Improving treatment of patients with psychosis in low-and-middle-income countries in Southeast Europe: Results from a hybrid effectiveness-implementation, pragmatic, cluster-randomized clinical trial (IMPULSE).

BACKGROUND: In Southeast Europe (SEE) standard treatment of patients with psychosis is largely based on pharmacotherapy with psychosocial interventions rarely available. DIALOG+ is a digital psychosocial intervention designed to make routine care therapeutically effective. This trial simultaneously examined effectiveness of DIALOG+ versus standard care on clinical and social outcomes (Aim 1) and explored intervention fidelity (Aim 2). METHODS: A hybrid type II effectiveness-implementation, cluster-randomized trial was conducted in five SEE countries: Bosnia and Herzegovina, Kosovo*, Montenegro, North Macedonia, and Serbia. The intervention was offered to patients six times across 12 months instead of routine care. The outcomes were subjective quality of life (primary), clinical symptoms, satisfaction with services, and economic costs. Intervention fidelity was operationalized as adherence to the protocol in terms of frequency, duration, content, and coverage. Data were analyzed using multilevel regression. RESULTS: A total of 81 clinicians and 468 patients with psychosis were randomized to DIALOG+ or standard care. The intervention was delivered with high fidelity. The average number of delivered sessions was 5.5 (SD = 2.3) across 12 months. Patients in the intervention arm had better quality of life (MANSA) at 6 months (p = 0.03). No difference was found for other outcomes at 6 months. Due to disruptions caused by the COVID-19 pandemic, 12-month data were not interpretable. CONCLUSIONS: DIALOG+ improved subjective quality of life of individuals with psychosis at 6 months (after four sessions), albeit with small effect size. The intervention has the potential to contribute to holistic care of patients with psychosis.

Covid-19-related stressors, mental disorders, depressive and anxiety symptoms: a cross-sectional, nationally-representative, face-to-face survey in Serbia.

AIM: The Covid-19 pandemic may be associated with an increase in mental disorders and mental distress. However, there are no representative studies testing the impact of stressors directly related to Covid-19. We aimed to determine whether Covid-19-related stressors were associated with mental disorders, depressive and anxiety symptoms in the second year of the pandemic. METHOD: This cross-sectional observational epidemiological survey was conducted from June to October 2021. We interviewed a representative sample of the adult population in Serbia (18-65 years) in the second year of the pandemic, at a time when large parts of the population had been affected by the pandemic in different ways. A multistage probabilistic household sampling of the adult population in 60 municipalities was used. Mental disorders were assessed by in-person interviews using the Mini International Neuropsychiatric Interview. Depressive and anxiety symptoms were measured by PHQ-9 and GAD-7 scales. Covid-19-related stressors (Sars-CoV-2 infection, the infection of a close relative, self-isolation and lack of protective equipment at work), as well as other stressors during the pandemic (not directly related to the risk of the infection), were measured. The associations with mental disorders, depressive and anxiety symptoms were explored through univariable and multivariable regression analyses. RESULTS: In total, 1203 individuals (mean age 43.7 ± 13.6 years, 48.7% male) were interviewed. Most respondents (67.8%) of the sample had already experienced Covid-19-related stressors (20.1% had Sars-CoV-2 infection; 43.2% had a close relative member who had Covid-19; 28.2% reported lack of appropriate protection; 27.5% had been quarantined) and about 50% had already been vaccinated. The prevalence of any mental disorder was 15.2% (95% CI 13.2-17.2): mood disorders 4.6%, anxiety disorders 4.3% and substance use disorders 8.0%. Mean PHQ-9 was 3.2 ± 3.8 and GAD-7 was 2.1 ± 3.1. In this study, one Covid-19 stressor, i.e. lack of protective equipment, was weakly associated with a greater frequency of anxiety disorders (p = 0.023), while the other stressors had significant associations with several groups of mental disorders and symptom levels. CONCLUSIONS: Our study did not provide any evidence that the prevalence of mental disorders exceeds the range of pre-pandemic data reported in the literature. Covid-related stressors, although frequently reported, did not dramatically influence the prevalence of mental disorders. The provision of the appropriate equipment at workplaces might lead to the reduction of anxiety disorders.

The Serbian COVID-19 Stress Scale and vaccine acceptance: is there a place for COVID-19-related distress in explaining attitudes towards vaccination?

