Publications by authors named "Sarah Tosato"

61 Publications

Lack of Support for the Genes by Early Environment Interaction Hypothesis in the Pathogenesis of Schizophrenia.

Schizophr Bull 2021 May 14. Epub 2021 May 14.

Department of Psychosis Studies, Institute of Psychiatry, Psychology & Neuroscience, King's College London, London, UK.

Ursini et al reported recently that the liability of schizophrenia explained by a polygenic risk score (PRS) derived from the variants most associated with schizophrenia was increased 5-fold in individuals who experienced complications during pregnancy or birth. Follow-up gene expression analysis showed that the genes mapping to the most associated genetic variants are highly expressed in placental tissues. If confirmed, these findings will have major implications in our understanding of the joint effect of genes and environment in the pathogenesis of schizophrenia. We examined the interplay between PRS and obstetric complications (OCs) in 5 independent samples (effective N = 2110). OCs were assessed with the full or modified Lewis-Murray scale, or with birth weight < 2.5 kg as a proxy. In a large cohort we tested whether the pathways from placenta-relevant variants in the original report were associated with case-control status. Unlike in the original study, we did not find significant effect of PRS on the presence of OCs in cases, nor a substantial difference in the association of PRS with case-control status in samples stratified by the presence of OCs. Furthermore, none of the PRS by OCs interactions were significant, nor were any of the biological pathways, examined in the Swedish cohort. Our study could not support the hypothesis of a mediating effect of placenta biology in the pathway from genes to schizophrenia. Methodology differences, in particular the different scales measuring OCs, as well as power constraints for interaction analyses in both studies, may explain this discrepancy.
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http://dx.doi.org/10.1093/schbul/sbab052DOI Listing
May 2021

Duration of Untreated Psychosis in First-Episode Psychosis is not Associated With Common Genetic Variants for Major Psychiatric Conditions: Results From the Multi-Center EU-GEI Study.

Schizophr Bull 2021 May 8. Epub 2021 May 8.

Department of Experimental Biomedicine and Clinical Neuroscience, University of Palermo, Palermo, Italy.

Duration of untreated psychosis (DUP) is associated with clinical outcomes in people with a diagnosis of first-episode psychosis (FEP), but factors associated with length of DUP are still poorly understood. Aiming to obtain insights into the possible biological impact on DUP, we report genetic analyses of a large multi-center phenotypically well-defined sample encompassing individuals with a diagnosis of FEP recruited from 6 countries spanning 17 research sites, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. Genetic propensity was measured using polygenic scores for schizophrenia (SZ-PGS), bipolar disorder (BD-PGS), major depressive disorder (MDD-PGS), and intelligence (IQ-PGS), which were calculated based on the results from the most recent genome-wide association meta-analyses. Following imputation for missing data and log transformation of DUP to handle skewedness, the association between DUP and polygenic scores (PGS), adjusting for important confounders, was investigated with multivariable linear regression models. The sample comprised 619 individuals with a diagnosis of FEP disorders with a median age at first contact of 29.0 years (interquartile range [IQR] = 22.0-38.0). The median length of DUP in the sample was 10.1 weeks (IQR = 3.8-30.8). One SD increases in SZ-PGS, BD-PGS, MDD-PGS or IQ-PGS were not significantly associated with the length of DUP. Our results suggest that genetic variation does not contribute to the DUP in patients with a diagnosis of FEP disorders.
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http://dx.doi.org/10.1093/schbul/sbab055DOI Listing
May 2021

Perceived major experiences of discrimination, ethnic group, and risk of psychosis in a six-country case-control study.

Psychol Med 2021 Mar 2:1-9. Epub 2021 Mar 2.

Department of Psychiatry, University of Cambridge, CambridgeCB2 0SZ, UK.

Background: Perceived discrimination is associated with worse mental health. Few studies have assessed whether perceived discrimination (i) is associated with the risk of psychotic disorders and (ii) contributes to an increased risk among minority ethnic groups relative to the ethnic majority.

Methods: We used data from the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions Work Package 2, a population-based case-control study of incident psychotic disorders in 17 catchment sites across six countries. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) for the associations between perceived discrimination and psychosis using mixed-effects logistic regression models. We used stratified and mediation analyses to explore differences for minority ethnic groups.

Results: Reporting any perceived experience of major discrimination (e.g. unfair treatment by police, not getting hired) was higher in cases than controls (41.8% v. 34.2%). Pervasive experiences of discrimination (≥3 types) were also higher in cases than controls (11.3% v. 5.5%). In fully adjusted models, the odds of psychosis were 1.20 (95% CI 0.91-1.59) for any discrimination and 1.79 (95% CI 1.19-1.59) for pervasive discrimination compared with no discrimination. In stratified analyses, the magnitude of association for pervasive experiences of discrimination appeared stronger for minority ethnic groups (OR = 1.73, 95% CI 1.12-2.68) than the ethnic majority (OR = 1.42, 95% CI 0.65-3.10). In exploratory mediation analysis, pervasive discrimination minimally explained excess risk among minority ethnic groups (5.1%).

Conclusions: Pervasive experiences of discrimination are associated with slightly increased odds of psychotic disorders and may minimally help explain excess risk for minority ethnic groups.
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http://dx.doi.org/10.1017/S0033291721000453DOI Listing
March 2021

Migration history and risk of psychosis: results from the multinational EU-GEI study.

Psychol Med 2021 Feb 10:1-13. Epub 2021 Feb 10.

Univ Paris Est Creteil (UPEC), AP-HP, Hôpitaux Universitaires « H. Mondor », DMU IMPACT, INSERM, IMRB, Fondation FondaMental, F-94010Creteil, France.

Background: Psychosis rates are higher among some migrant groups. We hypothesized that psychosis in migrants is associated with cumulative social disadvantage during different phases of migration.

