Čedo Miljević

Lipid status, anti-oxidant enzyme defence and haemoglobin content in the blood of long-term clozapine-treated schizophrenic patients.

OBJECTIVE Despite clozapines unique effectiveness in patients with schizophrenia, a number of adverse effects have been recognised including abnormalities in lipid and glucose metabolisms. A high clozapine level in red blood cells (RBCs) and disturbed anti-oxidant enzyme activities in blood from schizophrenic patients prompted us to investigate lipid status and anti-oxidant enzyme defence in the blood of chronic schizophrenic patients on long-term clozapine therapy. METHODS Plasma lipids, RBC anti-oxidant enzyme activities and haemoglobin (Hb) content were measured using established procedures in a group of eighteen chronically-medicated (average 630 days of therapy) schizophrenic patients receiving clozapine (average dose of 295 mg/day) and data were compared with those from a group of eighteen well-matched normal controls. RESULTS Significantly higher levels of plasma triglycerides (by 47%, p<0.01) and total cholesterol and phospholipids (by 8% and 11%, respectively p<0.05) in patients were found. CuZn-superoxide dismutase (SOD1) activity was markedly higher (by 35%, p<0.001) while selenium-dependent glutathione peroxidase (GSH-Px1) activity was markedly lower (by 41%, p<0.001) in patients. In addition, metHb and HbA1c levels in patients were significantly higher (by 58% and 25%, respectively p<0.001). SOD1 activity was negatively correlated (p<0.001) to GSH-Px1 activity in patients. CONCLUSIONS The findings support the view that ongoing oxidative stress may be a mechanism by which clozapine induces some adverse effects that increase the risk of diabetes and metabolic syndrome. If valid, this would indicate that in parallel with long-term clozapine treatment, schizophrenic patients could be encouraged to make some lifestyle changes to limit the detrimental effects of the medication.

Effect of atypical antipsychotics on antioxidant enzyme activities in human erythrocytes (in vitro study)

This study was set out to examine the impact of atypical antipsychotic drugs: aripiprazole, clozapine, ziprasidone, olanzapine, quetiapine, sertindole and amisulpride on the activity of antioxidant defence enzymes in human erythrocytes in vitro.

Correlation analysis confirms differences in antioxidant defence in the blood of types I and II schizophrenic male patients treated with anti-psychotic medication

The activities of antioxidant defence enzymes were determined in erythrocytes isolated from types I and II schizophrenic male patients and from healthy controls. Significant differences in superoxide dismutase (SOD) activity (type I: 3284+/-577; type II: 2959+/-697 compared with controls: 3778+/-577; analysis of variance (ANOVA) P<0.001), catalase (CAT) activity (type I: 17.8+/-1.8 compared to type II: 19.2+/-1.5 and both compared with controls: 19.2+/-1.5; ANOVA P<0.05), glutathione peroxidase (GSH-Px) activity (controls: 17.8+/-2.3; type I: 13.9+/-2.9 and type II: 11.6+/-1.9; ANOVA P<0.001) as well as in glutathione reductase (GR) activity (controls: 5,0+/-0.8; type I: 4.3+/-0.9 and type II: 4.5+/-0.8; ANOVA P<0.01) were apparent. Correlation analysis of antioxidant defence enzymes showed significant negative correlation between GSH-Px and CAT activities (P<0.01) in type I patients. In type II patients, GSH-Px activity was significantly positively correlated with GR (P<0.01). Canonical discriminant analysis separated type I and type II patients from controls (and among each other) with a high degree of certainty according to the overall group composition of antioxidant defence enzymes. Our results indicate differences in the composition of antioxidant defence between controls and anti-psychotic treated type I and type II patients with a possible negative feedback influence on the pathological process, which could provide a rationale for applying antioxidants during schizophrenic therapy.

Improving Current Treatments for Schizophrenia.

