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Currently, the world is entering the fourth industrial revolution - marked by artificial intelligence (AI) powered technologies. The growing ubiquity of AI technologies is already present in many sectors of modern society, but caution still prevails in medicine where their application is far from routine, although it is on the constant rise. Psychiatry has been recognized as one of the disciplines where significant contribution of AI technologies is expected for prediction, diagnosis, treatment and monitoring of persons with psychiatric disorders. Nearly half of the world's population live in countries that have fewer than one psychiatrist per 100 000 inhabitants, which is far below the health needs as the prevalence of psychiatric disorders is within the range of 10-20%. Thus, the question arises - whether AI technologies can help to fill the gap in unmet needs in psychiatry? The main types of autonomous technologies currently applied in psychiatry are machine learning and its subsets deep learning and computer vision, alongside natural language processing and chatbots. The present review will focus on the brief history of the concept, the utility of AI technologies in psychiatry, clinicians' attitudes, ethical dilemmas, clinical and scientific challenges. This review emphasizes that the psychiatric community should not be ignorant but could try to leave the comfort zone and do more to raise the awareness of AI technologies development achievements.

Objective Despite an increased interest in research of theory of mind (ToM) in recent years — both related to psychopathology (depression and anxiety spectrum disorders) and within the typical adults, the existing literature is scarce and presents some conflicting results. Present study aimed to explore sex differences in ToM, alongside its associations with current anxiety and depression symptoms, in a large sample of typical adults collected online. Method Participants completed the 15-minutes survey obtaining socio-demographic data, current self-reported depression and anxiety symptom severity, and ToM ability (the Reading the Mind in the Eyes Task). The sample comprised 605 participants —mostly younger adults, women, and high school graduate/student population. Results The majority of participants reported minimal/mild depressive and anxiety symptoms that were significantly more severe in women. Women also displayed significantly better overall ToM ability than men. Significant negative correlation between the severity of current depressive and anxiety symptoms and ToM ability was also observed, but only in individuals expressing the symptoms requiring clinical attention (such association was absent in those exhibiting minimal/mild symptoms). Conclusions Present research adds to the existing knowledge on the association between ToM ability, anxiety, and depressive symptoms in typical adults as well as on the sex-differences in this important social cognitive domain. Exploring the factors representing indicators of vulnerability for depression–anxiety spectrum disorders is important for their timely detection and treatment.

European Community, FP7 [HEALTH-F2-2009-241909]; Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III [SAM16PE07CP1, PI16/02012, PI19/024]; CIBERSAM; Madrid Regional Government [B2017/BMD-3740 AGES-CM-2]; Fundación Familia Alonso and Fundación Alicia Koplowitz, Fusar-Poli, L., Pries, L.-K., van Os, J., Radhakrishnan, R., Pençe, A.Y., Erzin, G., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Üçok, A., Alptekin, K., Saka, M.C., Aguglia, E., Arango, C., Rutten, B.P., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

BackgroundThere 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.MethodsWe 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.ResultsThe 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).ConclusionsThe 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.

Introduction: Prescribing trends in maintenance therapy of patients with primary psychotic disorders (PSD) may vary worldwide. Present study aimed to investigate prescription patterns in a sample of outpatients with PSD from Serbia. Methods: In a sample of 73 PSD outpatients we analysed the rate of antipsychotic polypharmacy and psychotropic polypharmacy, concomitant continual benzodiazepine use, and associations between therapy, psychotic symptoms and quality of life. Results: Maintenance therapy (median daily dose 321mg of chlorpromazine equivalents) predominantly consisted of monotherapy with second generation antipsychotics (45.2%), followed by antipsychotic polypharmacy based on first and second generation combination (25.0%). The median number of psychotropicdrugs was 3. Benzodiazepines were continually prescribed to more than 60% of patients (meandaily dose 2.9 ± 2.0mg lorazepam equivalents). Patients with benzodiazepine use had significantly morepsychotropic medications and more antipsychotic polypharmacy, poorer quality of life and more severepsychopathology in comparison to another group. Conclusion: The present study demonstrated new information regarding the prescription patterns of psychotropic drugs in outpatients with PSD in Serbia, amplified with clinically relevant information. This study also revealed distinct prescription patterns concerning antipsychotic/benzodiazepine polypharmacy. Overall, such findings are likely to contribute to improving clinical practice and care for patients with PSD in general

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. ispartof: WORLD PSYCHIATRY vol:18 issue:2 pages:173-182 ispartof: location:Italy status: published