Methods: We used data from the EUropean Network of National Schizophrenia Networks studying Gene-Environment Interactions (EU-GEI) case-control study. We defined a set of three indicators of social disadvantage for each phase: pre-migration, migration and post-migration. We examined whether social disadvantage in the pre- and post-migration phases, migration adversities, and mismatch between achievements and expectations differed between first-generation migrants with first-episode psychosis and healthy first-generation migrants, and tested whether this accounted for differences in odds of psychosis in multivariable logistic regression models.

Results: In total, 249 cases and 219 controls were assessed. Pre-migration (OR 1.61, 95% CI 1.06-2.44, p = 0.027) and post-migration social disadvantages (OR 1.89, 95% CI 1.02-3.51, p = 0.044), along with expectations/achievements mismatch (OR 1.14, 95% CI 1.03-1.26, p = 0.014) were all significantly associated with psychosis. Migration adversities (OR 1.18, 95% CI 0.672-2.06, p = 0.568) were not significantly related to the outcome. Finally, we found a dose-response effect between the number of adversities across all phases and odds of psychosis (⩾6: OR 14.09, 95% CI 2.06-96.47, p = 0.007).

Conclusions: The cumulative effect of social disadvantages before, during and after migration was associated with increased odds of psychosis in migrants, independently of ethnicity or length of stay in the country of arrival. Public health initiatives that address the social disadvantages that many migrants face during the whole migration process and post-migration psychological support may reduce the excess of psychosis in migrants.
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http://dx.doi.org/10.1017/S003329172000495XDOI Listing
February 2021

Cognitive functioning throughout adulthood and illness stages in individuals with psychotic disorders and their unaffected siblings.

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Dokuz Eylül University, School of Medicine, Izmir, Turkey.

Important questions remain about the profile of cognitive impairment in psychotic disorders across adulthood and illness stages. The age-associated profile of familial impairments also remains unclear, as well as the effect of factors, such as symptoms, functioning, and medication. Using cross-sectional data from the EU-GEI and GROUP studies, comprising 8455 participants aged 18 to 65, we examined cognitive functioning across adulthood in patients with psychotic disorders (n = 2883), and their unaffected siblings (n = 2271), compared to controls (n = 3301). An abbreviated WAIS-III measured verbal knowledge, working memory, visuospatial processing, processing speed, and IQ. Patients showed medium to large deficits across all functions (ES range = -0.45 to -0.73, p < 0.001), while siblings showed small deficits on IQ, verbal knowledge, and working memory (ES = -0.14 to -0.33, p < 0.001). Magnitude of impairment was not associated with participant age, such that the size of impairment in older and younger patients did not significantly differ. However, first-episode patients performed worse than prodromal patients (ES range = -0.88 to -0.60, p < 0.001). Adjusting for cannabis use, symptom severity, and global functioning attenuated impairments in siblings, while deficits in patients remained statistically significant, albeit reduced by half (ES range = -0.13 to -0.38, p < 0.01). Antipsychotic medication also accounted for around half of the impairment in patients (ES range = -0.21 to -0.43, p < 0.01). Deficits in verbal knowledge, and working memory may specifically index familial, i.e., shared genetic and/or shared environmental, liability for psychotic disorders. Nevertheless, potentially modifiable illness-related factors account for a significant portion of the cognitive impairment in psychotic disorders.
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http://dx.doi.org/10.1038/s41380-020-00969-zDOI Listing
January 2021

The incidence of psychotic disorders among migrants and minority ethnic groups in Europe: findings from the multinational EU-GEI study.

Psychol Med 2020 Sep 22:1-10. Epub 2020 Sep 22.

Rivierduinen Institute for Mental Health Care, Sandifortdreef 19, 2333 ZZ Leiden, The Netherlands.

Background: In Europe, the incidence of psychotic disorder is high in certain migrant and minority ethnic groups (hence: 'minorities'). However, it is unknown how the incidence pattern for these groups varies within this continent. Our objective was to compare, across sites in France, Italy, Spain, the UK and the Netherlands, the incidence rates for minorities and the incidence rate ratios (IRRs, minorities v. the local reference population).

Methods: The European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study was conducted between 2010 and 2015. We analyzed data on incident cases of non-organic psychosis (International Classification of Diseases, 10th edition, codes F20-F33) from 13 sites.

Results: The standardized incidence rates for minorities, combined into one category, varied from 12.2 in Valencia to 82.5 per 100 000 in Paris. These rates were generally high at sites with high rates for the reference population, and low at sites with low rates for the reference population. IRRs for minorities (combined into one category) varied from 0.70 (95% CI 0.32-1.53) in Valencia to 2.47 (95% CI 1.66-3.69) in Paris (test for interaction: p = 0.031). At most sites, IRRs were higher for persons from non-Western countries than for those from Western countries, with the highest IRRs for individuals from sub-Saharan Africa (adjusted IRR = 3.23, 95% CI 2.66-3.93).

Conclusions: Incidence rates vary by region of origin, region of destination and their combination. This suggests that they are strongly influenced by the social context.
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http://dx.doi.org/10.1017/S0033291720003219DOI Listing
September 2020

Neurological Signs at the First Psychotic Episode as Correlates of Long-Term Outcome: Results From the AESOP-10 Study.

Schizophr Bull 2021 01;47(1):118-127

Department of Psychological Medicine, Institute of Psychiatry, Psychology and Neuroscience, King's College London, London, UK.