Preclinical Research

Posttraumatic Stress Disorder after Vaginal Delivery at Primiparous Women

Although severe gynaecological pathology during delivery and negative outcome have been shown to be related with posttraumatic stress disorder (PTSD) little is known about traumatic experiences following regular delivery, at the expected time and with a healthy child. The objective of our study was to determine the prevalence of PTSD during postpartum period after vaginal delivery and its risk factors. The sample included 126 primiparous women. Monthly, for the next three months, the women were assessed for PTSD using the gold standard interview for PTSD, Clinician-Administered PTSD Scale (CAPS). Risk factors were assessed including sociodemographic variables, personal medical history and clinical variables. After the first month, 2.4% women had acute full PTSD and another 9.5% had clinically significant level of PTSD symptoms. Following the second and the third month, partial PTSD was found in 5.9% and 1.3% of the women, respectively, and none of participants had full PTSD. Obstetrical interventions were the only significant risk factor for the development of PTSD. Symptoms of postpartum PTSD are not rare after a traumatic delivery, and associated with specific obstetrical risk factors. Awareness of these risk factors may stimulate interventions to prevent this important and neglected postpartum disorder.

Effects of antipsychotic drug administration on antioxidative defense enzymes in male rat kidney

ABSTRACT The use of atypical antipsychotic drugs (APD) was reported to be associated with adverse effects on the kidneys. Thus, the aim of this study was to examine whether APD exerted their adverse effects by interfering with the renal antioxidant defense system. Male 3-mo-old Wistar rats were treated for 28 d with ziprasidone (ZIP), clozapine (CLO), or sertindole (SER) using a daily dose recommended for antipsychotic drug therapy. The expression and activities of antioxidant enzymes superoxide dismutase (SOD) type 1 and type 2, catalase (CAT), glutathione reductase (GR), and glutathione S-transferases (GSTs) activity were measured in the kidneys. Changes in the kidneys were also evaluated histologically. Ziprasidone, CLO, and SER reduced renal SOD type 1 and type 2 activities. Decreased CAT activity was observed only in SER-treated rats. An inhibition in GR activity and increased activity of GST was found only after treatment with CLO. Histological analysis showed dilatation of proximal tubules in kidneys with all three drugs. In conclusion, data indicate that redox disturbances may contribute to renal morphologic alterations in proximal tubules in rats treated with all APD.

Ex vivo effects of ibogaine on the activity of antioxidative enzymes in human erythrocytes.

ETHNOPHARMACOLOGICAL RELEVANCE Ibogaine is a naturally occurring alkaloid with psychotropic and metabotropic effects, derived from the bark of the root of the West African Tabernanthe iboga plant. The tribes of Kongo basin have been using iboga as a stimulant, for medicinal purposes, and in rite of passage ceremonies, for centuries. Besides, it has been found that this drug has anti-addictive effects. AIM OF THE STUDY Previous studies have demonstrated that ibogaine changed the quantity of ATP and energy related enzymes as well as the activity of antioxidant enzymes in cells thus altering redox equilibrium in a time manner. In this work, the mechanism of its action was further studied by measuring the effects of ibogaine in human erythrocytes in vitro on ATP liberation, membrane fluidity and antioxidant enzymes activity. MATERIALS AND METHODS Heparinized human blood samples were incubated with ibogaine (10 and 20 μM) at 37°C for 1h. Blood plasma was separated by centrifugation and the levels of ATP and uric acid were measured 10 min after the addition of ibogaine using standard kits. The activity of copper-zinc superoxide dismutase (SOD1), catalase (CAT), glutathione peroxidase (GSH-Px) and glutathione reductase (GR) were measured in erythrocytes after incubation period. The stability of SOD1 activity was further tested through in vitro incubation with H2O2 and scanning of its electrophoretic profiles. Membrane fluidity was determined using an electron paramagnetic resonance spin-labelling method. RESULTS Results showed that ibogaine treatment of erythrocytes in vitro increased ATP concentration in the blood plasma without changes in neither erythrocytes membrane fluidity nor uric acid concentration. Ibogaine also increased SOD1 activity in erythrocytes at both doses applied here. Treatment with 20 μM also elevated GR activity after in vitro incubation at 37°C. Electrophoretic profiles revealed that incubation with ibogaine mitigates H2O2 mediated suppression of SOD1 activity. CONCLUSION Some of the effects of ibogaine seem to be mediated through its influence on energy metabolism, redox active processes and the effects of discrete fluctuations of individual reactive oxygen species on different levels of enzyme activities. Overall, ibogaine acts as a pro-antioxidant by increasing activity of antioxidative enzymes and as an adaptagene in oxidative distress.

