …]

Subjects
Adult, Male, medicine.medical_specialty, antipsychotics, aripiprazole, clozapine, combination strategies, schizophrenia, medicine.drug_class, medicine.medical_treatment, Drug Resistance, Atypical antipsychotic, Quinolones, Piperazines, law.invention, Randomized controlled trial, law, Internal medicine, Brief Psychiatric Rating Scale, medicine, Haloperidol, Humans, Pharmacology (medical), humans, quinolones, drug resistance, brief psychiatric rating scale, antipsychotic agents, drug therapy, combination, haloperidol, piperazines, adult, female, male, Psychiatry, Antipsychotic, Settore MED/25 - Psichiatria, Clozapine, combination, Randomised Controlled Trial, Aripiprazole, ATYPICAL ANTIPSYCHOTICS, TREATMENT RESISTANCE, drug therapy, Psychiatry and Mental health, Tolerability, Treatment-resistant, Schizophrenia, Drug Therapy, Combination, Female, Psychology, Antipsychotic Agents, medicine.drug
Abstract

This multisite study was conducted to compare the efficacy and tolerability of combination treatment with clozapine plus aripiprazole versus combination treatment with clozapine plus haloperidol in patients with schizophrenia who do not have an optimal response to clozapine. Patients continued to take clozapine and were randomly assigned to receive daily augmentation with aripiprazole or haloperidol. Physicians prescribed the allocated treatments according to usual clinical care. Withdrawal from allocated treatment within 3 months was the primary outcome. Secondary outcomes included severity of symptoms on the Brief Psychiatric Rating Scale and antipsychotic subjective tolerability on the Liverpool University Neuroleptic Side Effect Rating Scale. A total of 106 patients with schizophrenia were randomly assigned to treatment. After 3 months, we found no difference in the proportion of patients who discontinued treatment between the aripiprazole and haloperidol groups (13.2% vs 15.1%, P = 0.780). The 3-month change of the Brief Psychiatric Rating Scale total score was similar in the aripiprazole and haloperidol groups (-5.9 vs -4.4 points, P = 0.523), whereas the 3-month decrease of the Liverpool University Neuroleptic Side Effect Rating Scale total score was significantly higher in the aripiprazole group than in the haloperidol group (-7.4 vs -2.0 points, P = 0.006). These results suggest that augmentation of clozapine with aripiprazole offers no benefit with regard to treatment withdrawal and overall symptoms in schizophrenia compared with augmentation with haloperidol. However, an advantage in the perception of adverse effects with aripiprazole treatment may be meaningful for patients.

Published
2011

5. Genomic and epigenetic evidence for oxytocin receptor deficiency in autism

Author

Worley Gordon, Langford Cordelia F, Ellis Peter, Wright Harry H, Abramson Ruth K, Lintas Carla, Markunas Christina A, Biscocho Dhani, Johnson Jessica, Towers Aaron J, Connelly Jessica J, Gregory Simon G, Delong G Robert, Murphy Susan K, Cuccaro Michael L, Persico Antonello, and Pericak-Vance Margaret A

Subjects
Medicine
Abstract

Abstract Background Autism comprises a spectrum of behavioral and cognitive disturbances of childhood development and is known to be highly heritable. Although numerous approaches have been used to identify genes implicated in the development of autism, less than 10% of autism cases have been attributed to single gene disorders. Methods We describe the use of high-resolution genome-wide tilepath microarrays and comparative genomic hybridization to identify copy number variants within 119 probands from multiplex autism families. We next carried out DNA methylation analysis by bisulfite sequencing in a proband and his family, expanding this analysis to methylation analysis of peripheral blood and temporal cortex DNA of autism cases and matched controls from independent datasets. We also assessed oxytocin receptor (OXTR) gene expression within the temporal cortex tissue by quantitative real-time polymerase chain reaction (PCR). Results Our analysis revealed a genomic deletion containing the oxytocin receptor gene, OXTR (MIM accession no.: 167055), previously implicated in autism, was present in an autism proband and his mother who exhibits symptoms of obsessive-compulsive disorder. The proband's affected sibling did not harbor this deletion but instead may exhibit epigenetic misregulation of this gene through aberrant gene silencing by DNA methylation. Further DNA methylation analysis of the CpG island known to regulate OXTR expression identified several CpG dinucleotides that show independent statistically significant increases in the DNA methylation status in the peripheral blood cells and temporal cortex in independent datasets of individuals with autism as compared to control samples. Associated with the increase in methylation of these CpG dinucleotides is our finding that OXTR mRNA showed decreased expression in the temporal cortex tissue of autism cases matched for age and sex compared to controls. Conclusion Together, these data provide further evidence for the role of OXTR and the oxytocin signaling pathway in the etiology of autism and, for the first time, implicate the epigenetic regulation of OXTR in the development of the disorder. See the related commentary by Gurrieri and Neri: http://www.biomedcentral.com/1741-7015/7/63

