Vladimir Janjic

Effectiveness of clozapine, haloperidol and chlorpromazine in schizophrenia during a five-year period

OBJECTIVE The aim of our study was to evaluate the effects of low doses of clozapine in flexible regime in comparison with haloperidol and chlorpromazine in long term. METHOD The naturalistic study was prospective, active-controlled with 325 adult outpatients of both genders (140 females), with mean year age of 34.8 (range 21-57), suffering from chronic schizophrenia. The first onset of illness was at the mean of 27.9 years (range 17-38), and subjects had the mean year age of 4.1+/-0.5 previous relapses. The patients were allocated to receive haloperidol (105 subjects, dose range 2-15 mg), chlorpromazine (n=105, 100-400 mg) or clozapine (n=115, 75-600 mg). The scores of psychometric instruments (GWB, PANSS, CGI) were regularly assessed during 5 year period. RESULTS The sixty-six responders were included in per-protocol analysis: 12, 10 and 16 with positive and 7, 6 and 15 with negative schizophrenic syndrome in haloperidol, chlorpromazine and clozapine group, respectively. The statistically significant differences in all psychometric scores was found, for both schizophrenic syndromes, favoring clozapine. The distribution of eighteen different types of adverse events, which we noted, were significantly different among treatment groups ( chi2=315.7, df=34, p<0.001). Clozapine was safer and had fewer adverse effects (average of 0.9 adverse events per patient) than haloperidol (2.7) and chlorpromazine (3.2). CONCLUSIONS Clozapine, in low doses of flexible regime, in long term (five years) showed better effectiveness in chronic schizophrenics with positive and negative symptoms than typical antipsychotics.

Burnout, Depression and Proactive Coping in Underground Coal Miners in Serbia - Pilot Project

Abstract Mining is unsurprisingly considered a high-risk occupation because it involves continuous hard labour under highly demanding and stressful conditions. Many of these work stressors can impair individuals’ well-being in both a physiological and psychological sense. The aims of this study were to assess the prevalence of burnout and depressive symptoms and to evaluate aspects of proactive coping among underground coal miners in Serbia. The study involved 46 male underground coal miners. Burnout was measured with the Copenhagen Burnout Inventory, depression was assessed with the Patient Health Questionnaire-9, and level of proactive coping was measured with the Proactive Coping Inventory. The results showed a low level of burnout syndrome among the underground coal miners (12.46±4.879). Depression was slightly above the minimum (1.2±2.094), and the majority of the participants had no symptoms of depression (93.5%). Overall, the underground coal miners’ ability to proactively cope with work stress was very good (42.17±6.567). This is in contrast to the findings of the few previous international studies and is a good basis for further research using a larger sample in Serbia.

Parameters of Calcium Metabolism Fluctuated during Initiation or Changing of Antipsychotic Drugs.

Objective Serum parameters of calcium homeostasis were measured based on previously published evidence linking osteoporotic fractures and/or bone/mineral loss with antipsychotics. Methods Prospective, four-week, time-series trial was conducted and study population consisted of patients of both genders, aged 35-85 years, admitted within the routine practice, with acute psychotic symptoms, to whom an antipsychotic drug was either introduced or substituted. Serial measurements of serum calcium, phosphorous, magnesium, 25(OH)D, parathyroid hormone, calcitonin, osteocalcin and C-telopeptide were made from patient venous blood samples. Results Calcium serum concentrations significantly decreased from baseline to the fourth week (2.42±0.12 vs. 2.33±0.16 mmol/L, p=0.022, n=25). The mean of all calcemia changes from the baseline was -2.6±5.7% (-24.1 to 7.7) with more decreases than increases (78 vs. 49, p=0.010) and more patents having negative sum of calcemia changes from baseline (n=28) than positive ones (n=10) (p=0.004). There were simultaneous falls of calcium and magnesium from baseline (63/15 vs. 23/26, p<0.001; OR=4.75, 95% CI 2.14-10.51), phosphorous (45/33 vs. 9/40, p<0.001; 6.06, 2.59-14.20) and 25(OH)D concentrations (57/21 vs. 13/35, p<0.001; 7.31, 3.25-16.42), respectively. Calcemia positively correlated with magnesemia, phosphatemia and 25(OH)D values. Parathyroid hormone and C-telopeptide showed only subtle oscillations of their absolute concentrations or changes from baseline; calcitonin and osteocalcin did not change. Adjustment of final calcemia trend (depletion/accumulation) for relevant risk factors, generally, did not change the results. Conclusion In patients with psychotic disorders and several risks for bone metabolism disturbances antipsychotic treatment was associated with the decrease of calcemia and changes in levels of the associated ions.

