Background: Maintenance therapy of patients with primary psychosis spectrum disorders (PSD) in th... more 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 longterm 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.
Despite national and international guidelines recommending inclusion of psychotherapy and psychos... more Despite national and international guidelines recommending inclusion of psychotherapy and psychosocial interventions as regular part of treatment for patients with psychosis spectrum disorders (PSD), outpatient psychiatric care in Southeastern Europe (SEE) is mostly limited to medication prescription. DIALOG+ is a recently developed technology-based, patient centered psychosocial intervention that provides an economically viable intervention for treatment and comprehensive evaluation of multiple life domains. Its effectiveness in a range of psychiatric disorders has been shown in several studies conducted in high-income countries. Before an ongoing study evaluating DIALOG+ implementation and effectiveness in developing SEE countries is completed, we aimed to explore general impressions of mental health clinicians towards such an intervention and to compare the duration of treatment as usual (TAU) with DIALOG+ enriched appointments of PSD outpatients. The attendees of the national pr...
Background A cumulative environmental exposure score for schizophrenia (exposome score for schizo... more Background A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. Methods This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. Results ES-SCZ was associated with the GAF dimensions in patients (symptom: B = −1.53, p-value = 0.001; disabilit...
Hypothalamic-pituitary-adrenal (HPA) axis activity mediates the relationship between childhood tr... more 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.
BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectru... more 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 = ...
Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing t... more 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 bas...
BackgroundUbiquitous negative emotional states such as depression, anxiety and stress in adulthoo... more BackgroundUbiquitous negative emotional states such as depression, anxiety and stress in adulthood are related to individual life scenario, particularly influenced by exposure to environmental risk factors. Here, we investigated if sub-threshold negative emotional states in general population can be predicted by experience of trauma in the childhood.MethodA sample of 106 healthy young adult participants from Belgrade and surroundings (43.4% male, age 29.2 ± 6.6 years, mean IQ 106.4 ± 15.9) fulfilled Childhood Trauma Questionnaire (CTQ) to identify emotional or physical abuse/neglect or sexual abuse. Present level of negative affectivity was measured by Depression Anxiety Stress Scale (DASS). Hierarchical linear regression analysis was conducted to identify subtypes of trauma as predictors of the negative affectivity.ResultsMean CTQ and DASS scores were 31.2 ± 6.7 and 16.4 ± 16.8, respectively. An exposure to given risk factors in the past correlated significantly with intensity of t...
There is much concern about the widespread long-term use of benzodiazepines. Our manuscript addre... more 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 5 mg 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 sociodemographic 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 coprescribed 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.
IntroductionCurrent knowledge about the advantages of using split version of GAF scale – having s... more IntroductionCurrent knowledge about the advantages of using split version of GAF scale – having separate Symptom (GAF-S) and Functioning (GAF-F) subscales is insufficient and has number of gaps. Present study analyzed the manner in which young adult remitted psychotic patients with different functional levels vary in their symptom severity and how GAF-F reflects presence/absence of well-known psychosis risk factors.MethodsSample comprised 37 remitted psychotic patients (56.8% male, 29.4 ± 6.1 years), categorized based on GAF-F scores into groups: ‘Moderate remission’ (GAF-F 41–60, n = 19) and “Good remission” (GAF-F > 61, n = 18). Participants were assessed using the GAF-S, WAIS-R, Nottingham Onset Schedule, Premorbid Adjustment and Brief Core Schema scales, childhood trauma and bullying questionnaires. Mann–Whitney and Student's t-tests were used to assess between-group differences.ResultsGroups did not differ in age, sex and education. When compared to “Good remission” grou...
