Screening for depression in the Serbian general population sample: an alternative to the traditional patient health questionnaire-9 cut-off score.

BACKGROUND: The Patient Health Questionnaire (PHQ-9) score ≥ 10 balances best sensitivity and specificity when detecting probable depression in patients. In the general population, different cut-offs are suggested. European studies on general populations validating the PHQ-9 against a diagnostic interview to detect depression are rare. METHODS: This was a cross-sectional observational epidemiological survey using multistage household probabilistic sampling to recruit a representative adult sample (N = 1203; age = 43.7 ± 13.6; 48.7% male). Mental disorders including current major depressive episode (MDE) were observer-rated (Mini International Neuropsychiatric Interview). The PHQ-9, quality of life (QoL), and loneliness were self-assessed. We performed validity and reliability tests of the PHQ-9 and receiver operating curve (ROC) analysis. RESULTS: The Serbian PHQ-9 was internally consistent and correlated in the expected directions with QoL and loneliness. At the cut-off score ≥ 8, sensitivity was .85 and specificity was .91. ROC analysis showed that the area under the curve was .95, indicating that the Serbian PHQ-9 can discriminate very well between persons with/without MDE. CONCLUSIONS: When the PHQ-9 is assessed against the structured diagnostic interview in the general population to detect depression, the cut-off of ≥8 balances best sensitivity and specificity.

A Comparative Study on Mental Disorder Conceptualization: A Cross-Disciplinary Analysis.

The conceptualization of mental disorders varies among professionals, impacting diagnosis, treatment, and research. This cross-disciplinary study aimed to understand how various professionals, including psychiatrists, psychologists, medical students, philosophers, and social sciences experts, perceive mental disorders, their attitudes towards the disease status of certain mental states, and their emphasis on biological versus social explanatory attributions. A survey of 371 participants assessed their agreement on a variety of conceptual statements and the relative influence of biological or social explanatory attribution for different mental states. Our findings revealed a consensus on the need for multiple explanatory perspectives in understanding psychiatric conditions and the influence of social, cultural, moral, and political values on diagnosis and classification. Psychiatrists demonstrated balanced bio-social explanatory attributions for various mental conditions, indicating a potential shift from the biological attribution predominantly observed among medical students and residents in psychiatry. Further research into factors influencing these differing perspectives is necessary.

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

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.

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

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.

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

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.

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.

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.

Sex differences in facial emotion recognition in health and psychotic disorders.

BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

On the origin of schizophrenia: Testing evolutionary theories in the post-genomic era.

Considering the relatively high heritability of schizophrenia and the fact that it significantly reduces the reproductive fitness of affected individuals, it is not clear how the disorder is still maintained in human populations at a disproportionally high prevalence. Many theories propose that the disorder is a result of a trade-off between costs and benefits of the evolution of exclusively human adaptations. There have also been suggestions that schizophrenia risk alleles are accompanied with increase in fitness of affected persons or their relatives in both past and current social contexts. The discoveries of novel schizophrenia-related genes and the advancements in comparative genomics (especially comparisons of the human genome and the genomes of related species, such as chimpanzees and extinct hominids) have finally made certain evolutionary theories testable. In this paper, we review the current understanding of the genetics of schizophrenia, the basic principles of evolution that complement our understanding of the subject, and the latest genetic studies that examine long-standing evolutionary theories of schizophrenia using novel methodologies and data. We find that the origin of schizophrenia is complex and likely governed by different evolutionary mechanisms that are not mutually exclusive. Furthermore, the most recent evidence implies that schizophrenia cannot be comprehended as a trait that has elevated fitness in human evolutionary lineage, but has been a mildly deleterious by-product of specific patterns of the evolution of the human brain. In other words, novel findings do not support previous hypotheses stating that schizophrenia risk genes have an evolutionary advantage.

The emerging role of the FKBP5 gene polymorphisms in vulnerability-stress model of schizophrenia: further evidence from a Serbian population.

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.

Improving Current Treatments for Schizophrenia.

