Publications by authors named "Alp Üçok"

73 Publications

Association of the kynurenine pathway metabolites with clinical, cognitive features and IL-1β levels in patients with schizophrenia spectrum disorder and their siblings.

Schizophr Res 2021 Feb 17;229:27-37. Epub 2021 Feb 17.

Department of Psychiatry, Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address:

Objective: There is evidence suggesting that tryptophan (TRP)-kynurenine (KYN) pathway dysregulation is involved in the pathophysiology of schizophrenia and is regulated by inflammatory cytokines. The study investigate for the first time whether this dysregulation occurs in advanced stages of the disease as a byproduct or emerges as one of the early and inherited manifestations of schizophrenia.

Method: Sera of 148 patients with schizophrenia spectrum disorders (SCZ), 139 unaffected siblings (SIB) and 210 controls were investigated. Serum interleukin (IL)-1β levels were measured by ELISA, and TRP, KYN and kynurenic acid (KYNA) levels were measured by a high-performance liquid chromatography system. Also, we collected clinical data by applying Comprehensive Assessment of Symptoms and History in SCZ, and SIS-R in SIB and control groups.

Results: Compared to controls, SCZ and SIB groups had lower TRP and higher KYNA levels. TRP levels showed significant differences only between SCZ and controls (p < 0.01). KYNA levels of both SCZ (p ≤ 0.001) and SIB (p < 0.05) were higher than controls. No statistical significance was found for KYN levels across groups. SCZ and SIB groups had higher serum IL-1β levels than controls (p ≤ 0.001).

Conclusions: Patients with SCZ and their siblings exhibited similar clinical features and TRP metabolite levels suggesting that TRP-KYN dysregulation may be an inherited component of the disease putatively conferring increased risk to schizophrenia. Elevation of IL-1β is one of the factors promoting overconsumption of the TRP-KYN pathway leading to increased production of neuroregulatory KYNA and presumably to neurodegeneration.
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http://dx.doi.org/10.1016/j.schres.2021.01.014DOI Listing
February 2021

Predictors of discontinuation and hospitalization during long-acting injectable antipsychotic treatment in patients with schizophrenia spectrum disorder.

Int Clin Psychopharmacol 2021 Mar;36(2):89-96

Department of Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul.

The aim of this study was to evaluate discontinuation and hospitalization rates in patients with schizophrenia spectrum disorder who were treated with long-acting injectable (LAI) antipsychotics. We recorded clinical data about the period before the LAI treatment, when LAI treatment was initiated, and during the LAI treatment. Variables related to early (<8 weeks) and other LAI discontinuations and hospitalization were analyzed. Out of 452 patients, 14.4% of them discontinued their LAI treatment before 8 weeks, another 24.8% of the patients stopped their LAI by themselves later. Early discontinuers were younger, had shorter duration of illness, and less educated. Sixty-two (27.2%) of the patients were hospitalized under LAI treatment and 40% of the hospitalizations occurred in initial 6 months. Rate of hospitalization was 36.1% in the group who discontinued LAI after 8 weeks. In logistic regression analysis, younger age, history of combined antipsychotic treatment, number of hospitalizations before LAI, use of LAI for less than 6 months and alcohol abuse under LAI treatment were found related to hospitalization. Our findings suggested that discontinuation and hospitalization are still common among the patients who were treated with LAI antipsychotics.
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http://dx.doi.org/10.1097/YIC.0000000000000348DOI Listing
March 2021

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

Authors:
Eva Velthorst Josephine Mollon Robin M Murray Lieuwe de Haan Inez Myin Germeys David C Glahn Celso Arango Els van der Ven Marta Di Forti Miguel Bernardo Sinan Guloksuz Philippe Delespaul Gisela Mezquida Silvia Amoretti Julio Bobes Pilar A Saiz María Paz García-Portilla José Luis Santos Estela Jiménez-López Julio Sanjuan Eduardo J Aguilar Manuel Arrojo Angel Carracedo Gonzalo López Javier González-Peñas Mara Parellada Cem Atbaşoğlu Meram Can Saka Alp Üçok Köksal Alptekin Berna Akdede Tolga Binbay Vesile Altınyazar Halis Ulaş Berna Yalınçetin Güvem Gümüş-Akay Burçin Cihan Beyaz Haldun Soygür Eylem Şahin Cankurtaran Semra Ulusoy Kaymak Nadja P Maric Marina M Mihaljevic Sanja Andric Petrovic Tijana Mirjanic Cristina Marta Del-Ben Laura Ferraro Charlotte Gayer-Anderson Peter B Jones Hannah E Jongsma James B Kirkbride Caterina La Cascia Antonio Lasalvia Sarah Tosato Pierre-Michel Llorca Paulo Rossi Menezes Craig Morgan Diego Quattrone Marco Menchetti Jean-Paul Selten Andrei Szöke Ilaria Tarricone Andrea Tortelli Philip McGuire Lucia Valmaggia Matthew J Kempton Mark van der Gaag Anita Riecher-Rössler Rodrigo A Bressan Neus Barrantes-Vidal Barnaby Nelson Patrick McGorry Chris Pantelis Marie-Odile Krebs Stephan Ruhrmann Gabriele Sachs Bart P F Rutten Jim van Os Behrooz Z Alizadeh Therese van Amelsvoort Agna A Bartels-Velthuis Richard Bruggeman Nico J van Beveren Jurjen J Luykx Wiepke Cahn Claudia J P Simons Rene S Kahn Frederike Schirmbeck Ruud van Winkel Abraham Reichenberg

Mol Psychiatry 2021 Jan 7. Epub 2021 Jan 7.

Department of Psychiatry, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

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

Correlates of Patient Satisfaction in Psychiatric Inpatient Care: A Survey Study from a Tertiary Hospital in Turkey.

J Psychosoc Nurs Ment Health Serv 2020 Dec 9:1-10. Epub 2020 Dec 9.

In the current study, a questionnaire to evaluate satisfaction levels and related factors upon discharge was completed by 100 patients receiving care for mental illness in a tertiary care hospital in Turkey. The relationships among sociodemographic variables, nonpharmacological interventions, and participants' views about the treatment course and quality of care they received were investigated. Overall satisfaction levels of participants were good. Older participants reported more positive opinions. Involuntary hospitalization, use of restraints/seclusion, or electroconvulsive therapy did not change overall satisfaction. Participants who were hospitalized for the first time were more afraid of other patients, which may imply that this population needs special care from the treatment team. Spending an adequate amount of time and providing necessary information about their treatment plan impact patients' treatment experience positively. [Journal of Psychosocial Nursing and Mental Health Services, xx(xx), xx-xx.].
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http://dx.doi.org/10.3928/02793695-20201203-04DOI Listing
December 2020

Evidence, and replication thereof, that molecular-genetic and environmental risks for psychosis impact through an affective pathway.