Minor neurological signs are subtle deficits in sensory integration, motor coordination, and sequencing of complex motor acts present in excess in the early stages of psychosis. Still, it remains unclear whether at least some of these signs represent trait or state markers for psychosis and whether they are markers of long-term disease outcome of clinical utility. We examined the relationship between neurological function at illness onset assessed with the Neurological Evaluation Scale and subsequent illness course in 233 patients from AESOP-10 (Aetiology and Ethnicity in Schizophrenia and Other Psychoses), a 10-year follow-up study of a population-based cohort of individuals recruited at the time of their first episode of psychosis in the United Kingdom. In 56 of these patients, we also explored changes in neurological function over time. We included a group of 172 individuals without psychosis as controls. After 10 years, 147 (63%) patients had developed a non-remitting course of illness, and 86 (37%) a remitting course. Already at first presentation, patients who developed a non-remitting course had significantly more primary, motor coordination, and total signs than both remitting patients and healthy controls. While Motor Coordination signs did not change over time, rates of Primary, Sensory Integration, and Total signs increased, independently of illness course type. These findings suggest that motor coordination problems could be a useful early, quick, and easily detectable marker of subsequent clinical outcome. With other motor abnormalities, a measure of motor incoordination could contribute to the identification of the most vulnerable individuals, who could benefit from targeted and more assertive treatment approaches.
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http://dx.doi.org/10.1093/schbul/sbaa089DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7824991PMC
January 2021

Jumping to conclusions, general intelligence, and psychosis liability: findings from the multi-centre EU-GEI case-control study.

Psychol Med 2021 Mar 24;51(4):623-633. Epub 2020 Apr 24.

Section of Psychiatry, Azienda Ospedaliera Universitaria Integrata di Verona, Verona, Italy.

Background: The 'jumping to conclusions' (JTC) bias is associated with both psychosis and general cognition but their relationship is unclear. In this study, we set out to clarify the relationship between the JTC bias, IQ, psychosis and polygenic liability to schizophrenia and IQ.

Methods: A total of 817 first episode psychosis patients and 1294 population-based controls completed assessments of general intelligence (IQ), and JTC, and provided blood or saliva samples from which we extracted DNA and computed polygenic risk scores for IQ and schizophrenia.

Results: The estimated proportion of the total effect of case/control differences on JTC mediated by IQ was 79%. Schizophrenia polygenic risk score was non-significantly associated with a higher number of beads drawn (B = 0.47, 95% CI -0.21 to 1.16, p = 0.17); whereas IQ PRS (B = 0.51, 95% CI 0.25-0.76, p < 0.001) significantly predicted the number of beads drawn, and was thus associated with reduced JTC bias. The JTC was more strongly associated with the higher level of psychotic-like experiences (PLEs) in controls, including after controlling for IQ (B = -1.7, 95% CI -2.8 to -0.5, p = 0.006), but did not relate to delusions in patients.

Conclusions: Our findings suggest that the JTC reasoning bias in psychosis might not be a specific cognitive deficit but rather a manifestation or consequence, of general cognitive impairment. Whereas, in the general population, the JTC bias is related to PLEs, independent of IQ. The work has the potential to inform interventions targeting cognitive biases in early psychosis.
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http://dx.doi.org/10.1017/S003329171900357XDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020493PMC
March 2021

Daily use of high-potency cannabis is associated with more positive symptoms in first-episode psychosis patients: the EU-GEI case-control study.

Psychol Med 2020 Mar 18:1-9. Epub 2020 Mar 18.

Department of Psychiatry, Early Psychosis Section, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands.

Background: Daily use of high-potency cannabis has been reported to carry a high risk for developing a psychotic disorder. However, the evidence is mixed on whether any pattern of cannabis use is associated with a particular symptomatology in first-episode psychosis (FEP) patients.

Method: We analysed data from 901 FEP patients and 1235 controls recruited across six countries, as part of the European Network of National Schizophrenia Networks Studying Gene-Environment Interactions (EU-GEI) study. We used item response modelling to estimate two bifactor models, which included general and specific dimensions of psychotic symptoms in patients and psychotic experiences in controls. The associations between these dimensions and cannabis use were evaluated using linear mixed-effects models analyses.

Results: In patients, there was a linear relationship between the positive symptom dimension and the extent of lifetime exposure to cannabis, with daily users of high-potency cannabis having the highest score (B = 0.35; 95% CI 0.14-0.56). Moreover, negative symptoms were more common among patients who never used cannabis compared with those with any pattern of use (B = -0.22; 95% CI -0.37 to -0.07). In controls, psychotic experiences were associated with current use of cannabis but not with the extent of lifetime use. Neither patients nor controls presented differences in depressive dimension related to cannabis use.

Conclusions: Our findings provide the first large-scale evidence that FEP patients with a history of daily use of high-potency cannabis present with more positive and less negative symptoms, compared with those who never used cannabis or used low-potency types.
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http://dx.doi.org/10.1017/S0033291720000082DOI Listing
March 2020

Cannabis and Cognition: Connecting the Dots towards the Understanding of the Relationship.

Brain Sci 2020 Feb 27;10(3). Epub 2020 Feb 27.

Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, 37134 Verona, Italy.

Several studies have advanced the understanding of the effects of cannabis on cognitive function. A comprehensive reappraisal of such literature may help in drawing conclusions about the potential risks associated with cannabis use. In summary, the evidence suggests that earlier age of use, high-frequency and high-potency cannabis use, as well as sustained use over time and use of synthetic cannabinoids, are all correlated with a higher likelihood of developing potentially severe and persistent executive function impairments. While the exact mechanisms underlying the adverse effects of cannabis on cognition are not completely clear, Magnetic Resonance Imaging (MRI) studies support the presence of both structural and functional alterations associated with cannabis use. Cognitive dysfunction is also a core feature of many neuropsychiatric disorders and care must be taken regarding the effects of cannabis use in these patient populations. Cognitive impairments affect patients' daily functions, sociability, and long-term outcome, posing elevated economic, social, and clinical burdens. There is, thus, a compelling case for implementing behavioral and cognitive rehabilitation therapies for these patients, as well as investigating the endocannabinoid system in the development of new psychopharmacological treatments.
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http://dx.doi.org/10.3390/brainsci10030133DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139821PMC
February 2020

Childhood trauma and glucose metabolism in patients with first-episode psychosis.

Psychoneuroendocrinology 2020 03 3;113:104536. Epub 2019 Dec 3.

IRCCS Istituto Centro San Giovanni di Dio, Fatebenefratelli, Brescia, Italy; Faculty of Psychology, eCampus University, Novedrate (Como), Italy.

