An association between PPARα-L162V polymorphism and increased plasma LDL cholesterol levels after risperidone treatment.

Peroxisome proliferator-activated receptor alpha (PPARα) and antipsychotic medications both influence polyunsaturated fatty acids (PUFA) homeostasis, and thus PPARα polymorphism may be linked to antipsychotic treatment response. Here we investigated whether the functional leucine 162 valine (L162V) polymorphism in PPARα influenced antipsychotic treatment in a group of psychosis patients (N = 186), as well as in a patient subgroup with risperidone, paliperidone, or combination treatment (N = 65). Antipsychotic-naïve first-episode patients and nonadherent chronic individuals were genotyped by polymerase chain reaction analysis. At baseline, and after 8 weeks of treatment with various antipsychotic medications, we assessed the patients' Positive and Negative Syndrome Scale (PANSS) scores; PANSS factors; and metabolic syndrome-related parameters, including fasting plasma lipid and glucose levels, and body mass index. In the total patient group, PPARα polymorphism did not affect PANSS psychopathology or metabolic parameters. However, in the subgroup of patients with risperidone, paliperidone, or combination treatment, PPARα polymorphism influenced changes in plasma LDL cholesterol. Specifically, compared to PPARα-L162L homozygous patients, PPARα-L162V heterozygous individuals exhibited significantly higher increases of LDL cholesterol levels after antipsychotic treatment. The PPARα polymorphism had a strong effect size, but a relatively weak contribution to LDL cholesterol level variations (∼12.8 %).

Major depressive disorder: a possible typisation according to serotonin, inflammation, and metabolic syndrome.

OBJECTIVE: Major depressive disorder (MDD) is closely related to obesity, inflammation, and insulin resistance, all together being etiologically linked to metabolic syndrome (MetS) development. The depressive disorder has a neuroendocrinological component, co-influencing the MetS, while MetS is characterised by increased cytokine levels, which are known to cause a depressed mood. This study aimed to establish biological subtypes of the depressive disorder based on researched clinical, laboratory, and anthropometric variables. METHODS: We performed a cross-sectional study on a sample of 293 subjects (145 suffering from a depressive disorder and 148 healthy controls). Results were analysed with multivariate statistical methods as well as with cluster and discriminant analysis. In order to classify depressive disorder on the grounds of laboratory, anthropometric, and clinical parameters, we performed cluster analysis, which resulted in three clusters. RESULTS: The first cluster is characterised by low platelet serotonin, high cortisol levels, high blood glucose levels, high triglycerides levels, high Hamilton Depression Rating Scale score, high waist circumference, high C-Reactive Protein values, and a high number of previous depressive episodes, was named Combined (Metabolic) depression. The inflammatory depression cluster is defined with average platelet serotonin values, normal cortisol, and all other parameter levels, except for increased IL-6 levels. The serotoninergic depression cluster is characterised by markedly low platelet serotonin, and all other parameters are within the normal range. CONCLUSIONS: From a biological point of view, depressive disorder is not uniform, and as such, these findings suggest potential clinically useful and generalisable biological subtypes of depressive disorder.

Changes of neurocognitive status in patients with the first-episode psychosis after 18 months of treatment-A prospective cohort study.

Neurocognitive symptoms exert the most influence on treatment outcomes over the course of schizophrenia, starting from the first-episode of psychosis (FEP) onwards. Our aim was to analyze the neurocognitive status of FEP compared to healthy controls (HC), and its change after 18 months of treatment. We performed a study in a sample of 159 patients with FEP and 100 HC. We followed the patients up for 18 months after initial assessment with a battery of neurocognitive tests. We observed statistically significant improvement in the majority of neurocognitive tests after 18 months, but several tests of specific neurocognitive domains (verbal memory, language functions, executive functions) did not show significant differences between the two assessments. The results for the majority of tests obtained from patients with FEP after 18 months of treatment showed significant deterioration compared with HC. Although our study showed significant improvement of baseline neurocognitive deficits in FEP with treatment, this varied across domains and overall performance remained below that of HC. Thus, while it seems that treatment of FEP may help to delay or restore neurocognitive deterioration, it is unclear whether specific areas of neurocognitive deterioration (e.g. verbal domain) would benefit from more time or specific treatment approaches.