Psychol Med 2020 Oct 19:1-13. Epub 2020 Oct 19.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, The Netherlands.

Background: There is evidence that environmental and genetic risk factors for schizophrenia spectrum disorders are transdiagnostic and mediated in part through a generic pathway of affective dysregulation.

Methods: We analysed to what degree the impact of schizophrenia polygenic risk (PRS-SZ) and childhood adversity (CA) on psychosis outcomes was contingent on co-presence of affective dysregulation, defined as significant depressive symptoms, in (i) NEMESIS-2 (n = 6646), a representative general population sample, interviewed four times over nine years and (ii) EUGEI (n = 4068) a sample of patients with schizophrenia spectrum disorder, the siblings of these patients and controls.

Results: The impact of PRS-SZ on psychosis showed significant dependence on co-presence of affective dysregulation in NEMESIS-2 [relative excess risk due to interaction (RERI): 1.01, p = 0.037] and in EUGEI (RERI = 3.39, p = 0.048). This was particularly evident for delusional ideation (NEMESIS-2: RERI = 1.74, p = 0.003; EUGEI: RERI = 4.16, p = 0.019) and not for hallucinatory experiences (NEMESIS-2: RERI = 0.65, p = 0.284; EUGEI: -0.37, p = 0.547). A similar and stronger pattern of results was evident for CA (RERI delusions and hallucinations: NEMESIS-2: 3.02, p < 0.001; EUGEI: 6.44, p < 0.001; RERI delusional ideation: NEMESIS-2: 3.79, p < 0.001; EUGEI: 5.43, p = 0.001; RERI hallucinatory experiences: NEMESIS-2: 2.46, p < 0.001; EUGEI: 0.54, p = 0.465).

Conclusions: The results, and internal replication, suggest that the effects of known genetic and non-genetic risk factors for psychosis are mediated in part through an affective pathway, from which early states of delusional meaning may arise.
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http://dx.doi.org/10.1017/S0033291720003748DOI Listing
October 2020

A replication study of JTC bias, genetic liability for psychosis and delusional ideation.

Psychol Med 2020 Oct 13:1-7. Epub 2020 Oct 13.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Centre, Maastricht, the Netherlands.

Background: This study attempted to replicate whether a bias in probabilistic reasoning, or 'jumping to conclusions'(JTC) bias is associated with being a sibling of a patient with schizophrenia spectrum disorder; and if so, whether this association is contingent on subthreshold delusional ideation.

Methods: Data were derived from the EUGEI project, a 25-centre, 15-country effort to study psychosis spectrum disorder. The current analyses included 1261 patients with schizophrenia spectrum disorder, 1282 siblings of patients and 1525 healthy comparison subjects, recruited in Spain (five centres), Turkey (three centres) and Serbia (one centre). The beads task was used to assess JTC bias. Lifetime experience of delusional ideation and hallucinatory experiences was assessed using the Community Assessment of Psychic Experiences. General cognitive abilities were taken into account in the analyses.

Results: JTC bias was positively associated not only with patient status but also with sibling status [adjusted relative risk (aRR) ratio : 4.23 CI 95% 3.46-5.17 for siblings and aRR: 5.07 CI 95% 4.13-6.23 for patients]. The association between JTC bias and sibling status was stronger in those with higher levels of delusional ideation (aRR interaction in siblings: 3.77 CI 95% 1.67-8.51, and in patients: 2.15 CI 95% 0.94-4.92). The association between JTC bias and sibling status was not stronger in those with higher levels of hallucinatory experiences.

Conclusions: These findings replicate earlier findings that JTC bias is associated with familial liability for psychosis and that this is contingent on the degree of delusional ideation but not hallucinations.
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http://dx.doi.org/10.1017/S0033291720003578DOI Listing
October 2020

Relationship of negative symptom severity with cognitive symptoms and functioning in subjects at ultra-high risk for psychosis.

Early Interv Psychiatry 2020 Sep 18. Epub 2020 Sep 18.

Istanbul Faculty of Medicine, Department of Physiology, Istanbul University, Istanbul, Turkey.

Aim: Negative symptoms and cognition are related with functioning in schizophrenia. However, it is not clear whether they have a similar effect in individuals at ultra-high risk (UHR) for psychosis. In this study, we aimed to explore relationship of negative symptoms with cognition and functioning cross-sectionally in people with UHR for psychosis.

Methods: In total, 107 people participated in this study. We assessed negative symptoms with Scale for Negative Symptoms (SANS). We applied a cognitive battery including seven tests. We evaluated functioning by using Global Assessment of Functioning Scale and work/study status as an indicator of role functioning.

Results: SANS scores were correlated to global functioning cross-sectionally. SANS total score was correlated to cognitive test scores related to cognitive flexibility and attention. Only Trail Making Test B (TMT B) was negatively correlated to global functioning. SANS-affective blunting and SANS-avolition scores were independently related to global functioning. There was a significant indirect effect of the TMT B and composite attention scores on global functioning through negative symptoms indicating a complete mediation.

Conclusion: Our findings suggest that negative symptoms, particularly avolition have an impact on functioning and the association of cognition with functioning was mediated by negative symptoms in UHR.
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http://dx.doi.org/10.1111/eip.13042DOI Listing
September 2020

Reliability and validity of the Turkish version of comprehensive assessment of at risk mental states.

Early Interv Psychiatry 2020 Aug 4. Epub 2020 Aug 4.

Department of Psychiatry, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.

Aims: To perform the validation of the Comprehensive Assessment at Risk Mental State (CAARMS) in Turkish.

Methods: Sixty-five volunteers (15-24 years) were enrolled in this study. Concurrent validity was performed with Spearman's Correlation Test using Brief Psychiatric Rating Scale (BPRS). Median scores of the groups were compared using Mann-Whitney U Test. Interrater reliability was assessed by intragroup correlation coefficient method. Internal consistency was studied by the calculation of Cronbach Alfa Coefficient.

Results: The correlation of the severity scores of the CAARMS with unusual thought content, suspiciousness, hallucinations and conceptual disorganization items of the BPRS showed that the concurrent validity was good. ROC analysis revealed that CAARMS could discriminate between individuals with UHR and healthy volunteers well. We found a good correlation between the raters. Internal consistency was at very high level.

Conclusion: Analyses of concurrent validity, criterion validity, interrater reliability and internal consistency indicate that the Turkish version is valid and reliable.
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http://dx.doi.org/10.1111/eip.13014DOI Listing
August 2020

Efficacy and Safety of Paliperidone Palmitate Treatment in Patients With Schizophrenia: A Real-World Multicenter, Retrospective, Mirror-Image Study.