Although the associations between first-episode psychosis (FEP) and metabolic abnormalities on one side, and childhood trauma (CT) and risk of developing psychosis on the other are both well established, evidence on the relationship between CT and metabolic dysregulation in terms of abnormal glucose metabolism is very limited. We tested whether, already at illness onset, FEP patients with a history of CT show dysregulation of a broad range of glucose metabolism markers. In particular, in 148 FEP patients we evaluated serum concentrations of c-peptide, insulin, plasminogen-activator-inhibitor-1 (PAI-1), resistin, visfatin, glucagon, glucagon-like peptide-1 (GLP-1), gastric-inhibitor-peptide (GIP), leptin, and ghrelin. We also assessed CT with the Childhood Experience of Care and Abuse Questionnaire, and stressful life events (SLEs) with a semi-structured interview. Psychopathology, cannabis and tobacco habits, Body Mass Index (BMI) were recorded. Serum concentrations of markers were analyzed from peripheral blood. Ninety-five patients (56 % males, mean age 29.5) reported CT. Multivariate models showed that CT is associated only with the concentrations of c-peptide and insulin after adjusting for age, sex, BMI and SLEs. FEP patients who had experienced CT showed higher c-peptide and insulin serum concentrations. Our study reports that CT might be associated with the metabolic abnormalities in the first stage of psychosis, suggesting that a thorough anamnestic evaluation at psychosis onset that would include the history of CT could be helpful for clinicians in order to implement early programmes of healthy lifestyle education and to guide choice of therapeutic interventions for trauma.
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http://dx.doi.org/10.1016/j.psyneuen.2019.104536DOI Listing
March 2020

Dietary habits and physical activity in first-episode psychosis patients treated in community services. Effect on early anthropometric and cardio-metabolic alterations.

Schizophr Res 2020 02 2;216:374-381. Epub 2019 Dec 2.

Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Italy; UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI) di Verona, Italy.

People with psychosis often develop metabolic and cardiovascular disorders, due to several factors including unhealthy lifestyle and antipsychotic treatment. This study aims to evaluate in a sample of first episode psychosis (FEP) patients lifestyle factors, with a specific emphasis on dietary habits and physical activity, and cardio-metabolic and anthropometric profile at illness onset and at 9 months. Moreover, this study aims to evaluate the impact of lifestyle factors on short term changes in cardio-metabolic and anthropometric profile. A 9-month follow-up study was conducted on a sample of 96 FEP patients recruited within the context of the GET UP program. Standardised assessments of dietary habits (EPIC) and physical activity (IPAQ) were retrospectively performed at 9 months; cardiovascular measures (blood pressure, heart rate), metabolic parameters (glucose, cholesterol, triglycerides), BMI and antipsychotic treatment were assessed at illness onset and at 9 months. We found that most FEP patients (60%) displayed poor dietary habits, as defined in terms of adherence to the Mediterranean diet. A significant increase for both BMI and cholesterol levels was found in the overall sample over 9 months. However, when considering the effect of lifestyle factors, BMI and total cholesterol were specifically raised in patients with low adherence to Mediterranean diet. The association with antipsychotic medication was found for SGA only, with a significant increase in both BMI and total cholesterol overtime. Our findings confirm the need to implement specific and early strategies to promote healthy lifestyle in people with FEP, since metabolic alterations occur within the first months of treatment.
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http://dx.doi.org/10.1016/j.schres.2019.11.010DOI Listing
February 2020

Correlations between immune and metabolic serum markers and schizophrenia/bipolar disorder polygenic risk score in first-episode psychosis.

Early Interv Psychiatry 2020 08 21;14(4):507-511. Epub 2019 Nov 21.

Genetics Unit, IRCCS Istituto Centro San Giovanni di Dio Fatebenefratelli, Brescia, Italy.

Aims: There is a strong interest in identifying the biological mechanisms involved in the genetic risk for psychotic disorders. In this study, we evaluated the correlation between serum concentrations of specific molecular markers and the genetic component for schizophrenia and bipolar disorder.

Methods: We analysed the association between the polygenic risk score (PRS) and the serum levels of different inflammatory/metabolic markers in a sample of 81 first-episode psychosis patients (FEP) with a diagnosis of schizophrenia or bipolar disorder and 33 controls.

Results: A positive correlation of schizophrenia and bipolar disorder PRS with the inflammatory marker C-C Motif Chemokine Ligand 4 serum concentration (ρ = 0.42, P = 1.56 × 10 and ρ = 0.40, P = 1.65 × 10 , respectively) and a negative correlation with the serum ghrelin content (ρ = - 0.35, P = 4.27 × 10 and ρ = - 0.45, P = 6.05 × 10 , respectively) were observed.

Conclusion: These findings provide new insight into the biological underpinnings of the PRS component, thus supporting a role of the genetic liability on the inflammatory and metabolic alterations that characterize psychosis onset.
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http://dx.doi.org/10.1111/eip.12906DOI Listing
August 2020

Pathways to care, DUP, and types of interventions over 5 years following psychosis onset: findings from a naturalistic study conducted in routine generalist mental health services.

Soc Psychiatry Psychiatr Epidemiol 2020 Feb 11;55(2):175-186. Epub 2019 Sep 11.

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.

Purpose: To describe pathways to care, duration of untreated psychosis (DUP), and types of interventions provided to first-episode psychosis (FEP) patients by routine Italian mental health services over 5 years since the first service contact.

Methods: Naturalistic study conducted in Veneto, within the context of the Psychosis Incident Cohort Outcome Study (PICOS). A comprehensive set of measures was used, including schedules designed to collect information on referrals to psychiatric services and on psychological and pharmacological treatments at 1, 2, and 5 years since first service contact.