European Community's Seventh Framework Program, European Commission [HEALTH-F2-2009-241909]; Scientific and Technological Research Council of Turkey, 2219 International Postdoctoral Research Fellowship Program; Spanish Ministry of Science and Innovation, Instituto de Salud Carlos III (SAM16PE07CP1, PI16/02012, and PI19/024)..., Erzin, G., Pries, L.-K., van Os, J., Fusar-Poli, L., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altınyazar, V., Yalınçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Andric-Petrovic, S., Mirjanic, T., Bernardo, M., Mezquida, G., Amoretti, S., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M.C., Rutten, B.P.F., Guloksuz, S., Genetic Risk and Outcome of Psychosis (GROUP) investigators

Hypothalamic–pituitary–adrenal (HPA) axis activity mediates the relationship between childhood trauma (CT) and psychosis. The FKBP5 gene, one of the key regulators of HPA axis activity after stress exposure, has been found associated with psychosis. Allele-specific and CT related FKBP5 demethylation in intron 7 was revealed in different psychiatric disorders. However, no studies have investigated FKBP5 methylation in subjects with different genetic liability for psychosis. A total of 144 participants were included in the study: 48 patients with psychotic disorders, 50 unaffected siblings, and 46 healthy controls. CT was assessed by Childhood Trauma Questionnaire. The FKBP5 rs1360780 was genotyped and FKBP5 methylation analyses were performed using bisulfite conversion followed by Sanger sequencing at three CpG sites in intron 7. Mixed linear model was used to assess group differences depending on rs1360780 T allele and CT. Results showed a significant T allele-dependent decrease of FKBP5 methylation in patients compared to unaffected siblings and controls. Effect of interaction between T allele and CT exposure on FKBP5 demethylation was found in controls. No effect of both risk factors (T allele and CT) on FKBP5 methylation level was found in unaffected siblings. We confirmed previous evidence of the association between the FKBP5 rs1360780 T allele, CT, and decreased FKBP5 methylation in intron 7. Allele-specific FKBP5 demethylation found in patients could shed a light on altered HPA axis activity in a subgroup of patients related to stress-induced psychosis. FKBP5 methylation and potential protective mechanisms in unaffected siblings after trauma exposure require further investigation. © 2021 Elsevier Ltd

The EUGEI project was supported by the European Community’s Seventh Framework Program under grant agreement No. HEALTH-F2- 2009-241909 (Project EU-GEI). Dr. Arango was supported by the Spanish Ministry of Science and Innovation; Instituto de Salud Carlos III (SAM16-PE07CP1, PI16/02012, PI19/024); CIBERSAM (...), Fusar-Poli, L; Pries, LK; van Os, J; Erzin, G; Delespaul, P; Kenis, G; Luykx, JJ; Lin, BCD; Richards, AL; Akdede, B; Binbay, T; Altinyazar, V; Yalincetin, B; Gumus-Akay, G; Cihan, B; Soygur, H; Ulas, H; Cankurtaran, ES; Kaymak, SU; Mihaljevic, MM; Andric-Petrovic, S; Mirjanic, T; Bernardo, M; Mezquida, G; Amoretti, S; Bobes, J; Saiz, PA; Garcia-Portilla, MP; Sanjuan, J; Aguilar, EJ; Santos, JL; Jimenez-Lopez, E; Arrojo, M; Carracedo, A; Lopez, G; Gonzalez-Penas, J; Parellada, M; Maric, NP; Atbasoglu, C; Ucok, A; Alptekin, K; Saka, MC; Aguglia, E; Arango, C; O'Donovan, M; Rutten, BPF; Guloksuz, S

There is much concern about the widespread long-term use of benzodiazepines. Our manuscript addressed its use in the region of Southeastern Europe, which seems extensive, but insufficiently explored. At nine university psychiatric hospitals (Croatia, Macedonia and Serbia), we retrospectively analyzed discharge summary documents to find the prevalence of discharge benzodiazepine prescriptions and the prescribed benzodiazepine doses. This study included 1047 adult subjects and showed that 81.9% of them had benzodiazepines prescribed in the discharge summary document, with high mean daily dose of around 5mg lorazepam equivalents. Factors associated with the prescriptions were exclusively clinical factors (diagnosis of schizophrenia spectrum disorders, more lifetime hospitalizations, psychiatric comorbidity, co-prescription of antidepressant or mood stabilizer, shorter duration of the hospitalization), while socio-demographic factors were not found to influence benzodiazepine discharge prescriptions. Similarly, factors which influenced the prescription of higher daily benzodiazepine dose were more lifetime psychiatric hospitalizations and co-prescription of antidepressant or mood stabilizer, as well as the diagnosis of mental/behavioral disorders due to substance use and co-prescribed antipsychotic. Our data are emphasizing an urgent need for guidelines and improved education of both health care professionals and patients, in order to prevent long term benzodiazepine (mis)use and related side-effects.

