Maintenance phase treatment of psychotic disorders in outpatients from Serbia - focus on long-term benzodiazepine use.

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 321 mg 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 psychotropic drugs was 3. Benzodiazepines were continually prescribed to more than 60% of patients (mean daily dose 2.9 ± 2.0 mg lorazepam equivalents). Patients with benzodiazepine use had significantly more psychotropic medications and more antipsychotic polypharmacy, poorer quality of life and more severe psychopathology 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.KeypointsPresent exploratory research aimed to elucidate trends of antipsychotics polypharmacy and concomitant use of psychotropic medications including benzodiazepines in the maintenance treatment of outpatients with schizophrenia and other psychotic disorders, amplified with clinically relevant information (symptoms and quality of life).'Antipsychotic (AP) polypharmacy' was defined as concurrent use of more than one AP for at least 1 month; 'Psychotropic polypharmacy' was defined as the combination of AP and a different class of psychotropic drugs medication for at least one month.The median number of prescribed psychotropic drugs was 3 (mean 3.1 ± 1.1) and the average AP daily dose was moderate (median 321 mg of chlorpromazine equivalents). However, the rates of AP polypharmacy (45.2%) and benzodiazepine prescription on a continual basis (>60%) found in our sample could be considered relatively high.Outpatients with higher AP daily dose and higher BPRS symptom score were receiving more benzodiazepines.For improvement of the local, as well as general clinical practice and care for patients with psychotic disorders, and for education in psychiatry, such analyses need to be done on a regular basis and on larger samples.

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.

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.

Trend of suicide by self-immolation in a 13-year timeline: was the COVID-19 pandemic a potentially important stressor?

Introduction: Self-immolation is an uncommon way of attempting and committing a suicide, with a fatality rate of 80%. The risk factors in self-immolation victims vary depending on demographic characteristics, socio-economic and cultural factors as well as religious beliefs. Whether the COVID-19 pandemic was a potentially important stressor for self-immolation is still unknown, with insufficient studies examining this issue. Therefore, in this study, we aimed to examine the trend of self-immolation in a 13-year timeline, and the potential association of COVID-19 pandemic with the increase in the incidence and severity of self-immolation injuries in Serbia in 2021. Materials and methods: The study included hospitalized patients due to intentional burns caused by self-immolation in the period from January 1, 2008 to December 31, 2021. Joinpoint regression analysis was used for the analysis of continuous linear trends of self-immolation cases with change points. Results: While a rising trend was observed in the 2008-2013 time segment, followed by a decline in the upcoming 2013-2016 time segment, a significant increase reached its maximum during COVID-19 pandemic (2021), with annual percent change of 37.1% (p = 0.001). A significant increase in the median number of cases per year was observed during 2021 compared to the previous periods (7.5 vs. 2). Frequency of patients with a psychiatric diagnosis vs. those without a psychiatric diagnosis was significantly higher during than before the COVID-19 period (66.7 vs. 36.1%, p = 0.046). Conclusion: In our study, a significant increase in the frequency of suicide attempts by self-immolation during COVID-19 pandemic was noticed. There was also an increased frequency of pre-existing psychiatric illness among patients during the pandemic period. With limited high-quality data available, the study adds to a rising body of evidence for assessment of outcomes of the pandemic on mental health and recognition of stressors for self-immolation.

Smartphone addiction, sleep quality, depression, anxiety, and stress among medical students.

Introduction: Studies consistently link excessive smartphone use to poor sleep quality, depression, anxiety, and stress. This study specifically aimed to investigate these associations among medical students in Belgrade and Nis (Central Serbia). Materials and methods: The cross-sectional study included a sample of 761 students, who were selected from both the Faculties of Medicine at the University of Belgrade and the University of Nis. Questionnaires, including the International Physical Activity Questionnaire - Short Form (IPAQ-SF), Smartphone Addiction Scale - Short Version (SAS-SV), the Pittsburgh Sleep Quality Index (PSQI), and the Depression, Anxiety, and Stress Scale - 21 items (DASS-21), were completed by the participants. Statistical analysis techniques, such as the Chi-square test, student's t-test, and logistic regression, were employed to examine the relationship between smartphone addiction, physical activity, sleep quality, depression, anxiety, and stress. Results: The findings indicated a prevalence of smartphone addiction among medical students at 21.7%, with rates of 22.9% among males and 21.1% among females. Females exhibited significantly higher scores on the SAS-SV scale compared to males (p = 0.032). Univariate logistic regression analysis revealed significant associations between smartphone addiction and spending over 4 h daily on smartphones (OR = 2.39; p < 0.001), poor sleep quality (OR = 1.65; p = 0,005), as well as elevated levels of stress (OR = 1.75; p = 0.003), anxiety (OR = 2.04; p < 0.001), and depression (OR = 2.29; p < 0.001). Multivariate regression analysis identified spending more than 4 h daily on smartphones (OR = 2.39; p < 0.001) and increased levels of depression (OR = 2.51; p < 0.001) as independent significant factors associated with smartphone addiction. Conclusion: This study sheds light on the prevalence of smartphone addiction among medical students, with spending excessive time on smartphones and higher levels of depression standing out as significant factors. Future research should delve into the underlying mechanisms and causal relationships between smartphone addiction and these psychosocial factors. Understanding these connections will aid in developing effective interventions and strategies to tackle this growing public health concern.