Preclinical Research After the identification of the schizophrenia as an illness over a century ago, treatment of affected individuals included unspecific, mostly very robust methods including deep insulin coma and lobectomy/leucotomy. The first relatively specific treatment of schizophrenia started about 60 years ago with the antipsychotic chlorpromazine. All currently approved antipsychotic drugs block dopamine receptors, indicating that manipulation of dopaminergic function is fundamental to a therapeutic response in psychosis. Despite refinements in their mechanism of action, the therapeutic effects of subsequent generations of antipsychotics are insufficient in claiming superiority over the first generation, with the possible exception of clozapine. Dopamine receptor blockade is necessary but not always sufficient for antipsychotic response and improvements have been reported with molecules acting on other receptors (glutamate, glycine, cannabidiol, estrogen), intracellular signaling proteins, or products of identified risk genes. Here, we review the current status of drugs under investigation. In addition, we emphasize that the development of the novel compounds to target the underlying cognitive dysfunction and negative symptom dimension of full blown schizophrenia, or attenuated psychosis syndrome and specific endophenotypes related to the increased risk of psychosis in the general population, alongside efforts to deconstruct the concept of schizophrenia(s), represent the best way to meet patient needs for better therapies and more favorable outcomes. Drug Dev Res 77 : 357-367, 2016. © 2016 Wiley Periodicals, Inc.

Lymphocyte levels of redox-sensitive transcription factors and antioxidative enzymes as indicators of pro-oxidative state in depressive patients.

BACKGROUND: Oxidative stress is reliably observed in major depressive disorder (MDD). However, molecular data on the principal cellular redox-sensitive transcriptional factors and the levels of their downstream-regulated antioxidant enzymes in MDD are scarce. METHODS: In the peripheral blood mononuclear cells (PBMC) of subjects with a current episode of MDD (n = 30) and healthy controls (n = 35), we investigated alterations in the levels of redox-sensing nuclear factor (erythroid-derived 2)-like 2 (Nrf2) protein, its inhibitor Keap1, and nuclear factor-κB (NF-κB), along with their cognate downstream effectors, the antioxidant enzymes (AOEs): manganese and copper zinc superoxide dismutase (MnSOD and CuZnSOD, respectively), catalase (CAT), glutathione peroxidase (GPx) and glutathione reductase (GLR). RESULTS: MDD subjects exhibited higher levels of Nrf2 and its regulator Keap1, as well as NF-κB in the cytoplasm of PBMC compared to controls. This state was further reflected by increased levels of MnSOD, CuZnSOD and CAT proteins and by the lack of correlation between MnSOD and CAT, which could indicate impaired oxidative detoxification capacity in MDD patients. Moreover, increased levels of MnSOD, CuZnSOD and CAT in MDD patients positively correlated with levels of Nrf2, while increased levels of SODs were also positively related to NF-κB. There were no differences regarding the levels of GPx and GLR proteins, but the ratio of GLR/GPx was reduced, suggesting diminished capacity of GPx in antioxidative defence in PBMC of MDD subjects. CONCLUSION: These data provide evidence that MDD is characterized by up-regulation of redox-sensitive transcriptional factors (Nrf2 and NF-κB) and AOEs (MnSOD, CuZnSOD and CAT), indicating pro-oxidative state in the PBMC of MDD patients.

Electroconvulsive therapy practice in Serbia today.

This is the first survey of the practice of electroconvulsive therapy (ECT) in the Republic of Serbia. A retrospective chart review was undertaken including all patients having received ECT in Serbia in 2012. Only one center in Serbia offered ECT in 2012 to a total of 54 patients (54% women). Thirty-six (36) patients received acute ECT treatment and eighteen (18) patients maintenance ECT, yielding a ECT utilization rate of 0.05/100.000 population. ECT was delivered with a modern square-wave (brief pulse) machine with EEG and ECG monitoring. In all cases the electrode placement was bifrontal and treatment modified (with anesthesia). The most frequent indication was recurrent depressive disorder (66.7%) for both acute and maintenance treatment. The limited availability of ECT in Serbia raises serious concerns. Provision of updated and effective treatment modalities for severe psychiatric disorders is crucial and the need for additional ECT services in Serbia is urgent.

Pharmacological modulation of HPA axis in depression - new avenues for potential therapeutic benefits.

One of the most consistent biological findings in major depression (MDD) is the altered activity of the hypothalamic-pituitary-adrenal (HPA) axis. It is not surprising that glucocorticoid receptor (GR), the common mechanism for stress-related changes in brain function, is a potential target of antidepressant drugs and therapies. All effective antidepressant treatments should trigger and maintain GR-related cellular processes necessary for recovery from MDD. Classic antidepressants act indirectly, by affecting the dynamic interplay between serotonin neurotransmission and HPA. On the other hand, certain compounds acting at supra-hypothalamic, HPA axis, glucocorticoid receptors, and post-receptor levels are being considered as new therapeutic options with the potential to modulate the aforementioned system in affective disorders directly. Different classes of drugs pharmacologically modify the HPA axis. This article summarizes the efficacy of classic antidepressants, as well as drugs classified as "antiglucocorticoids" (GR agonists, GR antagonists, dehydroepiandrosterone- DHEA, steroid synthesis inhibitors drugs, etc) in their capacity to heal glucocorticoid-mediated damage in depression. New avenues investigating the potential therapeutic benefits of antiglucocorticoids in affective disorders are at the proof-of-concept stage and future developments in this area deserve the full attention of psychiatrists and neuroscientists, as the current pharmacological treatment of MDD is far from perfect.