Effects of aripiprazole long-acting injectable antipsychotic on hospitalization in recent-onset schizophrenia.

OBJECTIVE: Recent-onset schizophrenia (ROS) represents a critical period that can greatly influence the clinical course of schizophrenia. The use of long-acting injectable antipsychotics (LAIs) in this period is increasingly being considered as a first-line treatment option. Aripiprazole LAI (ALAI) is the newest of all LAI's available on the market, with limited data on its effects on hospitalization rates after first episode of schizophrenia. It was our goal to evaluate whether ALAI has an effect on hospitalization rates, number of bed days and clinical improvement in patients with ROS. METHODS: This mirror-image study included 138 inpatients suffering from schizophrenia. We collected sociodemographic data on all individuals, number of hospitalization days, hospitalization rates as well as Clinical Global Impression Scale-severity of illness (CGI-S) and Clinician-Rated Dimensions of Psychosis Symptom Severity (CRDPSS) scores at the initiation of ALAI and at the end of a 1 year follow up. RESULTS: Mean number of hospitalizations and hospitalization days in the year after starting ALAI significantly decreased compared to the year before (p = 0.005 and p < 0.001). Mean scores on both CGI and CRDPSS also significantly decreased after initiating ALAI (p < 0.001). CONCLUSION: Results suggest that ALAI is an important therapeutic option in patients with ROS. It leads to reduced usage of hospital services, potentially reducing the socio-economic healthcare burden.

General Functioning in Patients With First-Episode Psychosis After the First 18 Months of Treatment.

BACKGROUND: One of the main goals in the treatment of first-episode psychosis (FEP) is achieving functional remission. This study aims to analyze whether initial neurocognitive status and the use of specific pharmacological and psychosocial treatment options in FEP can predict general functioning after 18 months of treatment. METHODS: We conducted a longitudinal naturalistic study with a sample of 129 patients with FEP treated at 2 Croatian psychiatric clinics from 2016until 2018. Ordinal regression was used to predict the global level of functioning assessed with the Global Assessment of Functioning scale (GAF) at the 18th month of treatment from the baseline symptoms (assessed with a set of neurocognitive tests) and different treatment options. RESULTS: Higher score on GAF at the 18th month was significantly predicted by female sex, better baseline verbal memory and GAF scores, and the type of treatment. Group multimodal psychosocial treatment, antipsychotic polytherapy, and not being treated with sedatives at baseline predicted better GAF scores at follow-up. In the exploratory analysis, taking sedatives in the final assessment and being rehospitalized due to relapse predicted worse GAF scores at the end of follow-up. CONCLUSIONS: Although baseline neurocognitive features and baseline general functioning seem to influence the overall long-term functioning of persons with FEP, addition of a multimodal group psychosocial treatment program and appropriate medication seem to be equally important for improving the patients' level of functioning after the FEP.

EIGHTY YEARS OF ELECTROCONVULSIVE THERAPY IN CROATIA AND IN SESTRE MILOSRDNICE UNIVERSITY HOSPITAL CENTRE.

In 1937, Ugo Cerletti and Lucio Bini performed electroconvulsive treatment (ECT) in Rome for the first time. That was the time when different types of 'shock therapy' were performed; beside ECT, insulin therapies, cardiazol shock therapy, etc. were also performed. In 1938, Cerletti and Bini reported the results of ECT. Since then, this method has spread rapidly to a large number of countries. As early as 1940, just two years after the results of the ECT had been published, it was also introduced in Croatia, at Sestre milosrdnice Hospital, for the first time in our hospital and in the then state of Yugoslavia. Since 1960, again the first in Croatia and the state, we performed ECT in general anesthesia and continued it down to the present, with a single time brake.