J Clin Psychopharmacol 2019 Nov/Dec;39(6):604-610

Department of Psychiatry, Marmara University School of Medicine, Istanbul, Turkey.

Purpose: The aim of the study was to assess efficacy and safety of paliperidone palmitate (PP) in schizophrenic patients using real-life data.

Methods: This national, multicenter, retrospective, and mirror-image study was performed reviewing the medical records of patients in 18 centers. Adult schizophrenic patients receiving PP treatment (n = 205) were enrolled. Patients' data covering the last 12 months before the initial PP injection and the period until the end of study with at least 12 months after the initial PP injection were evaluated. Patients' characteristics, scale scores, and adverse events were recorded.

Results: Nonadherence to prior medication was the most frequent reason for switching to PP treatment. Comparing with the period before PP treatment, the rate of patients visiting the hospital for relapse (79.5% vs 28.9%, P < 0.001) and the median number of hospitalizations (2 vs 0, P < 0.001) were lower during PP treatment. During PP treatment, the Positive and Negative Syndrome Scale score decreased by 20% or more (response to treatment) in 75.7% of the patients. The frequency of adverse events did not differ between the period before and during PP treatment. Improvement in functionality was higher in those with disease duration of 5 years or less.

Conclusions: Paliperidone palmitate is effective and safe in treatment of schizophrenic patients and in switching to PP treatment in patients with schizophrenia, which reduced the percentage of patients admitted to the hospital for relapse and the median number hospitalization, and has positive effects on functionality.
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http://dx.doi.org/10.1097/JCP.0000000000001133DOI Listing
April 2020

Relapse rates following antipsychotic discontinuation in the maintenance phase after first-episode of schizophrenia: Results of a long-term follow-up study.

Schizophr Res 2020 11 22;225:31-38. Epub 2019 Oct 22.

Istanbul University Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey.

Background: When the antipsychotic treatment should be discontinued after first-episode of schizophrenia (FES) in patients who had a good response to initial treatment is still controversial. The aim of this naturalistic follow-up study was to determine the rate of antipsychotic discontinuation in the maintenance phase and its consequences, after FES.

Methods: FES patients (n = 105) were followed-up for at least 24 months and up to 22 years (mean = 99.1 months). After minimum one-year antipsychotic treatment without relapse, some patients' antipsychotics were discontinued by psychiatrist. We compared the clinical characteristics of this group to those who stopped their medication themselves and analyzed the predictors of being relapse-free after discontinuation.

Results: Seventeen (16.2%) of the patients' antipsychotic was discontinued by their psychiatrist. Using the same antipsychotic during the first year was the predictor of discontinuation by the psychiatrist in logistic regression analysis. Ten (58.8%) of them relapsed. Thirty-nine patients (37.1%) discontinued their antipsychotic themselves, relapse rate was 76.9% (n = 30). There was no clinical difference between these two groups. Overall, the patients who had no relapse after discontinuation had better role and global functioning at baseline, were more likely to meet remission criteria, and their antipsychotic was discontinued by psychiatrist and use same antipsychotic during the first year.

Conclusion: Our findings suggest that antipsychotic discontinuation by psychiatrist was possible for only small portion of the FES patients, and relapse rates are high after discontinuation even in these selected patients.
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http://dx.doi.org/10.1016/j.schres.2019.10.015DOI Listing
November 2020

White Noise Speech Illusions: A Trait-Dependent Risk Marker for Psychotic Disorder?

Front Psychiatry 2019 25;10:676. Epub 2019 Sep 25.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, Netherlands.

White noise speech illusions index liability for psychotic disorder in case-control comparisons. In the current study, we examined i) the rate of white noise speech illusions in siblings of patients with psychotic disorder and ii) to what degree this rate would be contingent on exposure to known environmental risk factors (childhood adversity and recent life events) and level of known endophenotypic dimensions of psychotic disorder [psychotic experiences assessed with the Community Assessment of Psychic Experiences (CAPE) scale and cognitive ability]. The white noise task was used as an experimental paradigm to elicit and measure speech illusions in 1,014 patients with psychotic disorders, 1,157 siblings, and 1,507 healthy participants. We examined associations between speech illusions and increasing familial risk (control -> sibling -> patient), modeled as both a linear and a categorical effect, and associations between speech illusions and level of childhood adversities and life events as well as with CAPE scores and cognitive ability scores. While a positive association was found between white noise speech illusions across hypothesized increasing levels of familial risk (controls -> siblings -> patients) [odds ratio (OR) linear 1.11, 95% confidence interval (CI) 1.02-1.21, = 0.019], there was no evidence for a categorical association with sibling status (OR 0.93, 95% CI 0.79-1.09, = 0.360). The association between speech illusions and linear familial risk was greater if scores on the CAPE positive scale were higher ( interaction = 0.003; OR 0.96, 95% CI 0.85-1.07; OR 1.26, 95% CI 1.09-1.46); cognitive ability was lower ( interaction < 0.001; OR 0.94, 95% CI 0.84-1.05; OR 1.43, 95% CI 1.23-1.68); and exposure to childhood adversity was higher ( interaction < 0.001; OR 0.92, 95% CI 0.82-1.04; OR 1.31, 95% CI 1.13-1.52). A similar, although less marked, pattern was seen for categorical patient-control and sibling-control comparisons. Exposure to recent life events did not modify the association between white noise and familial risk ( interaction = 0.232). The association between white noise speech illusions and familial risk is contingent on additional evidence of endophenotypic expression and of exposure to childhood adversity. Therefore, speech illusions may represent a trait-dependent risk marker.
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http://dx.doi.org/10.3389/fpsyt.2019.00676DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6774265PMC
September 2019

Estimating Exposome Score for Schizophrenia Using Predictive Modeling Approach in Two Independent Samples: The Results From the EUGEI Study.