Metabolic issues in psychotic disorders with the focus on first-episode patients: a review.

Before the onset of the illness, future schizophrenia patients do not weigh more comparing to their peers. However, during the later course of the illness, obesity is twice as prevalent as in general public, afflicting the half of schizophrenia patient population. There is a list of potential factors that contribute to this, including lifestyle, dietary habits, unsatisfactory monitoring of physical health etc, but nowadays side effects of antipsychotic medication become the most prominent concern when weight gain and metabolic issues in psychosis are addressed. The fact is that second generation antipsychotics (SGA) are associated with weight gain and metabolic syndrome, but that might be the case with the first generation antipsychotics (FGA) too. Besides, obesity might be evident in patients before any exposure to medications, and all that bring lot of dilemmas into the field. This paper critically reviews available data on metabolic problems in patients with psychotic disorders, raging from genetic to molecular and environmental factors, and highlights the necessity of screening for the early signs of metabolic disturbances, as well as of multidisciplinary assessment of psychiatric and medical conditions from the first psychotic episode.

Algorithms in psychiatry: state of the art.

INTRODUCTION: In literature, algorithms (guidelines) are often synonymous with problem-solving procedures. The importance of using algorithms in psychiatry can be seen in many areas. For physicians, algorithms ease clinical decision making, provide an adequate clinical basis for therapy, stimulate research, and stimulate sources of financing. For users of psychiatric services, algorithms tailor treatment to the individual, enhance the standard of care by using efficient therapeutic techniques, improve outcome, cut costs, and provide continuity of care after hospital treatment. AIM: Our goal with this paper is to present the advantages of using algorithms, but also to advise caution in their application. It is important to be aware and critical of limitations present in algorithm use. METHODS: A MEDLINE and KOBSON search was conducted combining the following key words and phrases: "treatment guidelines"; "algorithms"; "psychiatry"; "bipolar"; "depression"; "schizophrenia". RESULTS: We investigated the advantages and disadvantages of algorithms presented in the publications we found in our search. CONCLUSION: We consider algorithms to be a necessary component in the treatment of psychiatric patients, but recommend that one should maintain a critical attitude and remember that guideline proposed therapy should always be tailored to the individual.

Theory of Mind in Typical Adults: Sex-Differences and Its Associations with Anxiety and Depression Symptoms.

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.

Factor structure of the brief psychiatric rating scale-expanded among outpatients with psychotic disorders in five Southeast European countries: evidence for five factors.

The Brief Psychiatric Rating Scale (BPRS) is a useful tool for measuring the severity of psychopathological symptoms among patients with psychosis. Many studies, predominantly in Western countries, have investigated its factor structure. This study has the following aims: (a) to further explore the factor structure of the BPRS-Expanded version (BPRS-E, 24 items) among outpatients with psychotic disorders in Southeast European countries; (b) to confirm the identified model; and (c) to investigate the goodness-of-fit of the three competing BPRS-E factor models derived from previous studies. The exploratory factor analysis (EFA) produced a solution with 21 items grouped into five factors, thus supporting the existence of a fifth factor, i.e., Disorganization. A follow-up confirmatory factor analysis (CFA) revealed a 19-item model (with two items removed) that fit the data well. In addition, the stability of two out of three competing factor models was confirmed. Finally, the BPRS-E model with 5 factors developed in this cross-national study was found to include a greater number of items compared to competing models.

Examining the association between exposome score for schizophrenia and cognition in schizophrenia, siblings, and healthy controls: Results from the EUGEI study.