Association between neurological soft signs and antioxidant enzyme activity in schizophrenic patients

To determine the relationship between alterations in the activity of the enzymes participating in antioxidative defense system and neurological soft signs (NSS) in schizophrenic patients with the first episode psychosis (SFE, n = 19), patients in relapse (SR, n = 46), and healthy controls (HC, n = 20). NSS intensity and enzymatic plasma activities of superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPX) were compared between SFE, SR and HC subjects and a follow-up correlation analyses between the enzyme activities and NSS intensity was performed. NSS intensity was increased four times in schizophrenic patients compared with healthy controls. Activities of SOD and CAT were 40% decreased in SFE and these reductions were ameliorated by antipsychotic treatment. GPX activity was 20% decreased in both patient groups compared with controls. A negative correlation between NSS intensity and GPX activity was specifically found in the SFE patients. The data in this report argue that a reduction of GPX activity might be one of the causes for the emergence of NSS at the onset of schizophrenia, and provide the evidence that antipsychotic therapy can attenuate activity reductions of SOD and CAT, but not the activity reduction of GPX and the intensity of NSS.

Clozapine, ziprasidone, and sertindole-induced morphological changes in the rat heart and their relationship to antioxidant enzymes function

ABSTRACT Atypical antipsychotics produce severe side effects including myocarditis that may be attributed to oxidative stress. The aim of this study was to investigate the influence of clozapine, ziprasidone, and sertindole on rat heart morphology and determine whether redox imbalane plays a role in development of histopathological changes. Adult 3-month-old male Wistar rats were treated with recommended daily dose for selected drugs. After 4 week treatment histopathological analysis of the heart was performed and expression and activity of antioxidant enzymes determined. All examined drugs induced histopathological changes that were characterized as toxic myocarditis. Degenerative changes in cardiomyocytes were accompanied by lymphocytic infiltration as well as pericardial histopathological alterations in all treated groups. The least prominent changes were observed in sertindole-treated animals, and most severe with clozapine. Clozapine increased superoxide dismutase 1 (SOD1) activity while ziprasidone reduced glutathione reductase (GR) activity. Sertindole exerted no marked effect on antioxidant enzyme function in the heart even though myocardial degeneration was noted. In conclusion, treatment with clozapine or ziprasidone induced pathophysiological alterations in rat heart, which appeared to be associated disturbances in antioxidant capacity. Abbreviation: AAP, Atypical antipsychotics; ROS, reactive oxygen species; SOD1, Copper-zinc superoxide dismutase; SOD2, Manganese superoxide dismutase; CAT, Catalase; GPx, Glutathione peroxidase; GR, Glutathione reductase; H&E, hematoxylin and eosin stain; TNF- α, tumor necrosis factor alpha.

Efficacy and tolerability of trazodone retard monotherapy: results of the Serbian non-interventional study

Abstract Objective: Trazodone is an effective antidepressant. The present study was designed as a non-interventional open-label, multi-centre, post-marketing study. The aim of the study was to evaluate the therapeutic effectiveness and tolerability of trazodone retard formulation (Trittico® retard) in everyday clinical practice. Methods: Two hundred and forty-two patients with depressive disorder from 19 different centres were included in the study. The antidepressant and anxyolitic effects were assessed using Hamilton anxiety rating scale 14 items version, Hamilton depression rating scale 14 items version and Clinical Global Impression Severity scale. Results: After only two weeks of therapy, a statistically significant improvement in the HAM-D score, was observed. This observation was maintained over the whole study period, up to the day 56. Conclusions: Our study points toward clinical effectiveness of the prolonged-release formulation of trazodone in the treatment of unselected depressed patients in real-world practice.