Schizophr Bull 2019 09;45(5):960-965

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing the exposome paradigm to investigate the sum of nongenetic "risk" and show how predictive modeling approaches can be used to construct an exposome score (ES; an aggregated score of exposures) for schizophrenia. The training dataset consisted of patients with schizophrenia and controls, whereas the independent validation dataset consisted of patients, their unaffected siblings, and controls. Binary exposures were cannabis use, hearing impairment, winter birth, bullying, and emotional, physical, and sexual abuse along with physical and emotional neglect. We applied logistic regression (LR), Gaussian Naive Bayes (GNB), the least absolute shrinkage and selection operator (LASSO), and Ridge penalized classification models to the training dataset. ESs, the sum of weighted exposures based on coefficients from each model, were calculated in the validation dataset. In addition, we estimated ES based on meta-analyses and a simple sum score of exposures. Accuracy, sensitivity, specificity, area under the receiver operating characteristic, and Nagelkerke's R2 were compared. The ESMeta-analyses performed the worst, whereas the sum score and the ESGNB were worse than the ESLR that performed similar to the ESLASSO and ESRIDGE. The ESLR distinguished patients from controls (odds ratio [OR] = 1.94, P < .001), patients from siblings (OR = 1.58, P < .001), and siblings from controls (OR = 1.21, P = .001). An increase in ESLR was associated with a gradient increase of schizophrenia risk. In reference to the remaining fractions, the ESLR at top 30%, 20%, and 10% of the control distribution yielded ORs of 3.72, 3.74, and 4.77, respectively. Our findings demonstrate that predictive modeling approaches can be harnessed to evaluate the exposome.
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http://dx.doi.org/10.1093/schbul/sbz054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6737483PMC
September 2019

Replicated evidence that endophenotypic expression of schizophrenia polygenic risk is greater in healthy siblings of patients compared to controls, suggesting gene-environment interaction. The EUGEI study.

Psychol Med 2020 08 15;50(11):1884-1897. Epub 2019 Aug 15.

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, the Netherlands.

Background: First-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.

Methods: We conducted, using two different samples for discovery (n = 336 controls and 649 siblings of patients with psychotic disorder) and replication (n = 1208 controls and 1106 siblings), an analysis of association between PRS on the one hand and psychopathological and cognitive intermediate phenotypes of schizophrenia on the other in a sample at average genetic risk (healthy controls) and a sample at higher than average risk (healthy siblings of patients). Two subthreshold psychosis phenotypes, as well as a standardised measure of cognitive ability, based on a short version of the WAIS-III short form, were used. In addition, a measure of jumping to conclusion bias (replication sample only) was tested for association with PRS.

Results: In both discovery and replication sample, evidence for an association between PRS and subthreshold psychosis phenotypes was observed in the relatives of patients, whereas in the controls no association was observed. Jumping to conclusion bias was similarly only associated with PRS in the sibling group. Cognitive ability was weakly negatively and non-significantly associated with PRS in both the sibling and the control group.

Conclusions: The degree of endophenotypic expression of schizophrenia polygenic risk depends on having a sibling with psychotic disorder, suggestive of underlying gene-environment interaction. Cognitive biases may better index genetic risk of disorder than traditional measures of neurocognition, which instead may reflect the population distribution of cognitive ability impacting the prognosis of psychotic disorder.
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http://dx.doi.org/10.1017/S003329171900196XDOI Listing
August 2020

Lower prepulse inhibition in clinical high-risk groups but not in familial risk groups for psychosis compared with healthy controls.

Early Interv Psychiatry 2020 04 2;14(2):196-202. Epub 2019 Jul 2.

Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul University, Istanbul, Turkey.

Aim: Although the lower level of prepulse inhibition (PPI) of the startle response is well known in schizophrenia, the onset of this difference is not clear. The aim of the present study was to compare PPI in individuals with clinical and familial high risk for psychosis, and healthy controls.

Methods: We studied PPI in individuals within three groups: ultra-high risk for psychosis (UHR, n = 29), familial high risk for psychosis (FHR, n = 24) and healthy controls (HC, n = 28). The FHR group was chosen among siblings of patients with schizophrenia, whereas UHR was defined based on the Comprehensive Assessment of At-Risk Mental States (CAARMS). We collected clinical data using the BPRS-E, SANS and SAPS when individuals with UHR were antipsychotic-naïve. A cognitive battery that assessed attention, cognitive flexibility, working memory, verbal learning and memory domains was applied to all participants.

Results: PPI was lower in the UHR group compared with both the FHR and HC groups. Those with a positive family history for schizophrenia had lower PPI than others in the UHR group. There was no difference in PPI between the FHR and HC groups. We found no relationship between PPI and cognitive performance in the three groups. Startle reactivity was not different among the three groups. Positive and negative symptoms were not related to PPI and startle reactivity in the UHR group.

Conclusions: Our findings suggest that clinical and familial high-risk groups for psychosis have different patterns of PPI.
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http://dx.doi.org/10.1111/eip.12845DOI Listing
April 2020

A large European, multicenter, multinational validation study of the Brief Negative Symptom Scale.

Eur Neuropsychopharmacol 2019 08 27;29(8):947-959. Epub 2019 Jun 27.

Department of Psychiatry, University of Campania "Luigi Vanvitelli", Largo Madonna delle Grazie, 80138 Naples, Italy.

Negative symptoms represent an unmet need of treatment in schizophrenia. Although a consensus exists on negative symptom construct, and second generation assessment instruments reflecting the consensus are available, studies still rely upon old assessment instruments, that do not reflect recent conceptualizations and might limit progress in the search for effective treatments. This is often the case in the European context, where one of the challenges encountered in designing large studies is the availability of validated instruments in the many languages of the continent. To address this challenge and promote sound research on negative symptoms in Europe, the ECNP Schizophrenia Network coordinated a large multicenter, multinational validation study of the Brief Negative Symptom Scale (BNSS). Clinically-stable subjects with schizophrenia (SCZ, N = 249) were recruited from 10 European Countries. Apart from BNSS, subjects were administered the Positive and Negative Syndrome Scale (PANSS) and standardized instruments for depression, extrapyramidal symptoms and psychosocial functioning. Results showed an excellent internal consistency, convergent and discriminant validity of BNSS and replicated a 5 factor-model. A larger number of subjects with predominant negative symptoms, i.e. the target population for clinical trials, was identified by using the BNSS compared to the PANSS. Regression analysis showed that BNSS-avolition, a key negative symptom poorly assessed by PANSS, explained 23.9% of psychosocial functioning, while no combination of the PANSS core negative symptoms showed the same impact on functioning. The study demonstrated that BNSS has substantial advantages with respect to PANSS for the identification of the avolition domain and subjects with predominant negative symptoms.
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http://dx.doi.org/10.1016/j.euroneuro.2019.05.006DOI Listing
August 2019

Examining the independent and joint effects of molecular genetic liability and environmental exposures in schizophrenia: results from the EUGEI study.

World Psychiatry 2019 Jun;18(2):173-182

Department of Psychiatry and Neuropsychology, School for Mental Health and Neuroscience, Maastricht University Medical Center, Maastricht, The Netherlands.