OBJECTIVES: Previous research has shown that the COVID-19 Stress Scale (CSS), a measure assessing various dimensions of distress related to the COVID-19 pandemic, is associated with self-protective behaviours; however, it remains unknown whether this distress can be used to predict attitudes towards vaccination. The purpose of this study was to validate the Serbian CSS (Serbian-CSS) and to explore its predictive power over and above certain sociodemographic characteristics, individual difference variables (attitudes and personality) and general distress in relation to COVID-19 vaccine acceptance. STUDY DESIGN: An online cross-sectional study was conducted that targeted users of different social network groups at the beginning of the public COVID-19 vaccination programme in Serbia. METHODS: A large, online study sample (N = 3129) provided self-reported data on COVID-19-related distress, health and sociodemographic indicators, individual difference variables and attitudes towards vaccination. RESULTS: The Serbian-CSS is a valid and reliable instrument that assesses six dimensions of COVID-19 distress. The strongest predictors of vaccine acceptance were attitudes towards immigrants (adjusted odds ratio [AOR] = 0.36, 95% confidence interval [CI] 0.31, 0.41), followed by education (AOR = 1.51, 95% CI 1.27, 1.88) and prepandemic mental health issues (AOR = 1.61, 95% CI 1.30, 2.01). CONCLUSIONS: The level of distress measured by the CSS had a non-substantial contribution to vaccine acceptance, which is probably because of the mild level of distress that was observed at the time of assessment. Public health messaging that relies on the distribution of information is not sufficient to address strongly held beliefs against vaccination. The study provides a benchmark for future cross-cultural research regarding negative affective states associated with the COVID-19 pandemic.

Examining the independent and joint effects of genomic and exposomic liabilities for schizophrenia across the psychosis spectrum.

AIMS: Psychosis spectrum disorder has a complex pathoetiology characterised by interacting environmental and genetic vulnerabilities. The present study aims to investigate the role of gene-environment interaction using aggregate scores of genetic (polygenic risk score for schizophrenia (PRS-SCZ)) and environment liability for schizophrenia (exposome score for schizophrenia (ES-SCZ)) across the psychosis continuum. METHODS: The sample consisted of 1699 patients, 1753 unaffected siblings, and 1542 healthy comparison participants. The Structured Interview for Schizotypy-Revised (SIS-R) was administered to analyse scores of total, positive, and negative schizotypy in siblings and healthy comparison participants. The PRS-SCZ was trained using the Psychiatric Genomics Consortiums results and the ES-SCZ was calculated guided by the approach validated in a previous report in the current data set. Regression models were applied to test the independent and joint effects of PRS-SCZ and ES-SCZ (adjusted for age, sex, and ancestry using 10 principal components). RESULTS: Both genetic and environmental vulnerability were associated with case-control status. Furthermore, there was evidence for additive interaction between binary modes of PRS-SCZ and ES-SCZ (above 75% of the control distribution) increasing the odds for schizophrenia spectrum diagnosis (relative excess risk due to interaction = 6.79, [95% confidential interval (CI) 3.32, 10.26], p < 0.001). Sensitivity analyses using continuous PRS-SCZ and ES-SCZ confirmed gene-environment interaction (relative excess risk due to interaction = 1.80 [95% CI 1.01, 3.32], p = 0.004). In siblings and healthy comparison participants, PRS-SCZ and ES-SCZ were associated with all SIS-R dimensions and evidence was found for an interaction between PRS-SCZ and ES-SCZ on the total (B = 0.006 [95% CI 0.003, 0.009], p < 0.001), positive (B = 0.006 [95% CI, 0.002, 0.009], p = 0.002), and negative (B = 0.006, [95% CI 0.004, 0.009], p < 0.001) schizotypy dimensions. CONCLUSIONS: The interplay between exposome load and schizophrenia genetic liability contributing to psychosis across the spectrum of expression provide further empirical support to the notion of aetiological continuity underlying an extended psychosis phenotype.

UGT1A1 (TA)n Promoter Genotype: Diagnostic and Population Pharmacogenetic Marker in Serbia.