The impaired glucocorticoid receptor (GR) signaling has long been considered one of cornerstones ... more The impaired glucocorticoid receptor (GR) signaling has long been considered one of cornerstones in understanding the pathophysiology of depression. Phosphorylation of GR is very important for GR function, therefore we investigated: a) whether GR phosphorylation at serine 211 (pGR-S211) and serine 226 (pGR-S226) is altered in patients with episode of major depressive disorder (MDD); b) if neuroticism and negative affective states may be associated with altered GR phosphoisophorms of healthy adults. Phosphorylation at these sites is generally considered to be indicative of receptor activity. We studied leucocytes of : a) 30 MDD patients and 35 controls, andb) 37 healthy subjects, to assess the levels of nuclear total GR (tGR), pGR-S211 and pGR-S226 using Western blot technique. Our results demonstrated increased phosphorylation of GR at S226 and, to a less extent, at S211 in MDD compared to controls. Also, pGR-S226 positively correlated with neuroticism and self report of stress in healthy. In MDD, the pGRS211/ pGR-S226 ratio was decreased (p < 0.05) implying reduced transcriptional activity of GR in patients. In healthy, pGRS211/ pGR-S226 was negatively correlated with self-repored subclinical depression. MDD had higher cortisol levels than others and cortisol concentrations positively correlated with S226 levels from the same blood samples. We examined whether easily accessible peripheral markers of GR activity and disease status in depression exist. Although we examined leucocytes, we propose that reduced GR transcriptional activity could be one of mechanisms of impaired GR function in the brain, resulting in dysfunction of HPA axis observed as a risk for depression.
Dve decenije nakon što je Svetska Zdravstvena Organizacija ozvaničila desetu reviziju Međunarodne... more Dve decenije nakon što je Svetska Zdravstvena Organizacija ozvaničila desetu reviziju Međunarodne klasifikacije bolesti (MKB-10) i Američka asocijacija psihijatara objavila četvrto izdanje Dijagnostičkog i statističkog priručnika za mentalne poremećaje (DSM-IV), stručnoj javnosti je predstavljena naredna revizija datih klasifikacija (MKB-11 i DSM-5). U aktuelnom revijalnom radu uporedno su prikazane glavne novine koje MKB-11 i DSM-5 donose u pogledu kategorizacije i dijagnostičkih kriterijuma za poremećaje iz spektra psihoza, uz osvrt na najznačajnije razlike između pomenutih klasifikacionih sistema. Novine se odnose na eliminisanje kliničkih suptipova shizofrenije, modifikaciju dijagnostičkih kriterijuma za shizofreniju i shizoafektivni poremećaj, kao i rekonceptualizaciju katonije. Uz to, nove klasifikacije naglašavaju značaj
Introduction: Fluid intelligence is described as ability to rapidly solve novel problems and capa... more Introduction: Fluid intelligence is described as ability to rapidly solve novel problems and capacity to manage and easily adapt to new situations. Crystallized intelligence reflects ability to timely use lifetime-learned information and skills. Bearing in mind that intelligence is one of the impaired cognitive functions in psychosis, a question arises there are if any sex differences in patients, regarding total IQ, fluid or crystallized intelligence. Aim: To evaluate sex differences in psychosis and to analyze the differences between patients and sex, age and origin matched healthy controls. Materials and methods: This cross-sectional study evaluated schizophrenia spectrum patients (F20-29 based on ICD10; n = 52, age = 29,3±5,9 years, illness duration <10 years) and controls (n = 51, age = 29,8±6,3 years). Descriptive and inferential statistics were used to analyze data. Results: Analyzing sex differences in total IQ, fluid and crystalized IQ, it has been found that women exhibited lower crystallized intelligence scores both in the patient group (p = 0,039) and in the control group (p = 0,016). Among male patients, lower scores were found in comparison to the healthy male controls in all of the categories, while female patients scores in crystallized intelligence were not significantly different in comparison to female healthy group ((p = 0,160). Conclusion: In the male subjects with psychosis, a deficit was found in both subdomains of intelligence, while in female subjects it was found in fluid intelligence only. Factors which could serve as protective from greater cognitive impairment in female patients need further evaluation, as a sign of potential mechanisms that could ameliorate the course and prognosis of schizophrenia spectrum disorders.
Important questions remain about the profile of cognitive impairment in psychotic disorders acros... more 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.
Background First-degree relatives of patients with psychotic disorder have higher levels of polyg... more 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 be...
Before the onset of the illness, future schizophrenia patients do not weigh more comparing to the... more 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, ...
Background Data on benzodiazepine (BZD) use of on a long term basis (≥6 months) in outpatients wi... more 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 ...
Background: Maintenance therapy of patients with primary psychosis spectrum disorders (PSD) in th... more 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 longterm 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.