Results: Overall, 397 patients were assessed. Most engaged with services with the help of family members (47.4%) and through emergency routes (60.3%). Those referred by clinicians were more likely to access care in a non-emergency way. Mean DUP was 5.62 months (SD 11.8) and longer DUP was associated with poorer functioning at 2 and 5 years. Interventions provided over 5 years were mainly constituted by antipsychotic medications (95.4% at 1 year; 85.8% at 2 years; 80.6% at 5 years), whereas a lower percentage (69.1% at 1 year; 61.5% at 2 years; 44.9% at 5 years) also received some forms of psychological interventions, mainly consisting of unspecific support sessions. Other structured interventions, such as CBT or family interventions, were seldom provided at each time-point.

Conclusions: Mental health services in Veneto seem effective in engaging FEP patients within a short time since illness onset. However, type of care provided does not meet quality standards recommended by treatment guidelines, especially regarding psychological interventions.
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http://dx.doi.org/10.1007/s00127-019-01775-xDOI Listing
February 2020

Dimensional structure of first episode psychosis.

Early Interv Psychiatry 2019 12 15;13(6):1431-1438. Epub 2019 Jan 15.

UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI) Verona, Verona, Italy.

Aim: Current diagnostic systems, DSM-5 and ICD-10, still adopt a categorical approach to classify psychotic disorders. The present study was aimed at investigating the structure of psychotic symptomatology in both affective and non-affective psychosis from a dimensional approach.

Methods: Participants with a first episode psychosis (FEP) were recruited from a cluster-randomized controlled trial (GET-UP PIANO TRIAL), offered to all Community Mental Health Centres (CMHCs) located across two northern Italian regions. After clinical stabilization, patients were assessed with a comprehensive set of psychopathological measures including the Positive and Negative Syndrome Scale, the Hamilton Depression Rating Scale and the Bech-Rafaelsen Mania Rating Scale. A two-step cluster analysis was performed.

Results: Overall, 257 FEP patients (male, n = 171, 66.5%; mean age = 24.96 ± 4.56) were included in the study. The cluster analysis revealed a robust four-cluster solution: delusional-persecutory (n = 82; 31.9%), depressed (n = 95; 37%), excited (n = 26; 10.1%) and negative-disorganized (n = 54; 21%), thus suggesting a quadripartite structure with both affective and non-affective dimensions. Among non-affective dimensions, negative and disorganization symptoms constituted a unique construct apart from positive symptoms.

Conclusions: Symptom dimensions may represent a useful tool for dissecting the indistinct and non-specific psychopathology of FEP in order to better target specific interventions.
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http://dx.doi.org/10.1111/eip.12789DOI Listing
December 2019

The impact of gender and childhood abuse on age of psychosis onset, psychopathology and needs for care in psychosis patients.

Schizophr Res 2019 08 12;210:164-171. Epub 2019 Jan 12.

Section of Psychiatry, Department of Neuroscience, Biomedicine and Movement, University of Verona, Italy; UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI) di Verona, Verona, Italy.

Gender is associated with several features of psychotic disorders, including age of illness onset, symptomatology, a higher prevalence of history of childhood sexual abuse (CSA) and needs for care. Childhood sexual abuse is associated with adverse mental health consequences but as there is a gender difference in stress reactivity, there may be a differential impact of CSA on psychopathology, age of psychosis onset and needs for care in First Episode Psychosis (FEP) patients. We hypothesized that a history of abuse would be associated with lowering of age of onset, increased symptomatology and more unmet needs in women but not men. A total of 444 FEP patients have been recruited within the context of the GET UP trial. Symptomatology has been assessed using the PANSS scale, needs for care with the CAN scale and childhood abuse with the CECA-Q scale. Childhood sexual abuse was more frequent among female patients [22.6% in women vs 11.6% in men (OR = 0.45, p < 0.01)], whereas there was no gender difference in the prevalence of childhood physical abuse (29.0% in women vs 31.7% in men). Childhood abuse was associated with higher levels of negative symptoms in both men and women, with a reduced age of onset in women only and little increase in needs for care in both men and women. Our results seem to suggest that childhood sexual abuse in female FEP patients may be linked to a more severe form of psychosis whose presentation is characterized by earlier age of onset and higher levels of negative symptoms and we can also speculate that gender-specific protective factors in women, but not in men, may be outweighed by the consequences of childhood abuse.
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http://dx.doi.org/10.1016/j.schres.2018.12.046DOI Listing
August 2019

Prevalence of non-psychotic disorders in ultra-high risk individuals and transition to psychosis: A systematic review.

Psychiatry Res 2018 12 15;270:1-12. Epub 2018 Sep 15.

Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.

Despite the growing interest in the prodromes of psychosis, the proper identification of those Ultra High Risk (UHR) subjects who will convert to psychosis remains an unresolved issue. It remains to be fully understood whether the risk of transition to psychosis is incremented by the concomitant presence of non-psychotic symptoms. We performed a systematic review in order to estimate: prevalence rates of non-psychotic disorders in UHR individuals and whether any comorbid disorder impacts on the risk of transition to frank psychosis. The review was conducted using the PRISMA guidelines by searching PubMed until August 2017. The inclusion criteria were: studies with appropriate definition of UHR/ ARMS (At Risk Mental States for psychosis); cross-sectional design (for prevalence rates) or longitudinal design (for transition rates to psychosis); adolescents and/or adults; specified instrument/interview for the diagnosis of mental disorder/symptoms. We included 46 English-language articles. We found that non-psychotic symptoms are a prevalent concern in UHR individuals, and this is true for all comorbid disorders examined. None of the mental disorder examined appear to be a marker for transition to psychosis. Our systematic review found that the great majority of UHR individuals actually has a highly prevalent clearly defined, above-the-threshold mental disorder that should constitute the primary focus of intervention.
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http://dx.doi.org/10.1016/j.psychres.2018.09.028DOI Listing
December 2018

Immune and metabolic alterations in first episode psychosis (FEP) patients.

Brain Behav Immun 2018 05 13;70:315-324. Epub 2018 Mar 13.

IRCCS Centro S. Giovanni di Dio, Fatebenefratelli, Brescia, Italy; Dept. of Molecular and Translational Medicine, Division of Biology and Genetics, University of Brescia, Italy.