Meta-analysis of the changes in correlations between depression instruments used in longitudinal studies.

BACKGROUND Correlations between instruments measuring the same construct reflect their concurrent validity. Little is known about changes in correlations between such instruments employed in studies with repeated assessment. The aim of this meta-analysis was to examine the changes in correlations between depression instruments in the course of longitudinal studies. METHODS A literature search was conducted using MEDLINE and PsycINFO for the period from 1960 to 2013. The total number of collected articles was 3723, of which 61 were included. Three meta-analyses were performed for the changes in correlations between each pair of the three depression scales: Hamilton Rating Scale for Depression (HAMD), Montgomery-Asberg Depression Rating Scale (MADRS) and Beck Depression Inventory (BDI). The effect size in these meta-analyses was obtained by the z-transformation of correlation coefficients. RESULTS Correlations between depression scales increased over time in 52 studies. Significant changes in correlation coefficients were found for correlations between HAMD and BDI (p<0.001) and for correlations between HAMD and MADRS (p<0.001). An increase in correlations between the scales was associated with a decrease in depression scores and increase in their variability. LIMITATIONS Univariable and multivariable meta-regression models were not obtained in all three meta-analyses because of the lack of data. CONCLUSIONS A finding that correlations between depression instruments tended to increase over time has significant implications for assessment of the concurrent validity of these instruments. In longitudinal designs it is important to estimate correlations between depression scales over time because different thresholds for scale correlations indicate acceptable concurrent validity at different times.

Prescribing practices in Southeastern Europe – focus on benzodiazepine prescription at discharge from nine university psychiatric hospitals

There is much concern about the widespread long-term use of benzodiazepines. Our manuscript addressed its use in the region of Southeastern Europe, which seems extensive, but insufficiently explored. At nine university psychiatric hospitals (Croatia, Macedonia and Serbia), we retrospectively analyzed discharge summary documents to find the prevalence of discharge benzodiazepine prescriptions and the prescribed benzodiazepine doses. This study included 1047 adult subjects and showed that 81.9% of them had benzodiazepines prescribed in the discharge summary document, with high mean daily dose of around 5mg lorazepam equivalents. Factors associated with the prescriptions were exclusively clinical factors (diagnosis of schizophrenia spectrum disorders, more lifetime hospitalizations, psychiatric comorbidity, co-prescription of antidepressant or mood stabilizer, shorter duration of the hospitalization), while socio-demographic factors were not found to influence benzodiazepine discharge prescriptions. Similarly, factors which influenced the prescription of higher daily benzodiazepine dose were more lifetime psychiatric hospitalizations and co-prescription of antidepressant or mood stabilizer, as well as the diagnosis of mental/behavioral disorders due to substance use and co-prescribed antipsychotic. Our data are emphasizing an urgent need for guidelines and improved education of both health care professionals and patients, in order to prevent long term benzodiazepine (mis)use and related side-effects.

PSYCHOLOGICAL AND SOCIODEMOGRAPHIC CHARACTERISTICS AND DEVELOPMENT OF PHYSICAL EXERCISE DEPENDENCE

Introduction: Excessive physical exercise combined with certain psychic and sociodemographic factors can lead to dependence. Objective: To examine which factors lead to the emergence of exercise dependence. Methods: Sample consisted of 103 men (mean age 27.3 years, SD 6.127) who performed exercises at gyms at least three times a week in the last year or more in Novi Pazar, Sjenica, Raska and Tutin, Serbia. Participants completed questionnaires and took appropriate tests. Results: Our results showed that there is no association between exercise dependence and financial status, number of siblings, level of education, family stability, health, and medication use among the interviewees. However, it was found that the degree of exercise dependence is associated with marital status and problems with the law. Regression analysis showed that body dysmorphia, body mass index and aggressiveness are better predictors of exercise dependence. Conclusion: People whose self-perception is dismorphic have lower self-esteem, and exercise in gyms to improve their physical appearance. If we consider other characteristics, such as unfavorable BMI, problems with the lаw and being single, it is hardly surprising these individuals cross the line between healthy exercise and exercise dependence. An important finding is that aggressiveness and exercise dependence are related to problems with the law due to aggression, and body dysmorphia. Level of Evidence; Diagnostic studies Investigating a diagnostic test.