Despite national and international guidelines recommending inclusion of psychotherapy and psychos... more Despite national and international guidelines recommending inclusion of psychotherapy and psychosocial interventions as regular part of treatment for patients with psychosis spectrum disorders (PSD), outpatient psychiatric care in Southeastern Europe (SEE) is mostly limited to medication prescription. DIALOG+ is a recently developed technology-based, patient centered psychosocial intervention that provides an economically viable intervention for treatment and comprehensive evaluation of multiple life domains. Its effectiveness in a range of psychiatric disorders has been shown in several studies conducted in high-income countries. Before an ongoing study evaluating DIALOG+ implementation and effectiveness in developing SEE countries is completed, we aimed to explore general impressions of mental health clinicians towards such an intervention and to compare the duration of treatment as usual (TAU) with DIALOG+ enriched appointments of PSD outpatients. The attendees of the national pr...
Background A cumulative environmental exposure score for schizophrenia (exposome score for schizo... more Background A cumulative environmental exposure score for schizophrenia (exposome score for schizophrenia [ES-SCZ]) may provide potential utility for risk stratification and outcome prediction. Here, we investigated whether ES-SCZ was associated with functioning in patients with schizophrenia spectrum disorder, unaffected siblings, and healthy controls. Methods This cross-sectional sample consisted of 1,261 patients, 1,282 unaffected siblings, and 1,525 healthy controls. The Global Assessment of Functioning (GAF) scale was used to assess functioning. ES-SCZ was calculated based on our previously validated method. The association between ES-SCZ and the GAF dimensions (symptom and disability) was analyzed by applying regression models in each group (patients, siblings, and controls). Additional models included polygenic risk score for schizophrenia (PRS-SCZ) as a covariate. Results ES-SCZ was associated with the GAF dimensions in patients (symptom: B = −1.53, p-value = 0.001; disabilit...
Hypothalamic-pituitary-adrenal (HPA) axis activity mediates the relationship between childhood tr... more 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.
BackgroundThere is evidence that environmental and genetic risk factors for schizophrenia spectru... more 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 = ...
Exposures constitute a dense network of the environment: exposome. Here, we argue for embracing t... more 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 bas...
BackgroundUbiquitous negative emotional states such as depression, anxiety and stress in adulthoo... more BackgroundUbiquitous negative emotional states such as depression, anxiety and stress in adulthood are related to individual life scenario, particularly influenced by exposure to environmental risk factors. Here, we investigated if sub-threshold negative emotional states in general population can be predicted by experience of trauma in the childhood.MethodA sample of 106 healthy young adult participants from Belgrade and surroundings (43.4% male, age 29.2 ± 6.6 years, mean IQ 106.4 ± 15.9) fulfilled Childhood Trauma Questionnaire (CTQ) to identify emotional or physical abuse/neglect or sexual abuse. Present level of negative affectivity was measured by Depression Anxiety Stress Scale (DASS). Hierarchical linear regression analysis was conducted to identify subtypes of trauma as predictors of the negative affectivity.ResultsMean CTQ and DASS scores were 31.2 ± 6.7 and 16.4 ± 16.8, respectively. An exposure to given risk factors in the past correlated significantly with intensity of t...
There is much concern about the widespread long-term use of benzodiazepines. Our manuscript addre... more 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 5 mg 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 sociodemographic 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 coprescribed 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.
IntroductionCurrent knowledge about the advantages of using split version of GAF scale – having s... more IntroductionCurrent knowledge about the advantages of using split version of GAF scale – having separate Symptom (GAF-S) and Functioning (GAF-F) subscales is insufficient and has number of gaps. Present study analyzed the manner in which young adult remitted psychotic patients with different functional levels vary in their symptom severity and how GAF-F reflects presence/absence of well-known psychosis risk factors.MethodsSample comprised 37 remitted psychotic patients (56.8% male, 29.4 ± 6.1 years), categorized based on GAF-F scores into groups: ‘Moderate remission’ (GAF-F 41–60, n = 19) and “Good remission” (GAF-F > 61, n = 18). Participants were assessed using the GAF-S, WAIS-R, Nottingham Onset Schedule, Premorbid Adjustment and Brief Core Schema scales, childhood trauma and bullying questionnaires. Mann–Whitney and Student's t-tests were used to assess between-group differences.ResultsGroups did not differ in age, sex and education. When compared to “Good remission” grou...