Depressive symptoms in patients with hepatitis C treated with pegylated interferon alpha therapy: a 24-week prospective study.

OBJECTIVE: To prospectively evaluate depressive symptoms and risk factors for depression in patients with chronic hepatitis C (CHC) treated with pegylated interferon alpha therapy combined with oral ribavirin (PEG-IFN-α+RBV) and to analyze self-rating scale for depression in comparison to observer-based scale in the given population. SUBJECTS AND METHODS: The Hamilton Depression Rating Scale and Zung Self Rating Depression Scale were used to screen for depressive symptoms in 74 subjects with CHC before PEG- IFN-α (mean dose 152.6±25.6 mcg), and in the follow-up visits (4, 12 and 24 week). RESULTS: Incidence of depressive symptoms in patients (mean age 39.9±13.4 years; equal sex distribution p=0.225) treated by PEG- IFN-α was the highest on 12th week of the treatment, when more than a 20% of our sample had moderate/severe symptoms of depression, and about 30% had minor depressive symptoms. For the screening of depression during PEG- IFN-α self-assessment scale was equally reliable as observer-based assesment of depressive symptoms. Common clinical parameters- subject related risk factors (age (p=0.955 ), sex (p=0.008), lifetime psychiatric disorder (p=0.656)), illness related risk factors (duration of CHC (p=0.267 ), i.v drug aplication as way of transmission (p=0.292)) and therapy-related risk factors (recommended duration of PEG-IFN-α (p=0.993) and dose of PEG-IFN-α (p=0.841)) were not signifcantly associated with depressive symptoms on PEG-IFN-α. CONCLUSIONS: Liason-consultation services should collaborate with hepatologists in creating screening programmes, supplemented by objective criteria and guidelines, for early recognition and treatment of interferon-induced depression.

Sex differences in macular thickness of the retina in patients with psychosis spectrum disorders.

INTRODUCTION: Imaging of retinal structure in psychosis spectrum disorders (PSD) is a novel approach to studying effect of this illness class on CNS structure. Studies of optical coherence tomography (OCT) have revealed significant reductions in regarding: retinal nerve fiber layer (RNFL), macular thickness (MT), ganglion cell-inner plexiform layer (GC-IPL) and macular volume (MV). Sex differences in retinal structure in PSD have not been previously explored. METHODS: This cross-sectional pilot study included 81 participant of age matched patients and controls. There were no differences between genders regarding illness duration and antipsychotic daily dose in the patient group. SD-OCT assessed RNFL, GC-IPL, MT, MV, and optic nerve cup-to-disc (C/D) ratio. In order to assess the main effects of illness, sex, and illness × sex interaction on the retinal parameters, general linear model was performed. RESULTS: Patients demonstrated abnormalities on all OCT indices. Effects of sex were observed for central subfield MT and C/D ratio, which were lower in females. An illness × sex interaction effect was observed for the left MT, indicating greater thinning in female patients. CONCLUSION: Sex differences in OCT findings in PSD appear to be most prominent considering macular parameters. These preliminary data may have important implications for the valid interpretation of OCT findings as potential biomarkers for PSD.

Association of CYP2C19 and CYP2D6 Poor and Intermediate Metabolizer Status With Antidepressant and Antipsychotic Exposure: A Systematic Review and Meta-analysis.