Quality of Life in Primary Insomnia: Three-week Treatment With Zolpidem Vs. Lorazepam

Abstract Insomnia is a condition of inadequate quality or quantity of sleep that has extremely adverse effects on daytime activities. Th e aim of this study was to compare the quality of life in patients with primary insomnia before and after a 3-week treatment with lorazepam (n=20) and zolpidem (n=21) and to compare the potential differences in dysfunctional beliefs and attitudes regarding patients’ sleep between the two groups. Th e diagnosis of primary insomnia was established using the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision criteria, and patients had to complete a specially designed sleep log every day; on scheduled visits, we also administered a Visual Analogue Scale for quality of life and a self-evaluation questionnaire about Dysfunctional Beliefs and Attitudes related to Sleep at the beginning and end of this study. In summary, the examinees in our study had significantly decreased parameters of quality of life, quite lower than expected based on previous findings in this area. However, by the end of the study, quality of life significantly improved with treatment: it improved by approximately 2/3 in the Lorazepam group and more than twice in the Zolpidem group, with a significant difference in favour of Zolpidem (p=0.047). Th is finding is most likely a consequence of its better safety profile and in part its better efficiency in terms of influence on certain domains of sleep itself, as previously discussed. Further specialized studies in this area with larger samples and a more detailed methodology are clearly warranted.

Efficacy of Different Antipsyhotics in Combination with ECT in Resistant Schizophrenia

Introduction Combination different antipsyhotics with ECT in treatment resistant schizophrenia has been reported. However, the result are controversial. Our study investigated the long-term effects of combination ECT with three different antipsyhotic (haloperidol, amisulpride, olanzapine) in treatment of resistant schizophrenia. Aims The aims of our study were to investigated the long-term effects of combination ECT with three different antipsyhotic in treatment in resistant schizophrenia. Object and methods The clinical study was a naturalistic, prospective, open labelled, active controlled study in adult outpatients of both genders suffering from treatment resistant schizophrenia, (Dg F20) with follow-up of 2 years. The patient received amisulpride n=16 in range 50-200 mg/ mean daily doses 75,42. Haloperidol n=19, range 10-15 mg/day, mean daily doses 14,20 – 24,00. And olanzapine n=21, 5-15mg daily, mean daily doses 7,43.ECT was applied (8.0sec, and 0.8 amp) (Thymatron system IV somatic) in nine applications, twice a week. Clinical efficacy, was estimated using the ICD-10, PANNS and CGI psychometric scales. Results According to the result, the most effective treatment was combinatin with olananzapine plus ECT, than haloperidol plus ECT, while amisulprid plus ECT had lower clinical efficacy. Olanzapine plus ECT, was significantly superior in all scale scores vs amisulpiride plus ECT, as well as haloperidol plus ECT except for PANSS-P (t=1,85, p>0,05). During the study, 38 of 70 patients were withdrawn due to treatment failure (n=21), side effects (n=6)and non compliance (n=11). Conclusions Our steady show that the combination of different antipsycotic and ECT, is more effective in treatment of resistant schizophrenia.