The EUGEI project was supported by the grant agreement HEALTH-F2-2010-241909 from the European Community’s Seventh Framework Programme. The authors are grateful to the patients and their families for participating in the project. They also thank all research personnel involved in the GROUP project, in particular J. van Baaren, E. Veermans, G. Driessen, T. Driesen, E. van’t Hag and J. de Nijs. Bart PF Rutten was funded by a VIDI award number 91718336 from the Netherlands Scientific Organisation., Pries, L.-K., Lage-Castellanos, A., Delespaul, P., Kenis, G., Luykx, J.J., Lin, B.D., Richards, A.L., Akdede, B., Binbay, T., Altinyazar, V., Yalinçetin, B., Gümüş-Akay, G., Cihan, B., Soygür, H., Ulaş, H., Cankurtaran, E.Ş., Kaymak, S.U., Mihaljevic, M.M., Petrovic, S.A., Mirjanic, T., Bernardo, M., Cabrera, B., Bobes, J., Saiz, P.A., García-Portilla, M.P., Sanjuan, J., Aguilar, E.J., Santos, J.L., Jiménez-López, E., Arrojo, M., Carracedo, A., López, G., González-Peñas, J., Parellada, M., Maric, N.P., Atbaşoğlu, C., Ucok, A., Alptekin, K., Saka, M.C., Arango, C., O'Donovan, M., Rutten, B.P.F., van Os, J., Guloksuz, S.

BackgroundFirst-degree relatives of patients with psychotic disorder have higher levels of polygenic risk (PRS) for schizophrenia and higher levels of intermediate phenotypes.MethodsWe 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.ResultsIn 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.ConclusionsThe 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.

Previous studies examining sex-differences in facial emotion recognition (FER) in psychosis yielded inconsistent results. Although females are considered to be superior in FER in health, it remains unclear whether the specific sex-difference is present in psychosis. We aimed to examine whether women and men differ in FER ability in health and in psychosis, and to explore potential sex differences in the illness' effects on FER.Remitted psychotic patients and controls were assessed using the CANTAB Emotion Recognition Task (ERT) examining accuracies/response latencies in identifying basic emotional expressions. General linear model was performed to assess the effects of group, sex and their interactions on ERT performance.Healthy females showed FER advantage in comparison to healthy males, while the aforementioned sex-difference was not observed in remitted psychotic patients. Our results also demonstrated the existence of overall FER deficit in psychosis in comparison to healthy controls, as well as the differential illness' effects on the recognition accuracy of facial expression of anger in males and females-suggesting that females with psychotic disorders undergo more profound deterioration of FER ability than their male counterparts.The assessment of sex-differences in FER and other important features of psychosis is important for better understanding of its neurobiological basis and for the development of targeted treatments for improved functioning.

Aim: Unequal development of early detection (ED) and early intervention (EI) programs/services for psychosis has been shown across Europe. The present report aims to fill in the knowledge gap regarding the implementation and several other important aspects of ED/EI services in Central and Eastern Europe (CEE), a region with highly underdeveloped mental health service research. Methods: A 17-item questionnaire was created to address the information regarding ED/EI organization and factors limiting their implementation. This questionnaire was distributed to professionals recognized as experts in the field from 23 CEE countries. The data were collected between December 2017 and February 2018. Results: We found that ED/EI services were rather an exception than a rule in CEE. The majority of the countries involved in the present survey reported no national plans or programmes for ED/EI development. The existing services were mostly state-funded, hospital-based, healthcare sites for both adolescent and adult help-seekers. The lack of adequate infrastructure, finances and governmental support, as well as the insufficient number of staff, were identified as the most important factors limiting service implementation. Conclusions: Although ED/EI services for psychosis exist in some CEE countries, this could be largely attributed to enthusiastic individuals and organizations, rather than to a strategic development. To the best of our knowledge, this was the first mapping of ED/EI development in the region, which could be used as a starting point to plan the improvement of services, to accelerate their implementation and to facilitate timely detection of and intervention in psychosis across Europe.