Schizophrenia is a heritable complex phenotype associated with a background risk involving multiple common genetic variants of small effect and a multitude of environmental exposures. Early twin and family studies using proxy-genetic liability measures suggest gene-environment interaction in the etiology of schizophrenia spectrum disorders, but the molecular evidence is scarce. Here, by analyzing the main and joint associations of polygenic risk score for schizophrenia (PRS-SCZ) and environmental exposures in 1,699 patients with a diagnosis of schizophrenia spectrum disorders and 1,542 unrelated controls with no lifetime history of a diagnosis of those disorders, we provide further evidence for gene-environment interaction in schizophrenia. Evidence was found for additive interaction of molecular genetic risk state for schizophrenia (binary mode of PRS-SCZ above 75% of the control distribution) with the presence of lifetime regular cannabis use and exposure to early-life adversities (sexual abuse, emotional abuse, emotional neglect, and bullying), but not with the presence of hearing impairment, season of birth (winter birth), and exposure to physical abuse or physical neglect in childhood. The sensitivity analyses replacing the a priori PRS-SCZ at 75% with alternative cut-points (50% and 25%) confirmed the additive interaction. Our results suggest that the etiopathogenesis of schizophrenia involves genetic underpinnings that act by making individuals more sensitive to the effects of some environmental exposures.
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http://dx.doi.org/10.1002/wps.20629DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6502485PMC
June 2019

Reasons for clozapine discontinuation in patients with treatment-resistant schizophrenia.

Psychiatry Res 2019 05 19;275:149-154. Epub 2019 Mar 19.

Sanliurfa Research and Training Hospital, Psychiatry Clinic, Urfa, Turkey.

Although clozapine is more effective than other antipsychotics in the treatment of schizophrenia, the rate of its discontinuation is also high. The aim of this retrospective chart-review study was to investigate the causes of clozapine discontinuation in patients with treatment-resistant schizophrenia. This study included a total of 396 patients with schizophrenia, 240 still on clozapine therapy and 156 who discontinued clozapine, and compared their clinical characteristics. Those who discontinued clozapine had a longer history of illness and more hospitalizations before clozapine and tended to be older. Inadequate response was more common among clozapine discontinuers compared to continuers. The most common reason for discontinuation was the side-effects associated with clozapine (49%). Discontinuation from patient decision or by the psychiatrist due to noncompliance was the second (29.7%) and discontinuation due to lack of efficacy was the third most frequent reason (21.3%). The patients who discontinued clozapine because of cardiac side effects were younger, had shorter duration of clozapine use, and had lower maximum clozapine dose compared to the other discontinuers. Our findings point out the importance of enhancing psychiatrists' ability to handle manageable side effects to minimize discontinuations and maximize the benefits of clozapine in patients with treatment-resistant schizophrenia.
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http://dx.doi.org/10.1016/j.psychres.2019.01.110DOI Listing
May 2019

Psychometric liability to psychosis and childhood adversities are associated with shorter telomere length: A study on schizophrenia patients, unaffected siblings, and non-clinical controls.

J Psychiatr Res 2019 04 8;111:169-185. Epub 2019 Feb 8.

Brain Research Center, Ankara University, Ankara, Turkey. Electronic address:

Compared to the general population, individuals diagnosed with Schizophrenia (SCZ) experience a higher frequency and an earlier onset of chronic medical disorders, resulting in a reduction in life expectancy by an average of 15-25 years. Recently, it has been hypothesized that SCZ is a syndrome of accelerated aging. Childhood adversity was also associated with the pathogenesis and course of SCZ. Our hypothesis was that both SCZ patients and their unaffected siblings would have shorter telomere length (TL) compared to of non-clinical controls. Our additional goals were to determine (1) whether shorter TL correlates with intermediate phenotypes of SCZ (i.e. Psychosis-like symptoms and schizotypal traits); and (2) whether childhood adversities have a moderating role in TL shortening among SCZ and their unaffected siblings. To this end, SCZ patients (n = 100), their unaffected siblings (n = 100) and non-clinical controls (n = 100) were enrolled. The main variables were TL, measured by aTL-qPCR; psychotic-like and schizotypal symptoms, assessed by The Community Assessment of Psychic Experience (CAPE) and the Structured Interview for Schizotypy-Revised (SIS-R), respectively; and childhood adversities evaluated by the Childhood Experience of Care and Abuse (CECA)-Interview. Potentially relevant variables also included in the analyses were: Global Assessment of Functioning (GAF) scores, cognitive performance, and socio-demographic features. In contrast to our hypothesis patients had similar TL when compared to the non-clinical controls. Interestingly, unaffected siblings had longer TL compared to both patients and controls (p < 0.001). Independent from group status a negative correlation was observed between TL and psychotic-like symptoms as rated by the CAPE (p < 0.01). Childhood adversities, especially loneliness between ages 0 and 11 were also negatively associated with TL (p < 0.05). Our findings suggest that psychometric liability to psychosis and childhood adversities may be associated with shorter TL. Unaffected siblings had longer TL, suggesting the potential role of resilience on both the TL and the clinical presentation. These findings must be considered preliminary, calling for larger-scale replication efforts.
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http://dx.doi.org/10.1016/j.jpsychires.2019.01.022DOI Listing
April 2019

Relationship of obsessive-compulsive symptoms to clinical variables and cognitive functions in individuals at ultra high risk for psychosis.

Psychiatry Res 2018 03 6;261:332-337. Epub 2018 Jan 6.

Istanbul University,Istanbul Faculty of Medicine, Department of Psychiatry, Istanbul, Turkey. Electronic address:

Few studies have investigated the relationship between obsessive-compulsive symptoms (OCS) and clinical variables, and cognition in individuals at ultra high-risk (UHR) for psychosis. The aim of this study was to evaluate the frequency of OCS and their relationship with clinical variables and cognitive functions in individuals at UHR. Eighty-four individuals at UHR for psychosis were administered the Brief Psychiatric Rating Scale, the Yale-Brown Obsession Compulsion Symptom Check List and, the Calgary Depression Scale for Schizophrenia. A cognitive test battery was also applied. We compared the clinical, functional, and cognitive parameters of individuals at UHR with and without OCS and healthy controls. Thirty-five percent of the UHR sample had at least two obsessions/compulsions. The duration of subthreshold psychotic symptoms was longer in individuals with OCS. Those who can work/study before first presentation were more frequent in OCS-positive group. CDSS scores were higher in those with OCS. Compared to controls, OCS-negative group's performance was worse in 8 cognitive test items, while OCS-positive group performed worse in only one cognitive test item. Our findings suggest that OCS are common in the UHR group. OCS might be related to higher level of depression, but better work/study performance, and less cognitive deficits in UHR group.
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http://dx.doi.org/10.1016/j.psychres.2018.01.004DOI Listing
March 2018

Higher schizotypy predicts better metabolic profile in unaffected siblings of patients with schizophrenia.

Psychopharmacology (Berl) 2018 04 6;235(4):1029-1039. Epub 2018 Jan 6.

Maastricht University Medical Centre, Maastricht, Netherlands.