Published
2009
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6. Combinations of QTc-prolonging drugs: towards disentangling pharmacokinetic and pharmacodynamic effects in their potentially additive nature

Author

A. D. Meid, I. Bighelli, S. Mächler, G. Mikus, G. Carrà, M. Castellazzi, C. Lucii, G. Martinotti, M. Nosè, G. Ostuzzi, T. Acciavatti, A. Adamo, A. Aguglia, C. Albanese, S. Baccaglini, F. Bardicchia, R. Barone, Y. Barone, F. Bartoli, C. Bergamini, F. Bertolini, S. Bolognesi, A. Bordone, P. Bortolaso, M. Bugliani, C. Calandra, S. Calò, G. Cardamone, M. Caroleo, E. Carra, D. Carretta, L. Chiocchi, E. Cinosi, M. Clerici, M. Corbo, E. Corsi, R. Costanzo, G. Costoloni, F. D’Arienzo, S. Debolini, A. De Capua, W. A. Di Napoli, M. Dinelli, E. Facchi, F. Fargnoli, F. Fiori, A. Franchi, F. Gardellin, C. Gastaldon, E. Gazzoletti, L. Ghio, M. Giacomin, M. Gregis, N. Iovieno, D. Koukouna, A. Lax, C. Lintas, A. Luca, M. Luca, M. Lussetti, M. Madrucci, N. Magnani, L. Magni, E. Manca, C. Martorelli, R. Mattafirri, C. Paladini, D. Papola, M. Percudani, G. Perini, P. Petrosemolo, M. Pezzullo, S. Piantanida, F. Pinna, K. Prato, D. Prestia, D. Quattrone, C. Reggianini, F. Restaino, M. Ribolsi, G. Rinosi, C. Rizzo, R. Rizzo, M. Roggi, G. Rossi, S. Rossi, S. Ruberto, M. Santi, R. Santoro, G. Sepede, M. S. Signorelli, F. Soscia, P. Staffa, M. Stilo, S. Strizzolo, F. Suraniti, N. Tavian, L. Tortelli, F. Tosoni, M. Valdagno, V. Zanobini, C. Barbui, W. E. Haefeli, Meid, A, Bighelli, I, Mächler, S, Mikus, G, Carrà, G, Castellazzi, M, Lucii, C, Martinotti, G, Nosè, M, Ostuzzi, G, Acciavatti, T, Adamo, A, Aguglia, A, Albanese, C, Baccaglini, S, Bardicchia, F, Barone, R, Barone, Y, Bartoli, F, Bergamini, C, Bertolini, F, Bolognesi, S, Bordone, A, Bortolaso, P, Bugliani, M, Calandra, C, Calò, S, Cardamone, G, Caroleo, M, Carra, E, Carretta, D, Chiocchi, L, Cinosi, E, Clerici, M, Corbo, M, Corsi, E, Costanzo, R, Costoloni, G, D’Arienzo, F, Debolini, S, De Capua, A, Di Napoli, W, Dinelli, M, Facchi, E, Fargnoli, F, Fiori, F, Franchi, A, Gardellin, F, Gastaldon, C, Gazzoletti, E, Ghio, L, Giacomin, M, Gregis, M, Iovieno, N, Koukouna, D, Lax, A, Lintas, C, Luca, A, Luca, M, Lussetti, M, Madrucci, M, Magnani, N, Magni, L, Manca, E, Martorelli, C, Mattafirri, R, Paladini, C, Papola, D, Percudani, M, Perini, G, Petrosemolo, P, Pezzullo, M, Piantanida, S, Pinna, F, Prato, K, Prestia, D, Quattrone, D, Reggianini, C, Restaino, F, Ribolsi, M, Rinosi, G, Rizzo, C, Rizzo, R, Roggi, M, Rossi, G, Rossi, S, Ruberto, S, Santi, M, Santoro, R, Sepede, G, Signorelli, M, Soscia, F, Staffa, P, Stilo, M, Strizzolo, S, Suraniti, F, Tavian, N, Tortelli, L, Tosoni, F, Valdagno, M, Zanobini, V, Barbui, C, and Haefeli, W