THE USE OF ELECTRORETINOGRAPHY AND OPTICAL COHERENCE TOMOGRAPHY IN PATIENTS WITH SCHIZOPHRENIA.

The use of electroretinography (ERG) and optical coherence tomography (OCT) has currently expanded beyond ophthalmology alone. The aim of this review is to present the results and knowledge acquired by these two methods in patients suffering from schizophrenia. Reviewing the studies applying ERG and OCT methods in the field of psychiatry, one can conclude that results of the research imply morphological and functional changes of retina in patients with schizophrenia that are not consistent. However, in most studies there was reduction of the amplitude and changes in the implicit time related parameters on ERG and thinning of the retinal nerve fiber layer on OCT. Neurons in the eye use the same neurotransmitters as neurons in the basal brain structures that are most affected in schizophrenia, according to the dopamine hypothesis of schizophrenia. Unlike neurons in the basal brain structures, the neurons in the eye are in vivo available to ERG. Using the aforementioned tests together with clinical diagnostic criteria of schizophrenia, the subgroups with different prognostic and therapeutic specificities within schizophrenia as a group of diseases might be identified more precisely.

Vitamin D and Neurotrophin Levels and Their Impact on the Symptoms of Schizophrenia.

INTRODUCTION: Vitamin D is involved in brain development and functioning, as well as in regulation of neurotrophic factors. Changes in the expression of those factors are possibly responsible for morphologic abnormalities and symptoms in patients suffering from schizophrenia. OBJECTIVE: The main goal of this research was to investigate the interrelationship between vitamin D, nerve growth factors (NGF, brain-derived neurotrophic factor [BDNF], and neuregulin-1 [NRG1]), and schizophrenia symptom domains. METHODS: This research included 97 inpatients diagnosed with schizophrenia. Schizophrenia symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS). Blood samples were taken in order to analyze concentrations of vitamin D, BDNF, NRG1, and NGF growth factors. The obtained results were used in a multiple regression analysis. RESULTS: The vitamin D concentration positively affected the concentration of NRG1 (F = 8.583, p = 0.005) but not the concentration of other investigated growth factors (BDNF and NGF). The clinical characteristics and symptom domains of schizophrenia seemed to be unaffected by the concentrations of vitamin D, BDNF, and NGF, while the NRG1 concentration significantly affected positive symptom domains of schizophrenia (F = 4.927, p = 0.030). CONCLUSION: The vitamin D concentration positively affected NRG1 levels but not schizophrenia symptomatology as measured by PANSS. The as-sociation between the two could be intermediated via NRG1.

Integration of complementary biomarkers in patients with first episode psychosis: research protocol of a prospective follow up study.

In this project, we recruited a sample of 150 patients with first episode of psychosis with schizophrenia features (FEP) and 100 healthy controls. We assessed the differences between these two groups, as well as the changes between the acute phase of illness and subsequent remission among patients over 18-month longitudinal follow-up. The assessments were divided into four work packages (WP): WP1- psychopathological status, neurocognitive functioning and emotional recognition; WP2- stress response measured by saliva cortisol during a stress paradigm; cerebral blood perfusion in the resting state (with single photon emission computed tomography (SPECT) and during activation paradigm (with Transcranial Ultrasonography Doppler (TCD); WP3-post mortem analysis in histologically prepared human cortical tissue of post mortem samples of subjects with schizophrenia in the region that synaptic alteration was suggested by WP1 and WP2; WP4- pharmacogenetic analysis (single gene polymorphisms and genome wide association study (GWAS). We expect that the analysis of these data will identify a set of markers that differentiate healthy controls from patients with FEP, and serve as an additional diagnostic tool in the first episode of psychosis, and prediction tool which can be then used to help tailoring individualized treatment options. In this paper, we describe the project protocol including aims and methods and provide a brief description of planned post mortem studies and pharmacogenetic analysis.

Hikikomori silent epidemic: a case study.

