Comparative effects of aripiprazole and selected antipsychotic drugs on lipid peroxidation in plasma.

AIM: The aim of the present study was to evaluate and compare the effects of a new antipsychotic, aripiprazole (unique due to its mechanism of action), with the effects of selected antipsychotic drugs, such as quetiapine, olanzapine, clozapine, risperidone, and ziprasidone (at the final concentrations corresponding to clinically effective doses used for the treatment of acute episodes of schizophrenia) on lipid peroxidation in human plasma measured by the level of thiobarbituric acid reactive substances (TBARS), which is a marker of oxidative stress. METHODS: The levels of TBARS were measured spectrophotometrically, according to the modification of the Rice-Evans method. RESULTS: Our results indicate that antipsychotics at doses recommended for the treatment of acute episodes of schizophrenia may induce distinct changes in the levels of lipid peroxidation products (TBARS) in plasma. Aripiprazole had no effect on the level of a lipid peroxidation marker in plasma, although used at lower doses it showed insignificant prooxidative properties similar to clozapine. Quetiapine had the strongest antioxidant properties, contrary to prooxidative action of risperidone, ziprasidone or haloperidol, and clozapine at lower doses. Olanzapine reduced the level of TBARS in plasma only at a lower dose. CONCLUSION: Antipsychotics at doses recommended for the treatment of acute episode in schizophrenia may induce the distinct changes in plasma lipid peroxidation. Aripiprazole did not induce significant changes in plasma lipid peroxidation. In further studies, the role of oxidative stress in schizophrenic patients together with their clinical symptomatology and use of antipsychotics should be taken into account.

The effects of ziprasidone, clozapine and haloperidol on lipid peroxidation in human plasma (in vitro): comparison.

Oxidative injury in schizophrenia can be caused by the disease itself and probably by antipsychotics treatment. The aim of the study was to establish whether there is a difference between ziprasidone, clozapine and haloperidol effect on lipid peroxidation in human plasma, measured by the level of thiobarbituric acid reactive substances (TBARS). The samples of plasma from healthy subjects were incubated with the drugs (1 and 24 h) and compared with control samples. The levels of TBARS were measured spectrophotometrically, according to the Rice-Evans method. The multifactorial variance analysis ANOVA II test showed that the differences in TBARS levels significantly depended on the studied drugs (ziprasidone 40 ng/ml, haloperidol 4 ng/ml and clozapine 350 ng/ml) (F = 3.248 p = 0.047) and (ziprasidone 139 ng/ml, haloperidol 20 ng/ml and clozapine 420 ng/ml) (F = 2.248, p = 2.9 × 10(-5)). Statistically increased levels of TBARS after 24 h incubation of plasma with ziprasidone 139 ng/ml and haloperidol 20 ng/ml (p < 0.001, p < 0.05 respectively) in comparison with control samples were observed. Clozapine did not significantly (p > 0.05) increase TBARS level in plasma in comparison with control samples. The results obtained in the study showed that ziprasidone and haloperidol contrary to clozapine induced a significant increase in plasma lipid peroxidation.

Epicatechin inhibits human plasma lipid peroxidation caused by haloperidol in vitro.

Epicatechin belongs to flavonoids protecting cells against oxidative/nitrative stress. Oxidative/nitrative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics. The aim of our study was to establish the effects of epicatechin and antipsychotics action (the first generation antipsychotic (FGA)--haloperidol and the second generation antipsychotic (SGA)--amisulpride) on peroxidation of plasma lipids in vitro. Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The properties of epicatechin were also compared with the action of a well characterized antioxidative commercial polyphenol-resveratrol (3,4',5-trihydroxystilbene) and quercetin (3,5,7,3',4'-pentahydroxyflavone). Amisulpride, contrary to haloperidol (after 1 and 24 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples (P > 0.05). After incubation (1 and 24 h) of plasma with haloperidol in the presence of epicatechin we observed a significantly decreases the level of TBARS (P < 0.001, P < 0.001, respectively). In our other experiments, we found that epicatechin also decreased the amount of TBARS in human plasma treated with amisulpride. In conclusion, the presented results indicate that epicatechin-the major polyphenolic component of green tea reduced significantly human plasma lipid peroxidation caused by haloperidol. Moreover, epicatechin was found to be a more effective antioxidant, than the solution of pure resveratrol or quercetin.

The oxidative stress may be induced by the elevated homocysteine in schizophrenic patients.

The mechanisms of oxidative stress in schizophrenic patients are not fully understood. In the present study, we investigated the effect of elevated level of homocysteine (Hcys) on some parameters of oxidative stress, namely thiobarbituric acid reactive substances (TBARS), an index of lipid peroxidation in plasma, the level of carbonyl groups in plasma proteins, as well as the amount of 3-nitrotyrosine in plasma proteins isolated from schizophrenic patients. Patients hospitalised in I and II Psychiatric Department of Medical University in Lodz, Poland were interviewed with special questionnaire (treatment, course of diseases, dyskinesis and other EPS). According to DSM-IV criteria all patients had diagnosis of paranoid type. They were treated with antipsychotic drugs (clozapine, risperidone, olanzapine). Mean time of schizophrenia duration was about 5 years. High-performance liquid chromatography was used to analyse the total level of homocysteine in plasma. Levels of carbonyl groups and 3-nitrotyrosine residues in plasma proteins were measured by ELISA and a competition ELISA, respectively. The lipid peroxidation in plasma was measured by the level of TBARS. Our results showed that in schizophrenic patients the amount of homocysteine in plasma was higher in comparison with the control group. We also observed a statistically increased level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine in plasma proteins from schizophrenic patients. Moreover, our experiments indicate that the correlation between the increased amount of homocysteine and the oxidative stress exists. Considering the data presented in this study, we suggest that the elevated Hcys in schizophrenic patients may stimulate the oxidative stress.