The molecular underpinnings associated to first episode psychosis (FEP) remains to be elucidated, but compelling evidence supported an association of FEP with blood alterations in biomarkers related to immune system, growth factors and metabolism regulators. Many of these studies have not been already confirmed in larger samples or have not considered the FEP diagnostic subgroups. In order to identify biochemical signatures of FEP, the serum levels of the growth factors BDNF and VEGF, the immune regulators IL-1RA, IL-6, IL-10 and IL-17, RANTES/CCL5, MIP-1b/CCL4, IL-8 and the metabolic regulators C-peptide, ghrelin, GIP, GLP-1, glucagon, insulin, leptin, PAI-1, resistin and visfatin were analysed in 260 subjects collected in the GET UP project. The results indicated an increase of MIP-1b/CCL4, VEGF, IL-6 and PAI-1, while IL-17, ghrelin, glucagon and GLP-1 were decreased in the whole sample of FEP patients (p < 0.01 for all markers except for PAI-1 p < 0.05). No differences were evidenced for these markers among the diagnostic groups that constitute the FEP sample, whereas IL-8 is increased only in patients with a diagnosis of affective psychosis. The principal component analysis (PCA) and variable importance analysis (VIA) indicated that MIP-1b/CCL4, ghrelin, glucagon, VEGF and GLP-1 were the variables mostly altered in FEP patients. On the contrary, none of the analysed markers nor a combination of them can discriminate between FEP diagnostic subgroups. These data evidence a profile of immune and metabolic alterations in FEP patients, providing new information on the molecular mechanism associated to the psychosis onset for the development of preventive strategies and innovative treatment targets.
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http://dx.doi.org/10.1016/j.bbi.2018.03.013DOI Listing
May 2018

Common schizophrenia alleles are enriched in mutation-intolerant genes and in regions under strong background selection.

Nat Genet 2018 03 26;50(3):381-389. Epub 2018 Feb 26.

Department of Neurology, Center for Autism Research and Treatment, Semel Institute, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA, USA.

Schizophrenia is a debilitating psychiatric condition often associated with poor quality of life and decreased life expectancy. Lack of progress in improving treatment outcomes has been attributed to limited knowledge of the underlying biology, although large-scale genomic studies have begun to provide insights. We report a new genome-wide association study of schizophrenia (11,260 cases and 24,542 controls), and through meta-analysis with existing data we identify 50 novel associated loci and 145 loci in total. Through integrating genomic fine-mapping with brain expression and chromosome conformation data, we identify candidate causal genes within 33 loci. We also show for the first time that the common variant association signal is highly enriched among genes that are under strong selective pressures. These findings provide new insights into the biology and genetic architecture of schizophrenia, highlight the importance of mutation-intolerant genes and suggest a mechanism by which common risk variants persist in the population.
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http://dx.doi.org/10.1038/s41588-018-0059-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5918692PMC
March 2018

Epigenetics and gene expression profile in first-episode psychosis: The role of childhood trauma.

Neurosci Biobehav Rev 2017 Dec 19;83:226-237. Epub 2017 Oct 19.

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy. Electronic address:

Childhood Trauma (CT) mediation of the epigenome and its impact on gene expression profile could provide a mechanism for the gene-environment interaction underling psychosis. We reviewed the evidence concerning epigenetic and gene expression modifications associated with CT in both First-Episode Psychosis (FEP) and healthy subjects. In order to explore the relative role of psychosis itself in determining these modifications, evidence about FEP and epigenetics/gene expression was also summarized. We performed a systematic search on PubMed, last updated in December 2016. Out of 2966 potentially relevant records, only 41 studies were included. CT resulted associated: in FEP subjects, with global DNA hypo-methylation and reduced BDNF gene-expression; in healthy subjects, with hyper-methylation of SLC6A4, NR3C1, KITLG, and OXTR; hypo-methylation of FKBP5, IL-6, and BDNF; increased IL1B, IL8, and PTGS gene expression; and decreased SLC6A4 gene expression. FEP showed global DNA hypo-methylation; increased methylation and reduced gene expression of GCH1; hyper-expression of MPB, NDEL1, AKT1, and DICER1; and hypo-expression of DROSHA, COMT, and DISC1 in comparison with healthy controls.
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http://dx.doi.org/10.1016/j.neubiorev.2017.10.018DOI Listing
December 2017

Family Burden, Emotional Distress and Service Satisfaction in First Episode Psychosis. Data from the GET UP Trial.

Front Psychol 2017 16;8:721. Epub 2017 May 16.

Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of VeronaVerona, Italy.

Literature has documented the role of family in the outcome of chronic schizophrenia. In the light of this, family interventions (FIs) are becoming an integral component of treatment for psychosis. The First Episode of Psychosis (FEP) is the period when most of the changes in family atmosphere are observed; unfortunately, few studies on the relatives are available. To explore burden of care and emotional distress at baseline and at 9-month follow-up and the levels of service satisfaction at follow-up in the two groups of relatives (experimental treatment EXP vs. treatment as usual TAU) recruited in the cluster-randomized controlled GET UP PIANO trial. The experimental treatment was provided by routine public Community Mental Health Centers (Italian National Health Service) and consisted of Treatment as Usual plus evidence-based additional treatment (Cognitive Behavioral Therapy for psychosis for patients, Family Intervention for psychosis, and Case Management). TAU consisted of personalized outpatient psychopharmacological treatment, combined with non-specific supportive clinical management and informal support/educational sessions for families. The outcomes on relatives were assessed by the Involvement Evaluation Questionnaire (IEQ-EU), the General Health Questionnaire (GHQ-12), and the Verona Service Satisfaction Scale (VSSS-EU). Differences within and between groups were evaluated. At baseline, 75 TAU and 185 EXP caregivers were assessed. In the experimental group 92% of relatives participated in at least 1 family session. At follow-up both groups experienced improvement in all IEQ and GHQ items, but caregivers belonging to the EXP arm experienced a significantly greater change in 10 IEQ items (mainly pertaining to the "Tension" dimension) and in GHQ items. Due to the low sample size, a significant effectiveness was only observed for 2 IEQ items and 1 GHQ-12 item. With respect to VSSS data at follow-up, caregivers in the EXP arm experienced significantly greater satisfaction in 8 items, almost all pertaining to the dimensions "Relatives' Involvement" and "Professionals' Skills and Behavior." The Family intervention for psychosis delivered in the GET UP PIANO trial reduced family burden of illness and improved emotional distress and satisfaction with services. These results should encourage to promote FIs on caregivers of first-episode psychosis patients.
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http://dx.doi.org/10.3389/fpsyg.2017.00721DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5432637PMC
May 2017