The impaired glucocorticoid receptor (GR) signaling has long been considered one of cornerstones ... more The impaired glucocorticoid receptor (GR) signaling has long been considered one of cornerstones in understanding the pathophysiology of depression. Phosphorylation of GR is very important for GR function, therefore we investigated: a) whether GR phosphorylation at serine 211 (pGR-S211) and serine 226 (pGR-S226) is altered in patients with episode of major depressive disorder (MDD); b) if neuroticism and negative affective states may be associated with altered GR phosphoisophorms of healthy adults. Phosphorylation at these sites is generally considered to be indicative of receptor activity. We studied leucocytes of : a) 30 MDD patients and 35 controls, andb) 37 healthy subjects, to assess the levels of nuclear total GR (tGR), pGR-S211 and pGR-S226 using Western blot technique. Our results demonstrated increased phosphorylation of GR at S226 and, to a less extent, at S211 in MDD compared to controls. Also, pGR-S226 positively correlated with neuroticism and self report of stress in healthy. In MDD, the pGRS211/ pGR-S226 ratio was decreased (p < 0.05) implying reduced transcriptional activity of GR in patients. In healthy, pGRS211/ pGR-S226 was negatively correlated with self-repored subclinical depression. MDD had higher cortisol levels than others and cortisol concentrations positively correlated with S226 levels from the same blood samples. We examined whether easily accessible peripheral markers of GR activity and disease status in depression exist. Although we examined leucocytes, we propose that reduced GR transcriptional activity could be one of mechanisms of impaired GR function in the brain, resulting in dysfunction of HPA axis observed as a risk for depression.
Dve decenije nakon što je Svetska Zdravstvena Organizacija ozvaničila desetu reviziju Međunarodne... more Dve decenije nakon što je Svetska Zdravstvena Organizacija ozvaničila desetu reviziju Međunarodne klasifikacije bolesti (MKB-10) i Američka asocijacija psihijatara objavila četvrto izdanje Dijagnostičkog i statističkog priručnika za mentalne poremećaje (DSM-IV), stručnoj javnosti je predstavljena naredna revizija datih klasifikacija (MKB-11 i DSM-5). U aktuelnom revijalnom radu uporedno su prikazane glavne novine koje MKB-11 i DSM-5 donose u pogledu kategorizacije i dijagnostičkih kriterijuma za poremećaje iz spektra psihoza, uz osvrt na najznačajnije razlike između pomenutih klasifikacionih sistema. Novine se odnose na eliminisanje kliničkih suptipova shizofrenije, modifikaciju dijagnostičkih kriterijuma za shizofreniju i shizoafektivni poremećaj, kao i rekonceptualizaciju katonije. Uz to, nove klasifikacije naglašavaju značaj
Introduction: Fluid intelligence is described as ability to rapidly solve novel problems and capa... more Introduction: Fluid intelligence is described as ability to rapidly solve novel problems and capacity to manage and easily adapt to new situations. Crystallized intelligence reflects ability to timely use lifetime-learned information and skills. Bearing in mind that intelligence is one of the impaired cognitive functions in psychosis, a question arises there are if any sex differences in patients, regarding total IQ, fluid or crystallized intelligence. Aim: To evaluate sex differences in psychosis and to analyze the differences between patients and sex, age and origin matched healthy controls. Materials and methods: This cross-sectional study evaluated schizophrenia spectrum patients (F20-29 based on ICD10; n = 52, age = 29,3±5,9 years, illness duration <10 years) and controls (n = 51, age = 29,8±6,3 years). Descriptive and inferential statistics were used to analyze data. Results: Analyzing sex differences in total IQ, fluid and crystalized IQ, it has been found that women exhibited lower crystallized intelligence scores both in the patient group (p = 0,039) and in the control group (p = 0,016). Among male patients, lower scores were found in comparison to the healthy male controls in all of the categories, while female patients scores in crystallized intelligence were not significantly different in comparison to female healthy group ((p = 0,160). Conclusion: In the male subjects with psychosis, a deficit was found in both subdomains of intelligence, while in female subjects it was found in fluid intelligence only. Factors which could serve as protective from greater cognitive impairment in female patients need further evaluation, as a sign of potential mechanisms that could ameliorate the course and prognosis of schizophrenia spectrum disorders.
Important questions remain about the profile of cognitive impairment in psychotic disorders acros... more 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.
Background First-degree relatives of patients with psychotic disorder have higher levels of polyg... more 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 be...
Before the onset of the illness, future schizophrenia patients do not weigh more comparing to the... more 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, ...
Background Data on benzodiazepine (BZD) use of on a long term basis (≥6 months) in outpatients wi... more 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 ...
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