Psychiatry, as we know it, is at a crucial point because it needs to adapt to the modern time and still maintain the integrity and ethic aspects of the therapeutic alliance. Bearing in mind the rising prevalence of new addictions like Internet and online gaming addictions, one can see that, however, disputed, there is a whole new category of psychiatric illnesses on the rise. An example of these kinds of illnesses is Hikikomori. Hikikomori, or severe social withdrawal, pertains to patients who have stopped participating in everyday routine and would spend the majority of time confined in their room for the period of 6 months or more, with no evident psychosis. Although this syndrome was originally described in Japan, over the course of last few years it has been documented in several parts of the world, spreading like a silent epidemic. Our case study, being the first documented case in Southeast Europe, according to our experience and literature search, is a vivid example of this syndrome. In this report we discuss differential diagnosis, show what kind of therapy was efficient in the successful treatment of this syndrome and how it can be prevented in the future.

Differences in Facial Emotional Recognition Between Patients With the First-Episode Psychosis, Multi-episode Schizophrenia, and Healthy Controls.

OBJECTIVES: The aim of our study was to assess the differences in facial emotional recognition (FER) between patients with first-episode psychosis (FEP), patients with multi-episode schizophrenia (SCH), and healthy controls (HC) and to find possible correlations of FER with psychopathology in the two patient groups. METHODS: We performed a cross-sectional study enrolling 160 patients from two psychiatric hospitals in Croatia (80 FEP and 80 SCH) and 80 HC during the period from October 2015 until October 2017. Patients were assessed once during their hospital treatment, using the Penn Emotion Recognition Task for assessment of FER, rating scales for psychopathology and depression and self-reporting questionnaires for impulsiveness, aggression, and quality of life. RESULTS: The number of correctly identified emotions significantly decreased from HC to FEP [Δ -7%; 95% confidence interval (CI) [-12% to -3%], effect size r = 0.30] and more markedly in SCH (Δ -15%; 95% CI [-25% to -10%], effect size r = 0.59) after the adjustment for age and gender and correction for multiple testing. Correct FER for negative emotions, but not for happiness and neutral emotions, had a statistically significant negative correlation with some features on the scales of psychopathology, impulsivity and aggression in both patient groups. CONCLUSIONS: Impairment of FER is present from the first episode of schizophrenia and increases further with multiple psychotic episodes, but it may depend on or contribute to clinical symptoms. Therefore, assessment of FER should be included in the clinical assessment and integrated in the plan of treatment from the beginning of the illness. (JINS, 2019, 25, 165-173).

Integrated Specialized Early-Course Psychosis Treatment Services - University Psychiatric Hospital Vrapce Model.

First episode of psychosis presents a critical period in terms of numerous associated risks, but also possibilities for effective therapeutic interventions. There is a continued focus on early interventions in prodromal states and early course of frank psychosis, aimed at ensuring faster remission, reducing relapses, achieving better long-term functioning, and preventing adverse outcomes linked to untreated psychosis and chronic psychotic disorders. A number of different specialized treatment models and services exist trying to close knowledge gaps and provide clinical interventions to first-episode psychosis (FEP) patients, but there is still no generally accepted standard of care informing our every-day practice. FEP and early-course psychosis specialized treatment model developed in 2004 in University Psychiatric Hospital Vrapce rests on integration of care across different organization units and clinical presentation acuity levels and patient needs (intensive care, FEP inpatient unit, FEP outpatient services including day hospital). Such integration of FEP services allows for flexible entry point on multiple levels, earlier structuring of therapeutic alliance for those requiring inpatient care, reduction of risks associated with FEP, quicker formation of long-term treatment plans, reduction of delay in accessing specialized services, and a more coordinated diagnostic process and recruitment of FEP patient population. Detailed evaluations of outcomes and comparisons with different treatment models are necessary in order to assess strengths and weaknesses of each specific model and inform modifications to current practice models.

Approach to Emergencies in Schizophrenia in University Hospital "Vrapce".