BACKGROUND: People with schizophrenia spectrum disorders (SSD) frequently present cognitive impairments. Here, we investigated whether the exposome score for schizophrenia (ES-SCZ) - a cumulative environmental exposure score - was associated with impairments of neurocognition, social cognition, and perception in patients with SSD, their unaffected siblings, and healthy controls. METHODS: This cross-sectional sample consisted of 1200 patients, 1371 siblings, and 1564 healthy controls. Neurocognition, social cognition, and perception were assesed using a short version of the Wechsler Adult Intelligence Scale-Third Edition (WAIS-III), the Degraded Facial Affect Recognition Task (DFAR), and the Benton Facial Recognition Test (BFR), respectively. Regression models were used to analyze the association between ES-SCZ and cognitive domains in each group. RESULTS: There were no statistically significant associations between ES-SCZ and cognitive domains in SSD. ES-SCZ was negatively associated with T-score of cognition in siblings (B=-0.40, 95% CI -0.76 to -0.03) and healthy controls (B=-0.63, 95% CI -1.06 to -0.21). Additionally, ES-SCZ was positively associated with DFAR-total in siblings (B=0.83, 95% CI 0.26 to 1.40). Sensitivity analyses excluding cannabis use history from ES-SCZ largely confirmed the main findings. CONCLUSIONS: Longitudinal cohorts may elucidate how environmental exposures influence the onset and course of cognitive impairments in trans-syndromic psychosis spectrum.

Why schizophrenia genetics needs epigenetics: a review.

Schizophrenia (SZ) is a highly heritable disorder, with about 80% of the variance attributable to genetic factors. There is accumulating evidence that both common genetic variants with small effects and rare genetic lesions with large effects determine risk of SZ. As recently shown, thousands of common single nucleotide polymorphisms (SNPs), each with small effect, cumulatively could explain about 30% of the underlying genetic risk of SZ. On the other hand, rare and large copy number variants (CNVs) with high but incomplete penetrance, variable in different individual, could explain about additional 30% of SZ cases. Although these rare CNVs frequently develop de novo, it is not clear whether they affect risk independently or via interaction with a polygenic liability in the background. Finally, the role of environmental risk factors has been well established in SZ. Environmental factors are rarely sufficient to cause SZ independently, but act in parallel or in synergy with the underlying genetic liability. Epigenetic misregulation of the genome and direct CNS injury are probably the main mechanism to mediate prenatal environmental effects (e.g., viruses, ethanol, or nutritional deficiency) whereas postnatal risk factors (e.g., stress, urbanicity, cannabis use) may also affect risk via use-based potentiation of vulnerable CNS pathways implicated in SZ. In this review, we outline a general theoretical background of epigenetic mechanisms involved in GxE interactions, and then discuss epigenetic and neurodevelopmental features of SZ based on available information from genetics, epigenetics, epidemiology, neuroscience, and clinical research. We argue that epigenetic model of SZ provides a framework to integrate a variety of diverse empirical data into a powerful etiopathogenetic synthesis. The promising future of this model is the possibility to develop truly specific prevention and treatment strategies for SZ.

Maintenance Therapy of Psychosis Spectrum Disorders in a Real-World Setting: Antipsychotics Prescription Patterns and Long-Term Benzodiazepine Use.

Background: Maintenance therapy of patients with primary psychosis spectrum disorders (PSD) in the Western Balkans has received limited interest so far. The present study aimed to investigate long-term prescription patterns among outpatients with PSD. Methods: Information about prescription of antipsychotics (AP), benzodiazepines (BZD) and other psychotropic medication over a 6-month period was collected from outpatients (n = 134; ICD-10 diagnosis F20-29) recruited by a larger multi-site study, to find mean daily number of psychotropic drugs, AP prescription patterns (including AP daily dose, route of administration, monotherapy vs. polypharmacy) and BZD utilization (long-term add-on BZD therapy). Additionally, sex-differences in the variables were explored. Results: Clinically stable outpatients (age 41.7 ± 11.0; male 62.7%; duration of untreated illness 12.7 ± 8.7 years; mean number of lifetime hospitalizations 2.6 ± 0.7) were prescribed 2.8 ± 1.1 psychotropic medications daily. The mean 6-month AP dose was 14.2 ± 7.8 mg olanzapine equivalents. Long-acting injectable AP was prescribed to 25.2% of the patients. Long-term AP monotherapy was found in 52.7% patients and most of them were prescribed second generation AP (65.2%). Long-term AP polypharmacy (42.7%) was more common in males (p = 0.015). The most frequent co-prescription patterns were first generation AP plus clozapine. The highest rate of long-term AP co-prescription was found for BZD (in 42.7% cases, average 6-months daily dose of 2.8 ± 2.7 mg lorazepam equivalents) and anticholinergics (33.6%). Conclusion: Existing appropriately designed interventions aiming to safely switch the inappropriate therapeutic regimens, i.e. very high prevalence of long-term AP polypharmacy and non-rational BZD co-prescription, should be implemented in the region of Western Balkans.