Importance: Precise estimation of the drug metabolism capacity for individual patients is crucial for adequate dose personalization. Objective: To quantify the difference in the antipsychotic and antidepressant exposure among patients with genetically associated CYP2C19 and CYP2D6 poor (PM), intermediate (IM), and normal (NM) metabolizers. Data Sources: PubMed, Clinicaltrialsregister.eu, ClinicalTrials.gov, International Clinical Trials Registry Platform, and CENTRAL databases were screened for studies from January 1, 1990, to June 30, 2020, with no language restrictions. Study Selection: Two independent reviewers performed study screening and assessed the following inclusion criteria: (1) appropriate CYP2C19 or CYP2D6 genotyping was performed, (2) genotype-based classification into CYP2C19 or CYP2D6 NM, IM, and PM categories was possible, and (3) 3 patients per metabolizer category were available. Data Extraction and Synthesis: The Meta-analysis of Observational Studies in Epidemiology (MOOSE) guidelines were followed for extracting data and quality, validity, and risk of bias assessments. A fixed-effects model was used for pooling the effect sizes of the included studies. Main Outcomes and Measures: Drug exposure was measured as (1) dose-normalized area under the plasma level (time) curve, (2) dose-normalized steady-state plasma level, or (3) reciprocal apparent total drug clearance. The ratio of means (RoM) was calculated by dividing the mean drug exposure for PM, IM, or pooled PM plus IM categories by the mean drug exposure for the NM category. Results: Based on the data derived from 94 unique studies and 8379 unique individuals, the most profound differences were observed in the patients treated with aripiprazole (CYP2D6 PM plus IM vs NM RoM, 1.48; 95% CI, 1.41-1.57; 12 studies; 1038 patients), haloperidol lactate (CYP2D6 PM vs NM RoM, 1.68; 95% CI, 1.40-2.02; 9 studies; 423 patients), risperidone (CYP2D6 PM plus IM vs NM RoM, 1.36; 95% CI, 1.28-1.44; 23 studies; 1492 patients), escitalopram oxalate (CYP2C19 PM vs NM, RoM, 2.63; 95% CI, 2.40-2.89; 4 studies; 1262 patients), and sertraline hydrochloride (CYP2C19 IM vs NM RoM, 1.38; 95% CI, 1.27-1.51; 3 studies; 917 patients). Exposure differences were also observed for clozapine, quetiapine fumarate, amitriptyline hydrochloride, mirtazapine, nortriptyline hydrochloride, fluoxetine hydrochloride, fluvoxamine maleate, paroxetine hydrochloride, and venlafaxine hydrochloride; however, these differences were marginal, ambiguous, or based on less than 3 independent studies. Conclusions and Relevance: In this systematic review and meta-analysis, the association between CYP2C19/CYP2D6 genotype and drug levels of several psychiatric drugs was quantified with sufficient precision as to be useful as a scientific foundation for CYP2D6/CYP2C19 genotype-based dosing recommendations.

Retinal structural abnormalities in young adults with psychosis spectrum disorders.

BACKGROUND: Structural retinal architecture in living organisms became measurable with the development of optical coherence tomography (OCT) scanners. Single-layer analysis with spectral-domain OCT, among other techniques, may provide further insight into pathological changes in complex brain disorders such as psychosis spectrum disorders (PSD). METHODS: This study investigated potential thinning of retinal layers (retinal nerve fiber layer - RNFL, macular volume, macular thickness, ganglion cell-inner plexiform layer- GC-IPL, optic cup volume and cup-to-disk ratio) using a spectral-domain OCT device in 33 non-acute PSD patients (illness duration 5.9 ± 3.9 years) and 35 healthy controls. RESULTS: In comparison to age and gender matched controls, patients had bilateral reductions in GC-IPL layer thickness and macular volume. Macular central subfield thinning was found in the right eye, while average macular thickness was lower in the left eye only. RNFL thinning was not observed in patients in comparison to controls, but we noticed that status of this layer could be affected by daily dose of antipsychotics and by illness duration. CONCLUSION: Taken together, our results reveal that retinal thinning is present in young adults with PSDs, but in comparison to the literature we found more prominent changes in both GC-IPL and macular volume/thickness, than in RNFL. Our findings may reflect synaptic loss and neuronal atrophy in non-acute young patients with psychosis.

Glucocorticoid receptor alpha translational isoforms as mediators of early adversities and negative emotional states.

Childhood trauma (CT) increases the risk for psychopathology through disturbed acquisition and extinction of fear. The effects of CT are mediated by abnormalities of the hypothalamic-pituitary-adrenal axis and glucocorticoid receptor (GR). Since, the alterations in GRα translational isoforms have been documented in psychiatric disorders we sought to: 1) explore whether multiple GRα isoforms in the human peripheral blood mononuclear cells of two independent cohorts (whole cell n = 40; and nuclear extracts n = 43, adult subjects) mediate the effect of CT on negative affectivity (NA) measured by Depression, Anxiety and Stress Scales (DASS), and 2) examine their role/function during fear extinction in the animal model. In multiple regression analysis, CT, nuclear 40-kDa GRα, their interactions and FKBP5 explained 22%-35% of variance in DASS scores. Structural equation modeling showed that CT had a significant direct effect on 40-kDa and DASS in both cohorts, and on the nuclear 25-kDa GRα. The association between 40-kDa and total DASS was significantly mediated by nuclear FKBP5, whereas on DASS anxiety, over FKBP5 in both cohorts and nuclear full length GRα. Nuclear 40-kDa GRα and its interaction with CT had a significant direct effect on DASS anxiety. In mice, the successful extinction learning was followed by nuclear translocation of 40-kDa GRα and induction of BDNF exon IV expression. Our data revealed that the association between CT and adult NA in non-clinical subjects is mediated by the GRα translational isoforms, in particular 40-kDa GRα, and emphasized its role in fear extinction and neural plasticity.