Subjects
QT interval, medicine.medical_specialty, electrocardiography, 030204 cardiovascular system & hematology, 03 medical and health sciences, 0302 clinical medicine, Pharmacokinetics, Internal medicine, medicine, cohort study, 030212 general & internal medicine, drug–drug interaction, Pharmacology, Toxicology and Pharmaceutics (miscellaneous), Original Research, drug–drug interactions, psychiatry, medicine.diagnostic_test, business.industry, Pharmacodynamics, Cardiology, Psychology (miscellaneous), business, Electrocardiography, cohort study, drug–drug interactions, electrocardiography, psychiatry, QT interval, Cohort study
Abstract

Background:Whether arrhythmia risks will increase if drugs with electrocardiographic (ECG) QT-prolonging properties are combined is generally supposed but not well studied. Based on available evidence, the Arizona Center for Education and Research on Therapeutics (AZCERT) classification defines the risk of QT prolongation for exposure to single drugs. We aimed to investigate how combining AZCERT drug categories impacts QT duration and how relative drug exposure affects the extent of pharmacodynamic drug–drug interactions.Methods:In a cohort of 2558 psychiatric inpatients and outpatients, we modeled whether AZCERT class and number of coprescribed QT-prolonging drugs correlates with observed rate-corrected QT duration (QTc) while also considering age, sex, inpatient status, and other QTc-prolonging risk factors. We concurrently considered administered drug doses and pharmacokinetic interactions modulating drug clearance to calculate individual weights of relative exposure with AZCERT drugs. Because QTc duration is concentration-dependent, we estimated individual drug exposure with these drugs and included this information as weights in weighted regression analyses.Results:Drugs attributing a ‘known’ risk for clinical consequences were associated with the largest QTc prolongations. However, the presence of at least two versus one QTc-prolonging drug yielded nonsignificant prolongations [exposure-weighted parameter estimates with 95% confidence intervals for ‘known’ risk drugs + 0.93 ms (–8.88;10.75)]. Estimates for the ‘conditional’ risk class increased upon refinement with relative drug exposure and co-administration of a ‘known’ risk drug as a further risk factor.Conclusions:These observations indicate that indiscriminate combinations of QTc-prolonging drugs do not necessarily result in additive QTc prolongation and suggest that QT prolongation caused by drug combinations strongly depends on the nature of the combination partners and individual drug exposure. Concurrently, it stresses the value of the AZCERT classification also for the risk prediction of combination therapies with QT-prolonging drugs.

Published
2017

7. Rationale and design of an independent randomised controlled trial evaluating the effectiveness of aripiprazole or haloperidol in combination with clozapine for treatment-resistant schizophrenia

