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.

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.

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.

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.

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.

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).

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.

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.

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 %).

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.

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.

Infection or idiosyncratic reaction to antiepileptic drugs?

Idiosyncratic reactions are serious, unpredicted adverse effects of antiepileptic drugs which are in use in psychiatry as mood stabilizers. Severe idiosyncratic reactions can manifest as systemic symptoms or Dress syndrome clinically manifested with increased body temperature, peripheral lymphadenopathy and potential one or multiple organ failure. We present a 36 years old patient, who was hospitalized for the first time in our hospital after he attempted suicide by hanging. Patient was diagnosed as Bipolar affective disorder, current episode depressive with psychotic features and high suicidal risk. At the time of admission he was taking olanzapine and venlafaxine. Psychopharmacs were cross titrated to clozapine, valproic acid and lamotrigine. Two weeks later, patient's mood was stabilized but his somatic status worsened dramatically. He was forwarded to Clinic for Infective Diseases where he was diagnosed with severe sepsis. Dress syndrome, although initially suspected was not verified, but has to be taken into consideration in each patient prescribed with antiepileptic drugs.

Venlafaxine - quetiapine combination in the treatment of complicated clinical picture of enduring personality changes following PTSD in comorbidity with psychotic depression.

PTSD is a complex disorder, which frequently occurs in comorbidity with anxious disorder, personality disorder, addiction or substance abuse disorder, depressive disorder with or without psychotic symptoms and psychotic disorder. PTSD symptoms may result from deregulation of several different neurotransmitter systems. Pharmacotherapy of PTSD depends on clinical features and the presence of comorbid disorders. Pharmacotherapy of PTSD involves use of anxiolytics, adrenergic receptor antagonists, antidepressants, anticonvulsants and novel antipsychotics. Serotoninergic effect of antidepressants is not only effective in treating depression, but also appears to be helpful in PTSD treatment, particularly in reduction of intrusive symptoms, emotional reactivity, impulsiveness, aggression and suicidal ideation. Anypsychotics with serotoninergic-dopaminergic antagonism are being prescribed often in treatment of psychotic depression, while in PTSD treatment they are proved to be efficient in relieving intrusive symptoms and nightmares. Quetiapine as serotoninergic-dopaminergic antagonist is efficient in treatment of chronic insomnia as well as in reduction of aggressiveness. Considering PTSD refractoriness to therapy, high incidence of comorbidity and significant functional impairment, it is important to search for new psychopharmacological combinations in order to improve mental status of the patient. The paper presents 46 years old male patient with the diagnosis of Enduring personality changes following war PTSD (F62.0) in comorbidity with Recurrent depressive disorder with psychotic symptoms (F33.3), who was treated with combination of venlafaxine and quetiapine.

The role of CYP2D6 and TaqI A polymorphisms in malignant neuroleptic syndrome: two case reports with three episodes.

Malignant neuroleptic syndrome (MNS) is a serious and potentially fatal side-effect of neuroleptic treatment. Beside antipsychotic drugs, other psychotropic drugs such as antidepressants and lithium carbonate can cause this life threatening side-effect. Underlying mechanism of this side-effect is still unknown and debated. So far some risk factors have been identified, with clinical observations and recent pharmacogenetic research suggesting (with inconsistent findings) correlation between genetic mechanisms and predisposition to MNS. Polymorphisms of CYP2D6 enzyme through which most psychotropic drugs are metabolized and TaqIA DRD2 which is target for antipsychotic drugs could be the link between pharmacogenetic factors and potential for development of MNS. In this paper we present two case reports with clinical presentation of three consecutive MNS. One patient developed MNS while he was taking combination of drugs: first time haloperidol, promazine and fluphenazine, second time fluphenazine and perazine and third time clozapine, promazine and valproic acid consecutively. The other patient developed MNS while taking following combination of drugs: first time haloperidol and lithium carbonate, second time risperidone and third time clozapine consecutively. Pharmacogenetic analysis for CYP2D6 and TaqI A DRD2 polymorphisms for both patients was done. Genotypisation of CYP2D6*1*3*4*5*6 in both patients showed no evidence of poor metabolizer phenotype. On the other hand, first patient was heterozygous for CYP2D6*4 (genotype *1/*4). CYP2D6 polymorphisms could have clinical significance because may lead to toxicity and unwanted side-effects in standard usual antipsychotic dose ranges. Analysis Taql A DRD2 polymorphism for first patient showed that he is heterozygous for A1 allele (genotype A1A2) which is commonly associated with predisposition to MNS. According to our literature three consecutive MNS are rarely described, and incidence of MNS generally is too low to perform clinical research. Many patophysiological mechanisms may probably underlie this complex and potentially fatal syndrome, still unknown etiology. But, genetic mechanisms could be significant. Further pharmacogenetic research, findings and analysis in patients who develop single or repeated MNS are strongly recommended. In long term, pharmacogenetic analysis, implemented in daily clinical practice, could help in prevention of this extremely serious side-effect.

Comparative study on dermatoglyphics in alcoholic patients.

According to the world's prevalence rate, alcoholism is in the third place after heart and blood vessel diseases and malignant tumors. With the development of neuroscience, the causes of alcoholism's biological etiologic sources are still being studied. Considering that dermatoglyphics are highly determined by heritage, we contemplated the possibilities of their discrimination in alcoholic patients in relation to phenotypically healthy subjects. We analyzed the quantitative and qualitative dermatoglyphics properties of 100 alcoholic patients without psychiatric comorbidity, who have been cured in the Psychiatric Hospital Sveti Ivan two or more times, and those of 100 phenotypically healthy men. Through the t-test we evaluated the heterogeneity of the examined groups. Results showed a statistically significant difference on five examined variables. In the calculation of fluctuating asymmetry measure, we found no statistically significant differences in the correlation of values of the right and the left hand on the tested variables, beside one. Chi-square tests showed that there is no relation between the dermatoglyphic qualitative properties of alcoholic patients and those of the examinees from the comparison group. Despite the indisputable genetic role in the genesis of alcoholism, the analysis of the dermatoglyphics carried out in our study did not show any etiological connection between the results of the test on dermatoglyphics and the appearance of alcoholism.