Alterations in general intellectual ability and social cognition in schizophrenia are core features of the disorder, evident at the illness’ onset and persistent throughout its course. However, previous studies examining cognitive alterations in siblings discordant for schizophrenia yielded inconsistent results. Present study aimed to investigate the nature of the association between facial emotion recognition and general IQ by applying genetically sensitive cross-trait cross-sibling design. Participants (total n=158; patients, unaffected siblings, controls) were assessed using the Benton Facial Recognition Test, the Degraded Facial Affect Recognition Task (DFAR) and the Wechsler Adult Intelligence Scale-III. Patients had lower IQ and altered facial emotion recognition in comparison to other groups. Healthy siblings and controls did not significantly differ in IQ and DFAR performance, but siblings exhibited intermediate angry facial expression recognition. Cross-trait within-subject analyses showed significant associations between overall DFAR performance and IQ in all participants. Within-trait cross-sibling analyses found significant associations between patients’ and siblings’ IQ and overall DFAR performance, suggesting their familial clustering. Finally, cross-trait cross-sibling analyses revealed familial covariation of facial emotion recognition and IQ in siblings discordant for schizophrenia, further indicating their familial etiology. Both traits are important phenotypes for genetic studies and potential early clinical markers of schizophrenia-spectrum disorders.

The aim of this study was to examine executive functions (EF) in patients with treatment-resistant depression (TRD) before and after bitemporal electroconvulsive therapy (ECT) and to evaluate possible associations between the depression severity and executive tasks performances.Patients (n = 29), treated with bitemporal ECT, underwent assessment at three time points: baseline, immediately after ECT course and 1 month later. The Stockings of Cambridge (SOC, CANTAB) was used to assess EF: (1) number of problems solved in minimum moves (SOC-P), (2) initial thinking time (SOC-I) and (3) subsequent thinking time (SOC-T).The scores on the Hamilton Depression Rating Scale and the Clinical Global Impression scale were significantly reduced over time, with no negative effects on the EF. Among SOC subtests, only SOC-I improved over time, which was significantly correlated with the depressive symptoms reduction. SOC-T and SOC-P remained unchanged and did not correlate with mood. Interestingly, the patients with more lifetime psychiatric hospitalisations and more ECT applications were more likely to drop-out and to have longer SOC-T while performing the test.Our results support the view that ECT does not produce long-lasting EF deficits, nor exacerbates the pre-existing ones. The improvement of the EF performances during and after the ECT-induced alleviation of mood symptoms in TRD is based mostly on the reduction of time needed to plan the problem solution.

Aim To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits. Methods Fifty seven patients (males 54.4%; age = 29.9 ± 6.0 yrs; age at the illness onset = 24.9 ± 5.1 yrs; IQ = 93.5 ± 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables. Results Based on the most restrictive definition, the length of DUP in our sample was 77.8 ± 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = −0.804, P = 0.024). Conclusions We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis.

Background Data on benzodiazepine (BZD) use of on a long term basis (≥6 months) in outpatients with psychosis spectrum disorders (PSD) are scarce. However, prolonged BZD administration could be associated with different side effects, thus its use in actual practice must be described and questioned. According to the recent large-scale study of hospital discharge BZD prescription in Balkans, PSD patients had higher odds of receiving BZDs (80.4%) in comparison to patients with all other main ICD-10 psychiatric categories. This study explored the prevalence of long-term BZD use during maintenance therapy of patients with PSD and the associated clinical factors. Methods Outpatients with primary diagnosis of psychosis or related disorder (ICD-10 F20-29), history of at least one lifetime psychiatric hospital admission, capacity and will to provide informed consent and a history of attending the outpatient clinic for at least 6 months were included from two sites in Serbia - one university and one general psychiatric hospital (n=60; mean age (SD) = 43.4 (10.6) years; 63.3% male). Clinical assessment included Brief Psychiatric Rating Scale (BPRS, mean (SD) = 1.73 (0.49)), the split version of General Assessment of Functioning scale (GAF Functioning/Symptom, mean (SD) = 58.5 (11.7) and 58.6 (11.7), respectively), Global Assessment of Functioning - Cognition in Schizophrenia (GAF-CogS, mean (SD) = 60.4 (12.4)) and Recovering Quality of Life (ReQoL, mean (SD) = 29.0 (9.1)). Medical chart review was used to list all psychotropic medications prescribed over 6 months preceding the examination. We used student t-test and Pearson’s correlation to analyze the data. Effect sizes were provided. Present research was conducted as a part of the larger study aiming at implementation of the psychosocial intervention DIALOG+ for patients with psychotic disorders in low- and middle-income countries in South Eastern Europe (grant agreement No 779334). Results The prevalence of long term BZD use was 50.0% (30/60 patients). The mean BZD daily dose range was 0–14 mg of lorazepam equivalents (21.7% with ≥ 3mg of lorazepm equivalents). Total antipsychotic (AP) daily doses (chlorpromazine equivalents) at the time of evaluation were 371.6±191.4 mg in long-term BZD users and 275.0±214.7 mg in the other group (df=56, t= 1,811, p=0.075, Cohen’s d=0.5). The correlation between AP polypharmacy and long-term BZD use was positive (r=0.340, p=0.008). Long term BZD users were borderline older than non-users (df=58, t=1,957, p=0.055, Cohen’s d=0.5) and had higher total BPRS symptom scores (df=58, t= 2,806, p=0.007, Cohen’s d=0.7). In particular, higher symptom scores were noticed in two BPRS domains - negative symptom and reality distortion. Moreover, these patients were significantly more likely to have cognitive and functional impairments (GAF-CogS: df=56, t=-3.295, p=0.002, Cohen’s d=0.9; GAF-F: df=56, t=-3,186, p=0.002, Cohen’s d=0.8; GAF-S: df=56, t=-3,316, p=0.002, Cohen’s d=0.9). There were no between-group differences in ReQoL scores (df=58, t=-1.563, p=0.123). Discussion The present study demonstrated new information regarding the prescription patterns of BZD in outpatients with PSD in Serbia, amplified with clinically relevant information. High rate of long term BZD prescription could be considered as a therapeutic strategy toward patients with more severe cases of PSD, however our results could also suggest a link between long-term BZD prescription and disabling side effects, particularly related to cognitive functioning. Overall, this is an under-researched area and present findings are likely to contribute to improving clinical practice and care for patients with psychotic disorders.