Author

Paola Colombo, Luisa Ciammella, Giancarlo Giupponi, Francesco Barale, Luigi Grassi, Giorgio Di Lorenzo, Maria Frova, Michela Nosè, Gualtiero Guerrini, Liliana Cascone, Francesco Pontarollo, Rodolfo Tomasi, Alfredo Bisogno, Francesca Sartore, Guglielmo Occhionero, Claudio Santilli, Andrea Giambartolomei, Tiziana Sciarma, Marco Menchetti, Matteo Rossattini, Giuseppe Saraò, Farida Ferrato, Gabriele Cipresso, Alessandra Marsilio, Simone Accordini, Anna Maria Pacilli, Francesco Laddomada, Marianna Boso, Giuseppe Migliorini, Lara Malvini, Camilla Lintas, Antonio Ferro, Alessia Cicolini, Luciana Rillosi, Annamarie Tasser, Alberto Siracusano, Mauro Percudani, Roberto Quartesan, Nicoletta Fragomeno, Nicola Garzotto, Flavio Nosè, Corrado Barbui, Raffaella Bivi, Antonio Mautone, Rossella Beneduce, Gerardo Bertolazzi, Andrea Cipriani, Eleonora Esposito, Alberto Bozzani, Stylianos Nicholau, Barbara Dal Santo, Antonio Veronese, Gino Targa, Rossana Travaglini, Ermanna Lazzarin, Francesco Gardellin, Luigi Ferrannini, Stefania Roma, Giuseppe Rossi, Giovanni Rossi, Alessandra Sala, Bruno Biancosino, Massimo Carlo Mauri, Simona Ziero, Domenico Berardi, Roger Pycha, Walter Di Munzio, Serena Mulè, Michele De Francesco, Filippo Bogetto, Arcadio Erlicher, Carlo Piazza, Francesco Risso, Stefania Strizzolo, Marcello Casale, Vincenzo Fricchione Parise, Lorella Grecu, Silvio Scarone, Paola Artioli, Giuseppe Ducci, Raffella Rizzo, Michele Tansella, Natalia Grazian, Livio Marchiaro, Daniele Moretti, Marco Mollica, Paola Rocca, Piera Bucolo, Antonio Sarnicola, Stefania Pecchioli, Ennio Piantato, Francesca Malchiodi, Nosè M, Accordini S, Artioli P, Barale F, Barbui C, Beneduce R, Berardi D, Bertolazzi G, Biancosino B, Bisogno A, Bivi R, Bogetto F, Boso M, Bozzani A, Bucolo P, Casale M, Cascone L, Ciammella L, Cicolini A, Cipresso G, Cipriani A, Colombo P, Dal Santo B, De Francesco M, Di Lorenzo G, Di Munzio W, Ducci G, Erlicher A, Esposito E, Ferrannini L, Ferrato F, Ferro A, Fragomeno N, Parise VF, Frova M, Gardellin F, Garzotto N, Giambartolomei A, Giupponi G, Grassi L, Grazian N, Grecu L, Guerrini G, Laddomada F, Lazzarin E, Lintas C, Malchiodi F, Malvini L, Marchiaro L, Marsilio A, Mauri MC, Mautone A, Menchetti M, Migliorini G, Mollica M, Moretti D, Mulè S, Nicholau S, Nosè F, Occhionero G, Pacilli AM, Pecchioli S, Percudani M, Piantato E, Piazza C, Pontarollo F, Pycha R, Quartesan R, Rillosi L, Risso F, Rizzo R, Rocca P, Roma S, Rossattini M, Rossi G, Sala A, Santilli C, Saraò G, Sarnicola A, Sartore F, Scarone S, Sciarma T, Siracusano A, Strizzolo S, Tansella M, Targa G, Tasser A, Tomasi R, Travaglini R, Veronese A, and Ziero S.

Subjects
REFRACTORY SCHIZOPHRENIA, Schizophrenia, treatment-resistance, antipsychotics, medicine.medical_treatment, Aripiprazole, piperazines, Medicine (miscellaneous), Antipsychotic Agents, Clinical Protocols, Clozapine, Drug Therapy, Combination, Government Regulation, Haloperidol, Humans, Italy, Piperazines, Prospective Studies, Quinolones, Research Design, Treatment Outcome, Drug Resistance, Schizophrenic Psychology, law.invention, haloperidol, Study Protocol, DOUBLE-BLIND, Randomized controlled trial, law, Pharmacology (medical), schizophrenic psychology, humans, antipsychotic agents, clinical protocols, clozapine, drug resistance, drug therapy, combination, government regulation, haloperidol, humans, Italy, piperazines, prospective studies, quinolones, research design, schizophrenia, schizophrenic psychology, treatment outcome, lcsh:R5-920, treatment-resistant schizophrenia, aripiprazole, clozapine, ANTIPSYCHOTIC DRUGS, PRAGMATIC TRIALS, CLINICAL TRIALS, AUGMENTATION, METAANALYSIS, government regulation, antipsychotic agents, research design, drug therapy, lcsh:Medicine (General), medicine.drug, medicine.medical_specialty, Context (language use), medicine, clinical protocols, Antipsychotic, Psychiatry, Settore MED/25 - Psichiatria, Polypharmacy, combination, drug resistance, business.industry, medicine.disease, prospective studies, Clinical trial, schizophrenia, treatment outcome, quinolones, business
Abstract