BACKGROUND: An emergency in psychiatric setting is any disorder in thought process, feelings and/or behavior of the patient that requires urgent therapeutic intervention. In general, we can observe an increase in numbers of psychiatric emergencies throughout the world and in Croatia as well. Agitation and aggression are one of the most common causes of emergency in psychiatry. Agitation is common and frequent in patients suffering from schizophrenia. Patient can be agitated in various levels such as: mild, moderate or severe and can alternate between these levels in the same presentation. Agitated patients often require hospitalization that includes pharmacotherapy and sometimes physical restraining, in order to treat the cause of agitation and prevent auto and/or heterodestructive behavior. SUBJECTS AND METHODS: In this paper we focus on patients suffering from schizophrenia that were admitted in University Hospital "Vrapce" in 2017, and assess the numbers through the criteria of voluntary vs. involuntary admissions and physical restraint usage. RESULTS: Out of total observations, 130 (35.6%) were patients admitted for the first time and 179 (49%) were patients later diagnosed with schizophrenia spectrum and other psychotic disorders. Court ordered involuntary hospitalization was ordered for 35 (2.8%) patients out of total admitted patients, and 68.6% (N24) of them were diagnosed with schizophrenia spectrum and other psychotic disorders. Physical restraint was used for 122 patients out of total admissions and 28.7% (N35) of restrained patients were diagnosed with schizophrenia spectrum and other psychotic disorders. CONCLUSIONS: Emergencies in patient suffering from schizophrenia are extremely delicate and demanding situations in every-day clinical practice of psychiatrist. There is an increased risk involved for the patient but for the staff as well. All interventions should be individualized and patient should carefully monitored throughout the entire process. All professionals involved in care for a patient should be up to date with medical and legal issues.

INFLUENCE OF THE SEROTONERGIC SYSTEM POLYMORPHISM ON THE EXPRESSION OF DENTAL ANXIETY.

- The aim of the study was to test the correlation between 5-HTTLPR polymorphism and dental anxiety. Research hypothesis was that positive relation between the expression of dental anxiety and the S allele exists in the population of healthy Caucasians. We conducted a prospective study on 159 subjects, volunteers made up of medical and non-medical staff of the Sestre milosrdnice University Hospital Centre. Both genders were included, age range 19 to 59, mentally and physically healthy (according to DSM-5 classification of mental disorders). For the purpose of this research, we used a sociodemographic questionnaire containing the following information: age, gender, education level, work status, marital status and residence. Corah's Dental Anxiety Scale-Revised (DAS-R) was used to measure dental anxiety. Data distribution was tested by Kolmogorov-Smirnov test, difference between the groups by ?χ2-test and one-way analysis of variance, and correlation of variables by logistic regression. In the study population, we found positive correlation between S-allele and total result in DAS-R questionnaire. The presence of S allele suggests that the person will have a higher result in DAS-R questionnaire, i.e. higher expression of dental anxiety.

Cost-Utility Analysis of Depot Atypical Antipsychotics for Chronic Schizophrenia in Croatia.

OBJECTIVES: As a nation with a developing economy, Croatia is faced with making choices between pharmaceutical products, including depot injectable antipsychotics. We conducted a pharmacoeconomic analysis to determine the cost-effectiveness of atypical depots in Croatia. METHODS: A 1-year decision-analytic framework modeled drug use. We determined the average direct cost to the Croatian Institute for Health Insurance of using depot formulations of paliperidone palmitate long-acting injectable (PP-LAI), risperidone LAI (RIS-LAI), or olanzapine LAI (OLZ-LAI). An expert panel plus literature-derived clinical rates populated the core model, along with costs adjusted to 2012 by using the Croatian consumer price index. Clinical outcomes included quality-adjusted life-years, hospitalization rates, emergency room treatment rates, and relapse days. Robustness of results was examined with one-way sensitivity analyses on important inputs; overall, all inputs were varied over 10,000 simulations in a Monte Carlo analysis. RESULTS: Costs (quality-adjusted life-years) per patient were €5061 (0.817) for PP-LAI, €5168 (0.807) for RIS-LAI, and €6410 (0.812) for OLZ-LAI. PP-LAI had the fewest relapse days, emergency room visits, and hospitalizations. Results were sensitive against RIS-LAI with respect to drug costs and adherence rates, but were generally robust overall, dominating OLZ-LAI in 77.3% and RIS-LAI in 56.8% of the simulations. CONCLUSIONS: PP-LAI dominated the other drugs because it had the lowest cost and best clinical outcomes. Compared with depots of olanzapine and risperidone and oral olanzapine, PP-LAI was the cost-effective atypical LAI for treating chronic schizophrenia in Croatia. Using depot paliperidone in place of either olanzapine or risperidone would reduce the overall costs of caring for these patients.