Predictors of 9-month hospitalization in patients with first-episode affective and non-affective psychosis. Results from the GET UP pragmatic cluster randomized controlled trial.

Schizophr Res 2017 12 24;190:187-188. Epub 2017 Mar 24.

Section of Psychiatry, Department of Neurosciences, Biomedicine and Movement Sciences, University of Verona, Piazzale Ludovico Antonio Scuro 10, 37134 Verona, Italy.

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http://dx.doi.org/10.1016/j.schres.2017.03.037DOI Listing
December 2017

Predictors and moderators of treatment outcome in patients receiving multi-element psychosocial intervention for early psychosis: results from the GET UP pragmatic cluster randomised controlled trial.

Br J Psychiatry 2017 05 16;210(5):342-349. Epub 2017 Mar 16.

Antonio Lasalvia, MD PhD, UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona; Chiara Bonetto, PhD, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona; Jacopo Lenzi, PhD, Paola Rucci, PhD, Department of Biomedical and Neuromotor Sciences, Alma Mater Studiorum, University of Bologna, Bologna; Laura Iozzino, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona; Massimo Cellini, Department of Mental Health, Az. USL Firenze, Firenze; Carla Comacchio, MD, Doriana Cristofalo, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona; Armando D'Agostino, MD, Department of Psychiatry, University of Milano, Milano; Giovanni de Girolamo, MD, IRCSS St John of God Clinical Research Centre of Brescia, Brescia; Katia De Santi, MD, UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona; Daniela Ghigi, MD, Department of Mental Health, Az. USL Rimini, Rimini; Emanuela Leuci, MD, Department of Mental Health, Az. USL Parma; Maurizio Miceli, MD, Department of Mental Health, Az. USL Firenze, Firenze; Anna Meneghelli, AO Ospedale Niguarda Ca' Granda Milano, MHD Programma2000, Milan; Francesca Pileggi, MD, Department of Mental Health, Az. USL Bologna, Bologna; Silvio Scarone, MD, Department of Psychiatry, University of Milano, Milano; Paolo Santonastaso, MD, Department of Neurosciences, University of Padova and Azienda Ospedaliera, Padova; Stefano Torresani, MD, Department of Mental Health, Az. USL Bolzano, Bolzano; Sarah Tosato, MD, PhD, Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona; Angela Veronese, MD, Department of Neurosciences, University of Padova and Azienda Ospedaliera, Padova; Angelo Fioritti, MD, Department of Mental Health, Az.USL Bologna, Bologna; Mirella Ruggeri, MD, UOC Psichiatria, Azienda Ospedaliera Universitaria Integrata (AOUI), Verona and Department of Neurosciences, Biomedicine and Movement Sciences, Section of Psychiatry, University of Verona, Verona, Italy.

The GET UP multi-element psychosocial intervention proved to be superior to treatment as usual in improving outcomes in patients with first-episode psychosis (FEP). However, to guide treatment decisions, information on which patients may benefit more from the intervention is warranted.To identify patients' characteristics associated with (a) a better treatment response regardless of treatment type (non-specific predictors), and (b) a better response to the specific treatment provided (moderators).Some demographic and clinical variables were selected as potential predictors/moderators of outcomes at 9 months. Outcomes were analysed in mixed-effects random regression models. (Trial registration: ClinicalTrials.gov, NCT01436331)Analyses were performed on 444 patients. Education, duration of untreated psychosis, premorbid adjustment and insight predicted outcomes regardless of treatment. Only age at first contact with the services proved to be a moderator of treatment outcome (patients aged ⩾35 years had greater improvement in psychopathology), thus suggesting that the intervention is beneficial to a broad array of patients with FEP.Except for patients aged over 35 years, no specific subgroups benefit more from the multi-element psychosocial intervention, suggesting that this intervention should be recommended to all those with FEP seeking treatment in mental health services.
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http://dx.doi.org/10.1192/bjp.bp.116.190058DOI Listing
May 2017

A Systematized Review of Atypical Antipsychotics in Pregnant Women: Balancing Between Risks of Untreated Illness and Risks of Drug-Related Adverse Effects.

J Clin Psychiatry 2017 May;78(5):e477-e489

Department of Psychiatry, University of Naples SUN, Naples, Italy.

Objective: To summarize risks related to (1) illness and (2) second-generation antipsychotic (SGA) treatment in pregnant women and their offspring. Concerning illness-related risks, we focused on bipolar disorder and schizophrenia, psychiatric disorders for which SGAs are preferentially prescribed.

Data Sources: PubMed, Ovid, Scopus, PsycINFO, and Cochrane Library were searched from the date of the first available article to October 2015 using the following key terms: pregnancy OR gestation OR bipolar disorder OR schizophrenia. We also included cross-references from identified articles.

Study Selection: We included 49 English-language articles regarding illness-related and SGA-related risks in bipolar disorder and schizophrenia. First, searches were done for epidemiologic or experimental studies (from January 2000 to October 2015), then for systematic reviews and meta-analyses.

Data Extraction: Data were extracted independently, after removing duplicates and studies that were not relevant or not pertinent.