Background One third to two thirds of people with schizophrenia have persistent psychotic symptoms despite clozapine treatment. Under real-world circumstances, the need to provide effective therapeutic interventions to patients who do not have an optimal response to clozapine has been cited as the most common reason for simultaneously prescribing a second antipsychotic drug in combination treatment strategies. In a clinical area where the pressing need of providing therapeutic answers has progressively increased the occurrence of antipsychotic polypharmacy, despite the lack of robust evidence of its efficacy, we sought to implement a pre-planned protocol where two alternative therapeutic answers are systematically provided and evaluated within the context of a pragmatic, multicentre, independent randomised study. Methods/Design The principal clinical question to be answered by the present project is the relative efficacy and tolerability of combination treatment with clozapine plus aripiprazole compared with combination treatment with clozapine plus haloperidol in patients with an incomplete response to treatment with clozapine over an appropriate period of time. This project is a prospective, multicentre, randomized, parallel-group, superiority trial that follow patients over a period of 12 months. Withdrawal from allocated treatment within 3 months is the primary outcome. Discussion The implementation of the protocol presented here shows that it is possible to create a network of community psychiatric services that accept the idea of using their everyday clinical practice to produce randomised knowledge. The employed pragmatic attitude allowed to randomly allocate more than 100 individuals, which means that this study is the largest antipsychotic combination trial conducted so far in Western countries. We expect that the current project, by generating evidence on whether it is clinically useful to combine clozapine with aripiprazole rather than with haloperidol, provides physicians with a solid evidence base to be directly applied in the routine care of patients with schizophrenia. Trial Registration Clincaltrials.gov Identifier: NCT00395915

Published
2009

8. Involvement of the PRKCB1 gene in autistic disorder: significant genetic association and reduced neocortical gene expression

Author

Antonio M. Persico, Krassimira A. Garbett, Karoly Mirnics, Raun Melmed, Barbara Manzi, Carmela Bravaccio, Maurizio Elia, Paolo Curatolo, Karl L. Reichelt, Roberto Sacco, Cindy Schneider, Tiziana Pascucci, Roberto Militerni, Stefano Puglisi-Allegra, Carla Lintas, Lintas, C, Sacco, R, Garbett, K, Mirnics, K, Militerni, R, Bravaccio, Carmela, Curatolo, P, Manzi, B, Schneider, C, Melmed, R, Elia, M, Pascucci, T, PUGLISI ALLEGRA, S, Reichelt, Kl, and Persico, A. M.

Subjects
Male, Autism, Gene Expression, Genome-wide association study, Neocortex, tgf-β, Protein kinase C-β, PRKCB1, Gene Frequency, protein kinase c-beta, Gene expression, pervasive developmental disorders, Temporal cortex, TGF-β, Adolescent, Adult, Autistic Disorder, Chi-Square Distribution, Child, Preschool, Family Health, Female, Genome-Wide Association Study, Genotype, Humans, Polymorphism, Single Nucleotide, Protein Kinase C, Protein Kinase C beta, Young Adult, Genetic Predisposition to Disease, Molecular Biology, Psychiatry and Mental Health, Cellular and Molecular Neuroscience, autism, prkcb1, protein kinase c beta, protein kinase c-β, temporal cortex, tgf beta, tgf-beta, Regulation of gene expression, Genetics, Child, Preschool, Gene isoform, Biology, Polymorphism, Single Nucleotide, medicine, Gene, Alternative splicing, medicine.disease, Molecular biology
Abstract

Protein kinase C enzymes play an important role in signal transduction, regulation of gene expression and control of cell division and differentiation. The fsI and betaII isoenzymes result from the alternative splicing of the PKCbeta gene (PRKCB1), previously found to be associated with autism. We performed a family-based association study in 229 simplex and 5 multiplex families, and a postmortem study of PRKCB1 gene expression in temporocortical gray matter (BA41/42) of 11 autistic patients and controls. PRKCB1 gene haplotypes are significantly associated with autism (P

Published
2008

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