BackgroundCurrent literature provides insufficient information on the degree of cognitive impairment during and after electroconvulsive therapy (ECT), mostly due to the fact that applied tests lacked sensitivity and flexibility. Our goal was to evaluate cognitive functioning in adult depressed patients treated with bi-temporal ECT, using tests sensitive for detection of possible acute and medium-term memory changes.MethodThirty adult patients with major depressive disorder, treated with a course of bi-temporal ECT, underwent clinical and cognitive measurements three times: at baseline, immediately after a course of ECT, and 1 month later. For cognition assessment, we used learning and visual, spatial and figural memory tests from the Cambridge Neuropsychological Test Automated Battery (CANTAB).ResultsBi-temporal ECT has proven to be an effective treatment. The linear mixed model, used to analyze changes in depression severity and patients’ cognitive performances over time and to assess dynamic correlations between aforementioned features, did not show any significant memory impairment as a potential acute or medium-term ECT effect. However, it yielded significant improvement on visual memory and learning at the follow-up, which positively correlated with the improvement of depression.ConclusionGood progress is being made in the search for ECT-related acute and medium-term cognitive side-effects by using the tests sensitive to detect memory dysfunction with parallel forms of the tasks (to counter practice effects on repeat testing). Our results on learning and memory in relation to ECT during treatment of depression did not bring forth any prolonged and significant bi-temporal ECT-related memory deficit.

Summary The introduction of antipsychotic medication in the 1950s forever changed the outlook on the treatment of schizophrenia, although there is still a large proportion of patients who do not reach functional recovery. At least 30% of patients do not respond to clozapine, the tricyclic dibenzodiazepine with complex pharmacological actions, which was proven to be more effective than any other antipsychotic in the treatment of schizophrenia. According to most of the therapeutic guidelines for schizophrenia, clozapine is the third line therapy for patients who did not respond to other antipsychotics. Large inter-individual variability exists for clozapine bioavailability and plasma steadystate concentrations and clearance. Clozapine is metabolized by the cytochrome P450 oxidase enzyme family (CYP450). Cytochrome P450 1A2 (CYP1A2), which is polymorphically expressed in humans, is the main enzyme of clozapine metabolism. This case report addresses the influence of CYP1A2*1F genetic polymorphism on cloza - pine metabolism, explains the primary non-response of a young patient with schizophrenia due to increased gene expression in homozygous genotype *1F/*1F (increased metabolism of clozapine) and underlies the importance of personalizing schizophrenia treatment by means of genetic and other molecular tools, at least in the cases of »treatment resistance«.