Rationale: Type 2 diabetes (T2D) is more frequent in schizophrenia (Sz) than in the general population. This association is partly accounted for by shared susceptibility genetic variants.

Objective: We tested the hypotheses that a genetic predisposition to Sz would be associated with higher likelihood of insulin resistance (IR), and that IR would be predicted by subthreshold psychosis phenotypes.

Methods: Unaffected siblings of Sz patients (n = 101) were compared with a nonclinical sample (n = 305) in terms of IR, schizotypy (SzTy), and a behavioural experiment of "jumping to conclusions". The measures, respectively, were the Homeostatic Model Assessment of Insulin Resistance (HOMA-IR), Structured Interview for Schizotypy-Revised (SIS-R), and the Beads Task (BT). The likelihood of IR was examined in multiple regression models that included sociodemographic, metabolic, and cognitive parameters alongside group status, SIS-R scores, and BT performance.

Results: Insulin resistance was less frequent in siblings (31.7%) compared to controls (43.3%) (p < 0.05), and negatively associated with SzTy, as compared among the tertile groups for the latter (p < 0.001). The regression model that examined all relevant parameters included the tSzTy tertiles, TG and HDL-C levels, and BMI, as significant predictors of IR. Lack of IR was predicted by the highest as compared to the lowest SzTy tertile [OR (95%CI): 0.43 (0.21-0.85), p = 0.015].

Conclusion: Higher dopaminergic activity may contribute to both schizotypal features and a favourable metabolic profile in the same individual. This is compatible with dopamine's regulatory role in glucose metabolism via indirect central actions and a direct action on pancreatic insulin secretion. The relationship between dopaminergic activity and metabolic profile in Sz must be examined in longitudinal studies with younger unaffected siblings.
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http://dx.doi.org/10.1007/s00213-017-4818-zDOI Listing
April 2018

Electrophysiological and Neuroimaging Research on Negative Symptoms: Future Challenges.

Clin EEG Neurosci 2018 01;49(1):3-5

3 Centre for Neuropsychiatric Schizophrenia Research, Mental Health Centre Glostrup, University of Copenhagen, Copenhagen, Denmark.

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http://dx.doi.org/10.1177/1550059417748074DOI Listing
January 2018

Relationship Between Persistent Negative Symptoms and Findings of Neurocognition and Neuroimaging in Schizophrenia.

Clin EEG Neurosci 2018 Jan;49(1):27-35

1 Department of Psychiatry, Faculty of Medicine, Istanbul University, Çapa, Istanbul, Turkey.

Negative symptoms are defined as loss or reduction of otherwise present behaviors or functions in illness situation, and they have constituted an important aspect of schizophrenia. Although negative symptoms have usually been considered as a single entity, neurobiological investigations yielded discrepant results. To overcome challenges that derive from this discrepancy, researchers have proposed several approaches to structure negative symptoms into more homogenous constructs. Concept of persistent negative symptoms (PNS) is one of the proposed approaches, and includes both primary and secondary negative symptoms that persist after adequate treatment. PNS is relatively easy to assess, and by definition, more inclusive; yet it represents an unmet therapeutic need. Therefore, it is a target of several neurobiological and pharmacological studies. There are several structural and functional brain alterations associated with negative symptoms. On the other hand, neurocognitive investigations in patients with schizophrenia have revealed deficits in several domains that showed correlations with negative symptoms. There are several shared features between negative symptoms and neurocognitive deficits in schizophrenia such as prevalence rates, course through the illness, prognostic importance, and impact on social functioning. However, exact mechanisms behind the neurobiology of PNS and how it interacts with neurocognition remain to be explained. Earlier reviews on neuroimaging and neurocognitive correlates of PNS have been focused on studies with broadly defined negative symptoms that were selected by methodological closeness to PNS. In this review, we focus on neural correlates and neurocognitive associations of PNS, and we discuss PNS findings available to date.
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http://dx.doi.org/10.1177/1550059417746213DOI Listing
January 2018

Deficits in Go and NoGo P3 potentials in patients with schizophrenia.

Psychiatry Res 2017 08 24;254:126-132. Epub 2017 Apr 24.

Department of Physiology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey. Electronic address:

Cognitive control processes elicited during a cued continuous performance test were evaluated using event-related potentials in 46 patients who were within the first 5 years of diagnosis of schizophrenia, and 29 healthy controls. Patients had longer reaction times, lower hit rates, and higher false alarm rates compared with controls. Patients had an overall P3 amplitude reduction that was more prominent on NoGo compared with Go trials. This greater P3 reduction on NoGo trials was present in central and parietal regions, but was absent in the frontal region, where the P3 reduction was comparable on NoGo and Go trials. Our findings suggest that the neural activity contributing to Go and NoGo P3s are both deteriorated in schizophrenia, but those contributing to central and parietal NoGo P3s are the most severely affected ones. We conclude that the cognitive control processes engaged during execution, and particularly during inhibition of a prepared motor response were disturbed in the early course of schizophrenia. Our findings might be related to our sample being in relatively early stages of schizophrenia and/or related to the use of atypical antipsychotics by most of our patients.
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http://dx.doi.org/10.1016/j.psychres.2017.04.052DOI Listing
August 2017

Treatment-Resistant Schizophrenia: Treatment Response and Resistance in Psychosis (TRRIP) Working Group Consensus Guidelines on Diagnosis and Terminology.

Am J Psychiatry 2017 Mar 6;174(3):216-229. Epub 2016 Dec 6.