Increased inflammation and lower platelet 5-HT in depression with metabolic syndrome.

BACKGROUND: Recent studies suggest comorbidity between major depressive disorder (MDD) and metabolic syndrome. For both disorders, impaired serotoninergic neurotransmission and inflammatory factors have been suggested. The objective of this study was to investigate the concentration of platelet serotonin, interleukin-6 (IL-6) and C-reactive protein (CRP) in MDD patients with and without metabolic syndrome. The second goal was to investigate the association of the concentrations of platelet serotonin, IL-6 and CRP with individual components of metabolic syndrome in MDD patients. METHODS: A total of 145 MDD patients were included in the study (diagnosed according DSM IV TR criteria). The metabolic syndrome was defined according to the criteria of the American National Cholesterol Education Program-Treatment Panel III (ATP III). Inflammation factors (IL-6 and CRP) and platelet serotonin concentration were assessed by the enzyme-linked immunosorbent assay (ELISA). RESULTS: MDD patients with metabolic syndrome showed lower platelet serotonin and higher IL-6 and CRP concentrations when compared to MDD patients without metabolic syndrome. An inverse correlation was found between platelet serotonin and waist circumference and serum glucose levels. A positive correlation was found between IL-6 and glucose or triglyceride concentrations, while the correlation with HDL cholesterol was negative. LIMITATIONS: Data on dietary habits or physical activity prior to hospitalisation were not collected. Also, the study was a cross-sectional without a prospective design. CONCLUSION: Metabolic syndrome in patients with MDD may be associated with reduced concentrations of platelet serotonin and increased concentrations of IL-6 and CRP.

Serum testosterone concentration in combat-related chronic posttraumatic stress disorder.

AIM: The primary aim of this study was to assess the testosterone levels of soldiers with posttraumatic stress disorder (PTSD), without considering their comorbid conditions, compared with the ones in the control group with combat experience. The secondary aim was to determine whether there was a difference in testosterone levels when the same group of soldiers with PTSD was divided according to their comorbid conditions into those with major depressive disorder (MDD) or alcohol dependence (ETOH) compared to the soldiers with PTSD with no comorbid conditions and the controls. METHODS: We analyzed serum testosterone in soldiers with PTSD without the division according to comorbid conditions (n = 66) in comparison to the controls (n = 34). We also analyzed testosterone in pure PTSD (n = 17), PTSD comorbid with MDD (n = 18), PTSD comorbid with ETOH (n = 31), and in the controls. RESULTS: Soldiers with PTSD, without considering comorbid conditions, did not show any difference in testosterone levels in comparison to the controls. However, when we divided the same PTSD sample based on comorbid conditions, pure PTSD showed significantly higher serum testosterone levels in comparison to PTSD comorbid with MDD, comorbid with ETOH, or controls. Also, there was no difference in testosterone levels between the PTSD groups with comorbid MDD, with comorbid ETOH, and the controls. CONCLUSIONS: We did not find any differences in testosterone levels between the soldiers with PTSD without considering comorbid conditions and the controls. Considering comorbid conditions, soldiers with PTSD without comorbid conditions had higher testosterone levels compared to soldiers with PTSD with comorbid MDD or ETOH, or the controls.