Objectives. To develop a structural equation model of negative affectivity (NA) that involves interaction of glucocorticoid receptor (GR) signaling, personality dimensions and recent stressful life events. Methods. Seventy participants -35 diagnosed with major depression and 35 healthy controls, were enrolled in the study. Morning plasma cortisol levels were determined by chemiluminescent immunometric assays. Molecular parameters (total nuclear and cytoplasmatic GR, nuclear GR phosphorylated at serine 211 (pGR-211) and at serine 226 (pGR-226) and cytoplasmic FKBP51) were analysed from peripheral blood lymphocytes by Western blot. NA, personality dimensions and stressful life events were assessed by self-report instruments. Results. GR signalling parameters had direct independent effect on measures of NA, with pGR-226 levels showing the strongest correlation, followed by FKBP51 and pGR-211 levels. Neuroticism and extraversion also demonstrated strong independent effect on NA, while recent stressful events did not predict NA directly, but demonstrated a significant effect on personality dimensions. Cortisol, total nuclear GR and total cytoplasmatic GR levels were excluded from the model due to non-significant correlations with NA. Conclusions. Negative affectivity is a transdiagnostic factor in vulnerability to affective disorders and possible therapeutic target. Molecular signature of negative affectivity should incorporate GR phosphorylation with other known biological underpinnings.

Aim The aim of the present study was to examine whether healthy individuals with higher levels of neuroticism, a robust independent predictor of psychopathology, exhibit altered facial emotion recognition performance. Methods Facial emotion recognition accuracy was investigated in 104 healthy adults using the Degraded Facial Affect Recognition Task (DFAR). Participants' degree of neuroticism was estimated using neuroticism scales extracted from the Eysenck Personality Questionnaire and the Revised NEO Personality Inventory. Results A significant negative correlation between the degree of neuroticism and the percentage of correct answers on DFAR was found only for happy facial expression (significant after applying Bonferroni correction). Conclusions Altered sensitivity to the emotional context represents a useful and easy way to obtain cognitive phenotype that correlates strongly with inter-individual variations in neuroticism linked to stress vulnerability and subsequent psychopathology. Present findings could have implication in early intervention strategies and staging models in psychiatry.

Humans are substantially a social species. Effective mental treatment cannot be obtained without addressing social behavior. Social cognition refers to the mental processes underlying social interactions, which allow individuals to make sense of the other peoples' behavior, to decipher emotions on their faces, and to draw conclusions about their intentions. The core domains of this multifaceted concept are theory of mind, social cue perception, attributional style and emotion perception/ processing. The amygdala, orbital frontal cortex and temporal cortex areas are typically activated during the processing of information within social-emotional context. The aforementioned brain areas are recognized as the major components of the so-called 'social brain'- specialized for the social interactions in humans. Adequate perceiving and processing of the social information is essential for an effective social functioning, which becomes obvious when it goes awry. Various psychiatric disorders are characterized by social cognitive deficits, among which schizophrenias, depression-anxiety and autism spectrum disorders were most broadly studied to date. Growing evidence suggest that these deficits underlie poor functional outcomes in patients with mental health impairments and have an important role in the initiation and maintenance of the disorders' symptoms. One of the most important goals of social neuroscience research is to provide a treatment intervention that will improve patients' social cognitive skills and the functional outcome. All together, the present review aims to provide a contemporary overview of the concept of social cognition, to outline its relation to psychopathology, and to discuss the implications for clinical practice and treatment.

Introduction: Emerging research suggests that being exposed to bullying during childhood can increase the risk of psychotic experiences in adulthood. Aggressive peer relations among adolescents are more frequent in boys, both for being victims or perpetrators. Aim: To evaluate whether bullying was more prevalent among Serbian clinical population of patients with psychosis in comparison to their healthy siblings and controls, and to analyze gender differences regarding bullying. Material and methods: This cross-sectional study evaluated schizophrenia spectrum patients (n = 52, age = 29.3 ± 5.9 yrs, in remission, illness duration

Aim Early detection/early intervention (ED/EI) programmes have been inconsistently implemented throughout Europe. We evaluated the ED/EI service distribution in European Psychiatric Association (EPA) member countries, considering indicators of socio-economic development, human and financial resources allocated in mental health (MH) as well as presence of a national branch of the Early Intervention in MH (IEPA). Contextually, we evaluated the duration of untreated psychosis (DUP) in relation to ED/EI service implementation. Methods EPA section "Prevention of Mental Disorders" conducted the cross-sectional survey administering the 16-item questionnaire to the representatives of its National Psychiatric Associations (NPAs). The survey addressed the Service status and profile, national guidelines, education and policy, DUP and IEPA national branch status. The data were analysed in relation to the indices of economic parameters and MH resources. Results Neither the national economic parameters, nor indices of MH financial resources were significantly associated with variables related to ED/EI implementation. However, more MH human resources per country were associated with shorter DUP. In comparison to countries without a national branch of IEPA, all of these with the branch had more MH human resources, ED/EI chapters in the national guidelines and services involving both adolescents and adults. Conclusions An unequal development of ED/EI services and related academic activities appears throughout Europe. The current results, besides providing a useful starting point to set the agenda for harmonizing ED/EI services, reveal that their implementation was more likely to be influenced by the IEPA membership status, rather than by country-specific financial and human resources allocated to MH.