From King's College London, Institute of Psychiatry, Psychology, and Neuroscience; MRC Clinical Sciences Centre; Institute of Clinical Sciences, Imperial College, and Hammersmith Hospital London; the Department of Psychiatry, University of Toronto, and the Centre for Addiction and Mental Health, Toronto; the Section of Psychiatry and Treatment Resistant Psychosis and the Laboratory of Translational Psychiatry, School of Medicine of Naples Federico II, Naples; the Departments of Psychiatry and Neuroscience, Erasmus Medical Center, and Antes Mental Health Care, Rotterdam, the Netherlands; the Feinstein Institute for Medical Research, Psychiatry Research, Zucker Hillside Hospital, Hofstra Northwell School of Medicine; the Division of Psychiatry, University College London; Laboratorio Interdisciplinar de Neurociencia Clinica, Universidade Federal de São Paulo, São Paulo; the Department of Psychiatry, Maryland Psychiatric Research Center, University of Maryland School of Medicine, Baltimore; the University of Melbourne and St. Vincent's Hospital, Sydney; the Department of Psychiatry and Behavioral Sciences, New York Medical College, New York; the Department of Psychiatry, Tel Aviv University, Tel Aviv; the Division of Health Sciences, School of Psychology and Mental Health, Faculty of Biology, Medicine, and Health, University of Manchester, and the Manchester Academic Health Science Centre, Manchester Mental Health and Social Care NHS Trust, Manchester; the Department of Psychiatry, University of Alberta, Edmonton; the Center for Neuropsychiatric Schizophrenia Research and the Center for Clinical Intervention and Neuropsychiatric Schizophrenia Research, Mental Health Center Glostrup, University of Copenhagen, Copenhagen; the Department of Psychiatry, University of São Paulo Medical School, São Paulo; the Department of Psychiatry, University of Munich, Munich; the Department of Psychiatry, Psychotherapy, and Psychosomatics, Medical University Innsbruck, Innsbruck, Austria; Programa de Esquizofrenia and Laboratorio Interdisciplinar de Neurociencia Clinica, Universidade Federal de São Paulo, São Paulo; the National Psychosis Service, South London and Maudsley NHS Foundation Trust; the Neuroscience and Behavior Department, School of Medicine of Ribeirão Preto, University of São Paulo, São Paulo; the Department of Psychiatry, University of British Columbia; Lundbeck LLC, Deerfield, Ill.; University Department of Psychiatry, Royal Edinburgh Hospital, Edinburgh; the Department of General Psychiatry, Institute of Mental Health, Singapore; the Deparment of Psychiatry and Psychotherapy, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Heidelberg; the Brain and Mind Centre, University of Sydney, Sydney; the School of Pharmacy, University of Auckland, Auckland, New Zealand; the Department of Psychiatry and Behavioral Sciences, Northwestern University Feinberg School of Medicine, Chicago; the Department of Psychiatry and Psychotherapy, Ludwig-Maximilians-University, Munich; the Department of Neuropsychiatry, School of Medicine, Keio University, Tokyo; the Department of Psychiatry, Melbourne Neuropsychiatry Centre, University of Melbourne, and Melbourne Health, Victoria; the Schizophrenia Division, Centre for Addiction and Mental Health, Toronto; the Centre for Mental Health, Swinburne University, the Monash Alfred Psychiatry Research Centre, and the Department of Psychiatry, St. Vincent's Hospital Melbourne, Sydney; the School of Pharmacy, University of Otago, Otago, New Zealand; COS and Associates Ltd., Hong Kong; the Department of Neuropsychiatry, Keio University School of Medicine, Keio, Japan; the Department of Neuroscience, University Medical Center Utrecht, Utrecht, the Netherlands; Swinburne University and Monash Alfred Psychiatry Research Centre, Brain and Psychological Sciences Research Centre, Melbourne; the Istanbul Faculty of Medicine, Istanbul University, Istanbul; Clinical Research and Early Development, F. Hoffmann -La Roche Ltd., Basel, Switzerland; the Division of Psychological Medicine and Clinical Neurosciences, Cardiff University, and the MRC Centre for Neuropsychiatric Genetics and Genomics, Cardiff; Psychiatry Research, Zucker Hillside Hospital, Long Island Jewish Medical Center, Hofstra Northwell School of Medicine, and the Feinstein Institute for Medical Research, New York.

Objective: Research and clinical translation in schizophrenia is limited by inconsistent definitions of treatment resistance and response. To address this issue, the authors evaluated current approaches and then developed consensus criteria and guidelines.

Method: A systematic review of randomized antipsychotic clinical trials in treatment-resistant schizophrenia was performed, and definitions of treatment resistance were extracted. Subsequently, consensus operationalized criteria were developed through 1) a multiphase, mixed methods approach, 2) identification of key criteria via an online survey, and 3) meetings to achieve consensus.

Results: Of 2,808 studies identified, 42 met inclusion criteria. Of these, 21 studies (50%) did not provide operationalized criteria. In the remaining studies, criteria varied considerably, particularly regarding symptom severity, prior treatment duration, and antipsychotic dosage thresholds; only two studies (5%) utilized the same criteria. The consensus group identified minimum and optimal criteria, employing the following principles: 1) current symptoms of a minimum duration and severity determined by a standardized rating scale; 2) moderate or worse functional impairment; 3) prior treatment consisting of at least two different antipsychotic trials, each for a minimum duration and dosage; 4) systematic monitoring of adherence and meeting of minimum adherence criteria; 5) ideally at least one prospective treatment trial; and 6) criteria that clearly separate responsive from treatment-resistant patients.

Conclusions: There is considerable variation in current approaches to defining treatment resistance in schizophrenia. The authors present consensus guidelines that operationalize criteria for determining and reporting treatment resistance, adequate treatment, and treatment response, providing a benchmark for research and clinical translation.
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http://dx.doi.org/10.1176/appi.ajp.2016.16050503DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6231547PMC
March 2017

Lack of progressive reduction in P3 amplitude after the first-episode of schizophrenia: A 6-year follow-up study.

Psychiatry Res 2016 Sep 21;243:303-11. Epub 2016 Jun 21.

Department of Psychiatry, Istanbul Faculty of Medicine, Istanbul University, 34093 Çapa, Istanbul, Turkey.

P3 event-related potential may track the course of neurophysiological pathology in schizophrenia. Reduction in the amplitude of the auditory P3 is a widely replicated finding, already present at the first psychotic episode, in schizophrenia. Whether a progressive deficit is present in auditory P3 in schizophrenia over the course of illness is yet to be clarified. Previous longitudinal studies did not report any change in P3 over time in schizophrenia. However, these studies have been inconclusive, because of their relatively short follow-up periods, lack of follow-up data on controls, and assessment of patients already at the chronic stages of schizophrenia. Auditory P3 potentials, elicited by an oddball paradigm, were assessed in 14 patients with first-episode schizophrenia and 22 healthy controls at baseline and at the 6-year follow-up. P3 amplitudes were smaller in patients with first-episode schizophrenia than in controls. Importantly, over the 6-year interval, the P3 amplitudes were reduced in controls, but they did not change in patients. The lack of P3 reduction over time in patients with schizophrenia might be explained by the maximal reduction in P3 already at baseline or by the alleviation of P3 reduction over time.
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http://dx.doi.org/10.1016/j.psychres.2016.02.065DOI Listing
September 2016

Validation of Turkish version of brief negative symptom scale.

Int J Psychiatry Clin Pract 2016 Nov 13;20(4):265-71. Epub 2016 Jul 13.

a Department of Psychiatry, School of Medicine , Ege University , Izmir , Turkey ;

Objective: Negative symptoms in schizophrenia have been assessed by many instruments. However, a current consensus on these symptoms has been built and new tools, such as the Brief Negative Symptom Scale (BNSS), are generated. This study aimed to evaluate reliability and validity of the Turkish version of BNSS.