Results: Abrupt discontinuation of treatment-exposed mothers with bipolar disorder or schizophrenia led to a high risk of relapses during pregnancy. Both bipolar disorder and schizophrenia were linked to a slightly increased risk of obstetric complications for mothers (schizophrenia) and the newborn (bipolar disorder and schizophrenia), although data on drug exposure during pregnancy were not given in the majority of studies. Maternal morbidity (schizophrenia but not bipolar disorder) may be associated with the worst neonatal outcomes (stillbirth, neonatal or infant deaths, and intellectual disability). Untreated bipolar disorder and schizophrenia may be considered independent risk factors for congenital malformations, while SGAs were not associated with increased recurring defects in fetuses. Evidence regarding the potential effects of SGAs on child neurodevelopment remains reassuring.

Conclusion: After taking into account the parents' will and after they provide informed consent, the most reasonable and less harmful choice for treating future mothers with bipolar disorder or schizophrenia appears to be maintaining them at the safest minimum dosage.
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http://dx.doi.org/10.4088/JCP.15r10483DOI Listing
May 2017

Classification of first-episode psychosis in a large cohort of patients using support vector machine and multiple kernel learning techniques.

Neuroimage 2017 01 12;145(Pt B):238-245. Epub 2015 Dec 12.

Department of Neurosciences and Mental Health, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico, University of Milan, Milan, Italy; Department of Psychiatry and Behavioral Sciences, University of Texas Health Science Center at Houston, TX, USA. Electronic address:

First episode psychosis (FEP) patients are of particular interest for neuroimaging investigations because of the absence of confounding effects due to medications and chronicity. Nonetheless, imaging data are prone to heterogeneity because for example of age, gender or parameter setting differences. With this work, we wanted to take into account possible nuisance effects of age and gender differences across dataset, not correcting the data as a pre-processing step, but including the effect of nuisance covariates in the classification phase. To this aim, we developed a method which, based on multiple kernel learning (MKL), exploits the effect of these confounding variables with a subject-depending kernel weighting procedure. We applied this method to a dataset of cortical thickness obtained from structural magnetic resonance images (MRI) of 127 FEP patients and 127 healthy controls, who underwent either a 3Tesla (T) or a 1.5T MRI acquisition. We obtained good accuracies, notably better than those obtained with standard SVM or MKL methods, up to more than 80% for frontal and temporal areas. To our best knowledge, this is the largest classification study in FEP population, showing that fronto-temporal cortical thickness can be used as a potential marker to classify patients with psychosis.
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http://dx.doi.org/10.1016/j.neuroimage.2015.12.007DOI Listing
January 2017

Association of AADAC Deletion and Gilles de la Tourette Syndrome in a Large European Cohort.

Biol Psychiatry 2016 Mar 3;79(5):383-391. Epub 2015 Sep 3.

Clinic of Psychiatry, Social Psychiatry and Psychotherapy, and Institute of Human Genetics, Hannover Medical School, Hannover, Germany.

Background: Gilles de la Tourette syndrome (GTS) is a complex neuropsychiatric disorder with a strong genetic influence where copy number variations are suggested to play a role in disease pathogenesis. In a previous small-scale copy number variation study of a GTS cohort (n = 111), recurrent exon-affecting microdeletions of four genes, including the gene encoding arylacetamide deacetylase (AADAC), were observed and merited further investigations.

Methods: We screened a Danish cohort of 243 GTS patients and 1571 control subjects for submicroscopic deletions and duplications of these four genes. The most promising candidate gene, AADAC, identified in this Danish discovery sample was further investigated in cohorts from Iceland, the Netherlands, Hungary, Germany, and Italy, and a final meta-analysis, including a total of 1181 GTS patients and 118,730 control subjects from these six European countries, was performed. Subsequently, expression of the candidate gene in the central nervous system was investigated using human and mouse brain tissues.

Results: In the Danish cohort, we identified eight patients with overlapping deletions of AADAC. Investigation of the additional five countries showed a significant association between the AADAC deletion and GTS, and a final meta-analysis confirmed the significant association (p = 4.4 × 10(-4); odds ratio = 1.9; 95% confidence interval = 1.33-2.71). Furthermore, RNA in situ hybridization and reverse transcription-polymerase chain reaction studies revealed that AADAC is expressed in several brain regions previously implicated in GTS pathology.

Conclusions: AADAC is a candidate susceptibility factor for GTS and the present findings warrant further genomic and functional studies to investigate the role of this gene in the pathogenesis of GTS.
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http://dx.doi.org/10.1016/j.biopsych.2015.08.027DOI Listing
March 2016

Bridging the gap between education and appropriate use of benzodiazepines in psychiatric clinical practice.

Neuropsychiatr Dis Treat 2015 30;11:1885-909. Epub 2015 Jul 30.

Department of Psychiatry, University of Naples SUN, Naples, Italy.

More than half a century after their discovery, benzodiazepines (BDZs) still represent one of the largest and most widely prescribed groups of psychotropic compounds, not only in clinical psychiatry but also in the entire medical field. Over the last two decades, however, there has been an increased focus on the development of antidepressants and antipsychotics on the part of the pharmaceutical industry, clinicians, and researchers, with a reduced interest in BDZs, in spite of their widespread clinical use. As a consequence, many psychiatric residents, medical students, nurses, and other mental health professionals might receive poor academic teaching and training regarding these agents, and have the false impression that BDZs represent an outdated chapter in clinical psychopharmacology. However, recent advances in the field, including findings concerning epidemiology, addiction risk, and drug interactions, as well as the introduction of the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition with related diagnostic changes, strongly encourage an updated appraisal of the use of BDZs in clinical practice. During a recent thematic event convened with the aim of approaching this topic in a critical manner, a group of young Italian psychiatrists attempted to highlight possible flaws in current teaching pathways, identify the main clinical pros and cons regarding current use of BDZs in clinical practice, and provide an updated overview of their use across specific clinical areas and patient populations. The main results are presented and discussed in this review.
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http://dx.doi.org/10.2147/NDT.S83130DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525786PMC
August 2015