Increased reactivity to stress is observed in patients with schizophrenia spectrum disorders and their healthy siblings in comparison with the general population. Additionally, higher levels of neuroticism, as a proposed psychological measure of stress sensitivity, increase the risk of schizophrenia. HPA axis dysregulation is one of the possible mechanisms related to the vulnerability-stress model of schizophrenia, and recent studies revealed a possible role of the functional genetic variants of FK506-binding protein 51 (FKBP5) gene which modulate activity of HPA axis. The purpose of the present study was to investigate impact of FKBP5 on schizophrenia in Serbian patients and to explore relationship between genetic variants and neuroticism by using the case-sibling-control design. In 158 subjects, we measured psychotic experiences, childhood trauma and neuroticism. Nine single-nucleotide polymorphisms (rs9295158, rs3800373, rs9740080, rs737054, rs6926133, rs9380529, rs9394314, rs2766533 and rs12200498) were genotyped. The genetic influence was modeled using logistic regression, and the relationship between genetic variants and neuroticism was assessed by linear mixed model. Our results revealed genetic main effect of FKBP5 risk alleles (A allele of rs9296158 and T allele of rs3800373) and AGTC "risk" haplotype combination (rs9296158, rs3800373, rs9470080 and rs737054, respectively) on schizophrenia, particularly when childhood trauma was set as a confounding factor. We confirmed strong relationship between neuroticism and psychotic experiences in patients and siblings and further showed relationship between higher levels of neuroticism and FKBP5 risk variants suggesting potential link between biological and psychosocial risk factors. Our data support previous findings that trauma exposure shapes FKBP5 impact on schizophrenia.

Background: Epigenetic changes of the FKBP5 locus in adults were reported to be allele specific and trauma related in different patient populations. However, DNA methylation status of FKBP5 and its relation to the circulating protein levels are still unknown in schizophrenia spectrum disorders.

In the last two decades, both early detection (ED) and early intervention (EI) programs and services have gradually become important and innovative components of contemporary mental health care. However, it is unclear whether ED/EI programs have consistently been implemented throughout Europe.Here, we report results of the EPA Survey on ED/EI Programs in Europe in 2016.A 16 item questionnaire was sent to representatives (presidents and secretariats) of 40 EPA National Societies/Associations (NPAs), representing 37 countries. The representatives were also invited to recommend a person for additional information about ED/EI services/programs in the country.The response rate was 59.4% (22 NPAs). Fifteen out of 28 NPAs were from developed, and 7 out of 8 from economies in transition. ED/EI services have been implemented in 54.5% of the included countries, mean duration 10.0 ± 4.9 yrs. Mostly, neither ED were separated from EI, not the adults from adolescents. National plans to develop ED/EI were reported in four countries. Although national guidelines for schizophrenia exist in most of the countries (73.9%), specific chapters focusing on ED/EI and/or at-risk mental states were not included in the majority of them. Duration of untreated psychosis was unknown in 63.6%. In those who gave the estimation it was 12–100 weeks (median in weeks: 33 developed economies; 44 economies in transition).The fields of ED/EI have been unequally developed across Europe. Still, many NPAs are without the development plans. EPA and its Sections should address the identified gaps and suggest how to harmonize services for the full range of assessments and interventions.Disclosure of interestThe authors have not supplied their declaration of competing interest.

The impaired glucocorticoid receptor (GR) signaling has long been considered one of the cornerstones in understanding the pathophysiology of depression. Since the phosphorylation of GR is very important for GR function, in this study we investigated whether GR phosphorylation at serine 211 (pGR-S211) and serine 226 (pGR-S226) is altered in patients with current episode of major depressive disorder (MDD). Particularly, in 30 MDD patients and 35 controls we assessed the levels of nuclear total GR (tGR), pGR-S211 and pGR-S226 in peripheral blood mononuclear cells (PBMC) using Western blot technique, along with plasma cortisol concentrations from the same blood samples. Our results demonstrated increased phosphorylation of GR at S226 (p LT 0.001) and, to a less extent, at S211 (p LT 0.05) in MDD patients compared to controls. Consequently, the pGR-S211/pGR-S226 ratio was decreased (p LT 0.05) implying reduced transcriptional activity of GR in MDD patients. MDD subjects had higher cortisol levels than controls and cortisol concentrations were positively correlated with PBMC pGR-S226 levels from the same blood samples. There was no difference in the levels of tGR between MDD and control subjects. The study showed that altered phosphorylation of GR could contribute to impaired GR function related to the pathophysiology of depression. (c) 2012 Elsevier Inc. All rights reserved.