The UGT1A1 enzyme is involved in the metabolism of bilirubin and numerous medications. Unconjugated hyperbilirubinemia, commonly presented as Gilbert syndrome (GS), is a result of decreased activity of the UGT1A1 enzyme, variable number of TA repeats in the promoter of the UGT1A1 gene affects enzyme activity. Seven and eight TA repeats cause a decrease of UGT1A1 activity and risk GS alleles, while six TA repeats contribute to normal UGT1A1 activity and non-risk GS allele. Also, the UGT1A1 (TA)n promoter genotype is recognized as a clinically relevant pharmacogenetic marker. The aim of this study was to assess diagnostic value of UGT1A1 (TA)n promoter genotyping in pediatric GS patients. Correlation of the UGT1A1 (TA)n genotypes and level of unconjugated bilirubin at diagnosis and after hypocaloric and phenobarbitone tests in these patients was analyzed. Another aim of the study was to assess pharmacogenetic potential of UGT1A1 (TA)n variants in Serbia. Fifty-one pediatric GS patients and 100 healthy individuals were genotyped using different methodologies, polymerase chain reaction (PCR) followed by acrylamide electrophoresis, fragment length analysis and/or DNA sequencing. Concordance of the UGT1A1 (TA)n promoter risk GS genotypes with GS was found in 80.0% of patients. Therefore, UGT1A1 (TA)n promoter genotyping is not a reliable genetic test for GS, but it is useful for differential diagnosis of diseases associated with hyperbilirubinemia. Level of bilirubin in pediatric GS patients at diagnosis was UGT1A1 (TA)n promoter genotype-dependent. We found that the frequency of pharmacogenetic relevant UGT1A1 (TA)n promoter genotypes was 63.0%, pointing out that UGT1A1 (TA)n promoter genotyping could be recommended for preemptive pharmacogenetic testing in Serbia.

[Vascular Vibration Injury and Paget-Shroetter Syndrome].

Paget-Schroetter syndrome is a relatively uncommon condition related to primary thrombosis of the axillary/subclavian vein at the costoclavicular junction. Vibration injury is an unusual cause of this syndrome. We report on a 28-year-old man who presented with acute onset left arm swelling after whole-day work with a pneumatic drill. Duplex ultrasound confirmed the presence of a thrombus in his left axillary and subclavian vein, which was treated with low molecular weight heparin, eventually switched to oral anticoagulation.

The acute and medium-term effects of treatment with electroconvulsive therapy on memory in patients with major depressive disorder.

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

EPA guidance on the early intervention in clinical high risk states of psychoses.

This guidance paper from the European Psychiatric Association (EPA) aims to provide evidence-based recommendations on early intervention in clinical high risk (CHR) states of psychosis, assessed according to the EPA guidance on early detection. The recommendations were derived from a meta-analysis of current empirical evidence on the efficacy of psychological and pharmacological interventions in CHR samples. Eligible studies had to investigate conversion rate and/or functioning as a treatment outcome in CHR patients defined by the ultra-high risk and/or basic symptom criteria. Besides analyses on treatment effects on conversion rate and functional outcome, age and type of intervention were examined as potential moderators. Based on data from 15 studies (n=1394), early intervention generally produced significantly reduced conversion rates at 6- to 48-month follow-up compared to control conditions. However, early intervention failed to achieve significantly greater functional improvements because both early intervention and control conditions produced similar positive effects. With regard to the type of intervention, both psychological and pharmacological interventions produced significant effects on conversion rates, but not on functional outcome relative to the control conditions. Early intervention in youth samples was generally less effective than in predominantly adult samples. Seven evidence-based recommendations for early intervention in CHR samples could have been formulated, although more studies are needed to investigate the specificity of treatment effects and potential age effects in order to tailor interventions to the individual treatment needs and risk status.

EPA guidance on the early detection of clinical high risk states of psychoses.

The aim of this guidance paper of the European Psychiatric Association is to provide evidence-based recommendations on the early detection of a clinical high risk (CHR) for psychosis in patients with mental problems. To this aim, we conducted a meta-analysis of studies reporting on conversion rates to psychosis in non-overlapping samples meeting any at least any one of the main CHR criteria: ultra-high risk (UHR) and/or basic symptoms criteria. Further, effects of potential moderators (different UHR criteria definitions, single UHR criteria and age) on conversion rates were examined. Conversion rates in the identified 42 samples with altogether more than 4000 CHR patients who had mainly been identified by UHR criteria and/or the basic symptom criterion 'cognitive disturbances' (COGDIS) showed considerable heterogeneity. While UHR criteria and COGDIS were related to similar conversion rates until 2-year follow-up, conversion rates of COGDIS were significantly higher thereafter. Differences in onset and frequency requirements of symptomatic UHR criteria or in their different consideration of functional decline, substance use and co-morbidity did not seem to impact on conversion rates. The 'genetic risk and functional decline' UHR criterion was rarely met and only showed an insignificant pooled sample effect. However, age significantly affected UHR conversion rates with lower rates in children and adolescents. Although more research into potential sources of heterogeneity in conversion rates is needed to facilitate improvement of CHR criteria, six evidence-based recommendations for an early detection of psychosis were developed as a basis for the EPA guidance on early intervention in CHR states.

Prescribing practices in psychiatric hospitals in Eastern Europe.