P.8.b.006 Side effects of zolpidem and temazepam in treating primary insomnia

There were no abnormalities in cardiovascular status. Baseline laboratory results again included a normal platelet count, normal liver enzymes and liver function tests. Hypomania was also excluded. After agomelatine discontinuation, symptoms improved. Adverse effect was determined by clinical pharmacist with the Naranjo probability scale and was probably associated with agomelatine use (6 points) and possibly associated with duloxetine hydrochloride use (4 points). After discussing the benefits and risks with the patient, a clinical pharmacist advised discontinuation of agomelatine and switching to trazodone 50mg daily at bedtime. The physician accepted our recommendations and the symptoms completely disappeared in three days after agomelatine discontinuation. Discussion: No case of agomelatine-induced sweating has been described. The interactions with agomelatine are reported to be mediated by cytochrome CYP1A2 enzymes. CYP1A2 and CYP2D6 have a major role in the metabolism of duloxetine hydrochloride and duloxetine hydrochloride increases the exposure of drugs that metabolized with CYP2D6, but not CYP1A2 [1]. Consequently any pharmacokinetics drug interaction between agomelatine and duloxetine hydrochloride had not occurred in this patient. An adverse effect was not induced by duloxetine hydrochloride itself, but pharmacodynamic drug–drug interaction between duloxetine hydrochloride and agomelatine could occur, which led to small additive adrenergic overstimulation. Such case has not yet been described in literature, however an adverse effect associated with drug–drug interaction can occur, as this report clearly demonstrates. No case of agomelatine-induced sweating has been described. Pharmacodynamic drug–drug interaction between agomelatine and duloxetine hydrochloride could occur, which led to small additive adrenergic overstimulation. Daily dose of duloxetine hydrochloride was not changed in switching time. This case serves to illustrate how clinical pharmacy can help ensure a satisfactory clinical outcome and prevent a potentially life threatening adverse drug reaction, similar to other case reports of timely recognition of adverse drug reactions from other psychotropic medications by clinical pharmacy that were followed by close collaboration between clinical pharmacy and psychiatry for successful management of the clinical disorder in question [2,3]. Conclusion: The benefit of this antidepressant combination needs to be carefully balanced with the risks associated with its use. Antidepressant combination treatment is common in some clinical practice settings, there is limited evidence to support this practice. Trazodone in small doses could be used in treating patients with agomelatine associated excessive sweating.

P.1.g.038 Olanzapine and simvastatin as medication in poststroke confuse-delirant syndromes

Early involvement of psychiatric treatment, for the patients who had a stroke is important because confuse delirant condition of patients after a stroke has a high negative clinical implications for the course of the disease. Our approach to this problem is based on the fact that stroke representes organic stress state in wich hyperlipidemia increases risk for reinsult. The aim of our study was to minimise agitation with olanzapine [1,3] and to decrease the risk for further damage of cerebral blood vessels with simvastatin [2]. Our study was conducted at the Neurological Clinic in Clinical Center and Medical Faculty, where we involved a total of 56 patients, of whom 31 women and 25 men. The average age in this study was 67 years. Fifty-six subjects were included, of both genders (31 females, 25 males) with mean age of 67±8 years. The diagnosis for ischemic stroke (I63), was based on valid clinical modalities and to Neurological state and MRI of the head, where to accompanied by other clinical parameters and diagnostic criteria as EEG and laboratory analyzes, which were yet another confirmation of the diagnosis. Confuse-delirant syndrome (F05) and hyperlipidemia (E 78.2) were established according to ICD-10 and the later was rated with Neuropsyciatric Inventory (NPI-10). When it comes to confuse-delirant syndrome (F05), the diagnosis of this apartment served us as the criteria and procedures for record ICD-10 and clinical findings psychiatrist. Confuse delirious state, during treatment was treated with scale NPI inventory, the 10 questions with a maximum score of 120 points. Also hyperlipidemia (E 78.2) was determined in laboratory search by measuring levels of cholesterol and triglycerides, wich is followed during the six weeks of treatment. What is significant is that, in all patient olanzapin was administered in the mean in oral daily dose, of 5±1.2mg (bedtime) and simvastatin in oral daily dose of 40mg. The treatment, lasted 6 weeks and drugs effects were measured at baseline, on third week and the end of the study. Our research has shown that olanzapine, administered in this manner (5mg in the evening dose), showed good efficacy in ameliorating the calming and confusing state of delirious agitation. They also, showed us the scores obtained on the NPI scale. Results showed that the mean scores on NPI were: at baseline for 69±1, (frequency × severity) and 26±5 (caregiver distress), after 3 weeks were 43±11 and 14±8, and after six weeks 29±9 and 10±6 (p< 0.01, one-way ANOVA). The cholesterol and trygliceride levels were stabilised in reference ranges for all patients at intermediate visit. There was no unusual adverse drug reaction. Our results suggest that olanzapine was very effective for ameliorating confusion and delirant signs in poststroke patiens, and also prevente reinsult. Its effects were augmented with fast regulation of lipid status. According to our results, we recommended using the controller of cholesterol and triglycerides, with an antipsychotic in this case olanzapine, in more efficient treatment poststroke, confuse delirant conditions and agitation.