Methods: The scale was translated to Turkish and backtranslated to English. After the approval of the translation, 75 schizophrenia patients were interviewed with BNSS, Positive and Negative Syndrome Scale (PANSS), Calgary Depression Scale for Schizophrenia (CDSS) and Extrapyramidal Symptom Rating Scale (ESRS). Reliability and validity analyses were then calculated.

Results: In the reliability analysis, the Cronbach's alpha coefficient was 0.96 and item-total score correlation coefficients were between 0.655-0.884. The intraclass correlation coefficient was 0.665. The inter-rater reliability was 0.982 (p < 0.0001). In the validity analysis, the total score of BNSS-TR was correlated with PANSS Total Score, Positive Symptoms Subscale, Negative Symptoms Subscale, and General Psychopathology Subscale. CDSS and ESRS were not correlated with BNSS-TR. The factor structure of the scale was consisting the same items as in the original version.

Conclusions: Our study confirms that the Turkish version of BNSS is an applicable tool for the evaluation of negative symptoms in schizophrenia.
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http://dx.doi.org/10.1080/13651501.2016.1207086DOI Listing
November 2016

Correlates of Clozapine Use after a First Episode of Schizophrenia: Results From a Long-term Prospective Study.

CNS Drugs 2016 10;30(10):997-1006

Psychiatry Research, North Shore Long Island Jewish Health System, The Zucker Hillside Hospital, Glen Oaks, NY, USA.

Background: Earlier commencement of clozapine has been related to a better response in treatment-resistant schizophrenia.

Objectives: To identify variables that predict clozapine use after a first episode of schizophrenia (FES).

Methods: Patients with FES and ≤15 days of lifetime antipsychotic treatment were followed up during naturalistic treatment, and the patients who were initiated on clozapine were compared with those receiving non-clozapine antipsychotics for ≥24 months regarding demographic and clinical baseline characteristics, adherence, and relapse patterns during follow-up. Treatment-resistant schizophrenia was defined as two or more antipsychotic trials of adequate dose for ≥6 weeks.

Results: Twenty-eight patients who used clozapine and 77 non-clozapine antipsychotic users were included. Clozapine was initiated after a mean of 2.5 ± 1.1 adequate antipsychotic trials. Eight of the 28 clozapine-treated patients (28.6 %) began their clozapine treatment during the first 12 months of follow-up (mean 7.1 ± 3.3 months) and their premorbid childhood adjustment was significantly worse than those who started clozapine later (mean 78.5 ± 43.0 months). Compared with non-clozapine users, patients who started clozapine had significantly more relapses in the first 6 months of follow-up prior to clozapine use (35.7 vs. 11.7 %, p = 0.005), and were significantly more likely to have a first relapse despite treatment adherence (38.1 vs. 73.3 %, p = 0.01). In the multivariate analyses, antipsychotic polypharmacy and first relapse despite adherence to antipsychotic treatment independently predicted subsequent clozapine use.

Conclusions: Clozapine use after a FES was predicted by a first relapse while being adherent to non-clozapine antipsychotics, especially if the first relapse occurred within the first 6 months. Developmental childhood difficulties predicted significantly earlier clozapine use.
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http://dx.doi.org/10.1007/s40263-016-0358-zDOI Listing
October 2016

Primary and persistent negative symptoms: Concepts, assessments and neurobiological bases.

Schizophr Res 2017 08 28;186:19-28. Epub 2016 May 28.

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

Primary and persistent negative symptoms (PPNS) represent an unmet need in the care of people with schizophrenia. They have an unfavourable impact on real-life functioning and do not respond to available treatments. Underlying etiopathogenetic mechanisms of PPNS are still unknown. The presence of primary and enduring negative symptoms characterizes deficit schizophrenia (DS), proposed as a separate disease entity with respect to non-deficit schizophrenia (NDS). More recently, to reduce the heterogeneity of negative symptoms by using criteria easily applicable in the context of clinical trials, the concept of persistent negative symptoms (PNS) was developed. Both PNS and DS constructs include enduring negative symptoms (at least 6months for PNS and 12months for DS) that do not respond to available treatments. PNS exclude secondary negative symptoms based on a cross-sectional evaluation of severity thresholds on commonly used rating scales for positive symptoms, depression and extrapyramidal side effects; the DS diagnosis, instead, excludes all potential sources of secondary negative symptoms based on a clinical longitudinal assessment. In this paper we review the evolution of concepts and assessment modalities relevant to PPNS, data on prevalence of DS and PNS, as well as studies on clinical, neuropsychological, brain imaging electrophysiological and psychosocial functioning aspects of DS and PNS.
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http://dx.doi.org/10.1016/j.schres.2016.05.014DOI Listing
August 2017

Paliperidone palmitate versus oral antipsychotics in recently diagnosed schizophrenia.

Schizophr Res 2015 Dec 1;169(1-3):393-399. Epub 2015 Oct 1.

Medical Affairs, Janssen Cilag EMEA, Neuss, Germany.

Objective: Relapse and acute exacerbation are common in schizophrenia and may impact treatment response and outcome. Evidence is conflicting in respect to superiority of long-acting injectable antipsychotic therapies versus oral antipsychotics in relapse prevention. This randomized controlled study assessed the efficacy of paliperidone palmitate versus oral antipsychotics for relapse prevention.

Method: Eligible patients with a recent diagnosis of schizophrenia (within 1-5 years) were randomized 1:1 to paliperidone palmitate (n=376) or oral antipsychotic monotherapy (n=388) and entered a 2-week initial acute oral treatment phase. Patients who met predefined response criteria were eligible to enter the 24-month rater-blinded core treatment phase. Patients were evaluated for relapse, symptoms, functioning, quality of life, treatment satisfaction, and tolerability.

Results: In the core treatment phase, time to relapse was significantly longer in the paliperidone palmitate (n=352) compared with the oral antipsychotics arm (n=363): 85% of patients were relapse-free at 469 versus 249 days (P=0.019). Significantly fewer patients receiving paliperidone palmitate met the relapse criteria (52 [14.8%] versus 76 [20.9%, oral antipsychotics]; P=0.032), representing a 29.4% relative risk reduction. For paliperidone palmitate, a significantly greater improvement in Positive and Negative Syndrome Scale total score on Day 8 (P=0.021) and a trend at endpoint (P=0.075) were observed. Functioning improvements were comparable between treatment arms. No new safety signals were identified.

Conclusion: The observed time to relapse superiority of paliperidone palmitate over oral antipsychotics provides further evidence for the value of long-acting injectable antipsychotic therapies in the treatment of schizophrenia, including during the early stages of illness.
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http://dx.doi.org/10.1016/j.schres.2015.08.015DOI Listing
December 2015