BACKGROUND: There has been no evidence about the prescribing practices in psychiatric care in Eastern Europe. AIMS: To examine the patterns of psychotropic prescribing in five countries of Eastern Europe. METHOD: We conducted a one-day census of psychiatric treatments used in eight psychiatric hospitals in Albania, Croatia, Macedonia, Serbia and Romania. We examined clinical records and medication charts of 1304 patients. RESULTS: The use of polypharmacy was frequent across all diagnostic groups. Only 6.8% of patients were on monotherapy. The mean number of prescribed drugs was 2.8 (SD 0.97) with 26.5% receiving two drugs, 42.1% receiving three drugs and 22.1% being prescribed four or more psychotropic drugs. Typical antipsychotics were prescribed to 63% and atypical antipsychotics to 40% of patients with psychosis. Older generations of antidepressants were prescribed to 29% of patients with depression. Anxiolitic drugs were prescribed to 20.4% and benzodiazepines to 68.5% of patients. One third of patients received an anticholinergic drug on a regular basis. CONCLUSIONS: Older generation antipsychotics and antidepressants were used more frequently than in the countries of Western Europe. Psychotropic polypharmacy is a common practice. There is a need for adopting more evidence-based practice in psychiatric care in these countries.

Psychiatric and neuropsychological changes in growth hormone-deficient patients after traumatic brain injury in response to growth hormone therapy.

OBJECTIVE: Traumatic brain injury (TBI) has been recently recognized as a risk factor for cognitive impairment and hypopituitarism, presented most frequently with GH deficiency (GHD). GHD is associated not only with changes in body composition, but also with impaired quality of life, cognitive dysfunctions and some psychiatric sequelae, usually classified as "depression" or "atypical depression". The impact of GH therapy on mental status in TBI patients is still unknown. DESIGN: Psychiatric and cognitive functions were tested in 6 GHD patients at baseline (minimum 3 yr after TBI), reassessed after 6 months of GH therapy as well as 12 months after discontinuation of GH therapy. Psychiatric and cognitive examinations included semi-structured interviews and 3 instruments: Symptom-checklist (SCL-90-R), Zung Depression Inventory, and standard composite neuropsychological battery. RESULTS: Six months of GH therapy in GHD TBI patients improved cognitive abilities (particularly verbal and non-verbal memory) and significantly improved psychiatric functioning. Severity of depression decreased, as well as intensity of interpersonal sensitivity, hostility, paranoid ideation, anxiety, and psychoticism. Somatization, obsessive-compulsive symptoms and phobic anxiety decreased in all except in one patient. In 3 GHD patients who stopped GH therapy for 12 months we registered worsening of the verbal and non-verbal memory, as well symptoms in 3 SCL dimensions: inter-personal sensitivity, anxiety, and paranoid ideation. CONCLUSION: GH-deficient TBI patients are depressed and have cognitive impairment. GH therapy induced reduction of depression, social dysfunction, and certain cognitive domains. Our preliminary data support the necessity of conducting randomized placebo-controlled trials on the effects of GH therapy on neuropsychological and psychiatric status in GHD TBI patients.

Postgraduate training for young psychiatrists--experience of the Berlin Summer School.

BACKGROUND: Growing professional exchange between Eastern and Western European countries increases the possibilities for international postgraduate training courses and by that satisfying the need for rapid and facilitation of travel and migration in the enlarged European Union increase achieving high standards. The purpose of this study was to evaluate a summer school program that trained young Eastern European psychiatrists and to assess the impact of the program on their professional development and future activities. METHOD: We evaluated the training effect of the first 3 years of the Berlin Summer School with respect to (1) the participants' satisfaction with the topics, quality and originality of the presentations, and (2) long-term effects and implications for their professional career. All participants (N=43) filled out anonymously the evaluation form at the end of each summer school. An evaluation of long-term effects was carried out 2 years later with a questionnaire that was sent via e-mail to all former participants. RESULTS: Participants were most satisfied with practical topics such as "how to prepare a paper", "how to evaluate a paper", or "how to participate in a congress." The appreciation of the presented topics and the appreciation of courses increased in each consecutive summer school. All summer school participants reported that the course had some influence on their future career, and one fifth of the participants felt that their professional development was influenced "a lot". CONCLUSIONS: Although limited to 1 week of intensive training, a summer school program can have a longer lasting positive influence on the professional development of the participants. Participants felt that particularly the training of practical skills improved their research performance. Former participants founded an independent multicentric and multinational research group and supported national courses that were organized similar to the Berlin Summer School.

Is our concept of schizophrenia influenced by Berkson's bias?