30th Congress of the European-College-of-Neuropsychopharmacology (ECNP), Sep 02-05, 2017, Paris, France

Background Hypothalamic–pituitary–adrenal (HPA) axis dysregulation is a potential neurobiological mechanism proposed by vulnerability-stress model for schizophrenia. Recent studies highlighted the role of functional genetic variants of FKBP5 gene, which affect the activity of HPA axis following stress exposure, and supported the hypothesis of increased stress sensitivity in schizophrenia. Additionally, FKBP5 demethylation in Intron 7 was observed in stress-related conditions thus the purpose of this pilot study was to investigate FKBP5 methylation levels at Intron 7 in schizophrenia. Methods Ethnically homogeneous Serbian sample of 24 schizophrenia spectrum patients and 24 controls matched by age and gender with patients’ group, were analyzed regarding DNA methylation levels at three CpG sites and average methylation level in Intron 7. Accordingly, we covered the area of GRE that has been reported to be associated with altered stress responsiveness. Epigenetic changes in FKBP5 Intron 7 were measured by Sanger sequencing and compared between the groups using t test as appropriate. Results Analyses revealed decreased FKBP5 methylation at the three targeted CpG sites (CpG1, CpG2, and CpG3) in patients compared to controls (p=0.026, p=0.017, and p=0.027, respectively). Similarly, when we averaged methylation scores of the observed region in Intron 7, significant demethylation was detected in patients (p=0.003). Discussion To the best of our knowledge this is the first study which explored FKBP5 epigenetic changes in schizophrenia. Conclusively to previous stress-related conditions, our preliminary results revealed significant decrease of FKBP5 methylation levels in Intron 7 in patients with schizophrenia. FKBP5 demethylation presents further insight into the reported FKBP5 genetic influence in psychosis and could be promising terapeutic target for the prevention of the onset and the course of schizophrenia.

To determine duration of untreated psychosis (DUP) in patients with schizophrenia-spectrum disorders from Serbia and to analyse factors that potentially contribute to the treatment delay, with focus on personality traits.Fifty seven patients (males 54.4%; age = 29.9 ± 6.0 yrs; age at the illness onset = 24.9 ± 5.1 yrs; IQ = 93.5 ± 12.2) were included. The assessment consisted of Nottingham Onset Schedule (NOS), Premorbid Adjustment Scale (PAS) and NEO Personality Inventory (NEO-PI-R). We used Cox regression model to evaluate relationship between DUP and explanatory variables.Based on the most restrictive definition, the length of DUP in our sample was 77.8 ± 120.6 weeks (MED = 25.0 weeks). DUP was negatively associated with openness to experience (B = -0.804, P = 0.024).We report the first evidence of DUP in Serbia, emphasizing that the personality domains are likely to impact the use of mental health care in persons with psychosis.

IntroductionTreatment with pegylated interferon alpha (PEG-IFN-α) in patients with chronic hepatitis C (CHC) is associated with depressive symptomatology more frequently than other inflammatory diseases treated with PEG-IFN-α.ObjectivesTo prospectively evaluate the onset, course and resolution of depressive symptomatology in CHC patients treated with PEG-IFN-α.MethodsHamilton depression rating scale (HAMD) was used to asses depressive symptoms in 103 subjects with CHC prior to initiation of PEG-IFN-α (mean dose 152.6 ± 25.6 mcg; duration of therapy 48 weeks) and at the follow-up visits (4th, 12th, 24th, 48th and 72th week). Control group consisted of 103 CHC subjects, without PEG-IFN-α.ResultsOur results showed a significant increase in HAMD scores as early as in the 4th week of PEG-IFN-a therapy compared to HAMD scores prior to initiation of PEG-IFN-α (38.8% vs. 24.3%). The peak of depressive symptomatology was evidenced in the 12th week (mean HAMD 9.34 ± 6.93), when almost 50% of patients had HAMD above 7. At the end of the treatment (48th week), 38.8% had HAMD above 7, and in the 72nd week (24 weeks after the therapy completion) prevalence of depression was decreased to the values lower than at baseline (23.3% vs. 24.3%). No change in prevalence of depression was detected in control group.ConclusionOur results are important because they show the overall course of depressive symptomatology during the interferon therapy. These data also show spontaneously resolution of depression 6 months after the completion of PEG-IFN-α. This study is the longest study in this area.Disclosure of interestThe authors have not supplied their declaration of competing interest.