BACKGROUND: If both positive and negative dimensions of schizophrenia independently influence need for care, a higher estimate of the comorbidity between these dimensions is expected in clinical samples than would be the case if non-clinical cases were investigated (i.e. Berkson's bias). The present paper investigates whether positive and negative dimensions independently contribute to mental health care use in a general population sample. METHOD: A prospective cohort study was conducted, in which 7076 individuals were interviewed with the Composite International Diagnostic Interview Schedule at baseline and 1 and 3 years later. Lifetime positive and negative psychotic experiences (PPE, NPE) were assessed at baseline. Mental health care use (MHC) was assessed at baseline, and prospectively 1 and 3 years later. RESULTS: The rating of MHC was strongly associated with NPE and PPE, both retrospectively and prospectively and the effects of both variables remained strong and significant in the analyses with both variables included. CONCLUSIONS: These results, therefore, suggest that the concept of schizophrenia, as a unitary entity with high comorbidity between positive and negative dimensions, is in part the result of Berkson's bias.

Hypopituitarism as a consequence of traumatic brain injury (TBI) and its possible relation with cognitive disabilities and mental distress.

Recent studies have demonstrated that hypopituitarism, in particular GH deficiency, is common among survivors of traumatic brain injury (TBI) tested several months or yr following head trauma. We present the results of endocrine, neurological, neuropsychological and psychiatric evaluation in a group of 67 patients who suffered TBI at least one yr ago. Our study shows that decreased endocrine function is either restricted to one or more anterior pituitary hormones and is present in 34% of patients with any pituitary hormone deficit, while multiple pituitary hormone deficiencies are found in 10% of patients. GH/IGF-I axis was evaluated by GHRH+GHRP-6 test and IGF-I measurement. Severe GHD is the most frequent deficiency present in 15% of TBI patients. Gonadotrophin deficiency was present in 9% of patients with TBI, while thyrotroph and corticotroph function seemed more refractory to impairment. Patients with moderate-to-severe trauma are not necessarily more likely to have hypopituitarism than those with mild injury. Neuropsychological testing revealed a significant positive correlation of peak GH levels after GHRH+GHJRP-6 test with verbal learning and verbal short term memory (RAVLT total score p = 0.06, immediate free recall p = 0.02 and delayed free recall p = 0.04). Verbal and visual memory was significantly lower in elderly patients and in males. Visoconstructional abilities (RCF copy) were significantly lower in the elderly (p < 0.01) and undereducated (p = 0.02). Visual memory (free recall of complex figure after 30 min) significantly correlated with lower IGF-I levels (p = 0.01). Gonadotrophins and testosterone correlated significantly with visoconstructional abilities. Simple and complex conceptual tracking (TMT A and B) was significantly more impaired in older TBI patients (p < 0.01) and with longer time from trauma (TMT B only, p = 0.03). The psychiatric evaluation by using two different scales showed depression, phobic anxiety and psychoticism to be more prominent in the TBI group. Paranoid ideation and somatization negatively correlated with the peak GH responses to GHRH+GHRP-6 test (p = 0.04 and p = 0.03, respectively). Depression scale showed that nearly half of patients suffered from mild to moderate depression. The benefits of hormone replacement therapy on cognitive functioning and mental distress in TBI patients are eagerly awaited.

Efficiency of biofeedback therapy for chronic constipation in children.

Chronic constipation is a common disorder in childhood. The underlying mechanisms responsible for chronic constipation remain unknown. Conventional methods of treatment often fail to produce satisfactory results. Favorable effects of biofeedback treatment for constipation have been suggested, however, with variable results reported in the literature. The main aim of the study was to evaluate biofeedback versus conventional therapeutic protocol in the treatment of chronic constipation over a short period of time (3 months). Forty-nine children with chronic idiopathic constipation, 24 allocated to conventional and 25 to biofeedback therapy were included in the study. Thorough history data on bowel function and symptoms, anorectal status and manometric testing were collected before and after treatment. Follow up consisted of a structured interview. Mean age was 94 and 92 months in the children treated by the conventional and biofeedback method, respectively. The initial prevalence of abnormal defecation dynamics was 58% and 56% in the group children allocated to conventional and biofeedback therapy, respectively. The difference was not statistically significant. After the treatment, the values of rectal sensation threshold, critical volume, and recto-anal inhibitory reflex volume were significantly higher, and the prevalence of abnormal defecation dynamics was significantly lower in the group on biofeedback therapy. Biofeedback is an effective method of treatment for chronic constipation in children in short term. Therapeutic results are especially favorable in the recovery of abnormal anorectal dynamics and manometric parameters. There is no clear evidence for long-term benefits of biofeedback therapy.