Quetiapine, olanzapine and haloperidol affect human plasma lipid peroxidation in vitro.

OBJECTIVE: Oxidative injury in schizophrenia may be caused not only by pathophysiological processes but partly also by treatment with antipsychotics. The purpose of the present study was to examine and to compare the effects of quetiapine (QUE), olanzapine (OLA) and haloperidol (HAL), at final concentrations corresponding to doses used for treatment of acute episodes of schizophrenia, on plasma lipid peroxidation in vitro, measured by the level of thiobarbituric acid-reactive substances (TBARS). METHODS: Blood from 30 healthy volunteers was collected into ACD (citric acid/citrate/dextrose) solution. The drugs in form of active substances were dissolved in 0.01% dimethyl sulfoxide, added to plasma at the final concentrations [QUE (175 and 275 ng/ml), OLA (20 and 40 ng/ml), HAL (4 and 20 ng/ml)] and incubated for 1 and 24 h at 37 °C. The level of TBARS was measured spectrophotometrically (according to the Rice-Evans method, 1991). RESULTS: The comparative study in vitro showed that QUE causes a decrease in the TBARS level in plasma, whereas HAL increases the plasma TBARS level. After 24 h of incubation of plasma with QUE or HAL (at lower and higher concentrations),thedifferences in TBARS levels between the drugs were significant (p = 5.9 × 10⁻4, p = 2.2 × 10⁻5, respectively). CONCLUSION: QUE and OLA, contrary to the prooxidative action of HAL, did not induce oxidative stress; moreover, QUE has antioxidant properties.

Comparative Study of the Effects of Atypical Antipsychotic Drugs on Plasma and Urine Biomarkers of Oxidative Stress in Schizophrenic Patients.

PURPOSE: Evidence that antipsychotic drugs (ADs) can affect oxidative stress estimated with various biomarkers in schizophrenic patients is controversial and limited. Therefore, in the present study, we assessed the ability of six atypical ADs (clozapine, olanzapine, quetiapine, risperidone, aripiprazole, and ziprasidone) used in schizophrenia treatment to modulate oxidative damage to different biomolecules such as lipids and proteins. PATIENTS AND METHODS: We measured the levels of oxidative stress markers in plasma and urine: total antioxidant capacity by FRAP (according to a modified method of Benzie & Strain), thiobarbituric acid reactive species - TBARS (spectrophotometric method), 4-hydroxy-2-nonenal (4-HNE) (OxiSelect™ HNE Adduct Competitive ELISA Kit), 3-nitrotyrosine (3-NT) (OxiSelect™ Nitrotyrosine ELISA Kit) in plasma, and F2-isoprostanes (BIOXYTECH® Urinary 8-epi-Prostaglandin F2α) in the urine of 60 schizophrenic patients (before and after treatment) and in 30 healthy subjects. RESULTS: Our results showed that in schizophrenic patients levels of lipid peroxidation markers (TBARS, F2-isoprostanes) were higher than in healthy subjects but FRAP in schizophrenic patients was lower than in healthy controls and increased after 4-week treatment with tested ADs. A 4-week treatment with ADs caused the improvement of psychopathology symptoms estimated by Positive and Negative Syndrome Scale (PANSS) that was accompanied by decreased lipid peroxidation (F2-isoprostanes, TBARS; p=2.9x10-6, p=7.6x10-5, respectively) and an increase in total antioxidative capacity (FRAP) (p=5.16x10-16). CONCLUSION: Atypical antipsychotics especially clozapine, olanzapine and quetiapine demonstrate the effective outcome of antipsychotic treatment, beneficial antioxidative action by reducing lipid peroxidation and increased total plasma antioxidant activity.

Lipid peroxidation in patients with schizophrenia.

AIMS: There is evidence that dysregulation of free radicals metabolism associated with abnormal activities of antioxidative enzymes in schizophrenia can lead to lipid peroxidation in plasma, erythrocytes, blood platelets and cerebrospinal fluid. Injury to neurons in schizophrenia may affect their function, i.e. membrane transport, impairment of energy production in mitochondria, changes in membrane phospholipid composition, alteration of receptors and transporters as well as neurotransmission. The purpose of the present study was to assess the total antioxidant capacity (TAC) and lipid peroxidation (expressed as the level of thiobarbituric acid reactive substances [TBARS]) in plasma from schizophrenic patients taking olanzapine or risperidone. The level of TBARS estimated according to the Rice-Evans method and TAC ([ABTS; 2,2'-azinobis-(3-ethylbenzothiazoline-6-sulfonic acid) radical cation decolorization assay]) in plasma from schizophrenic patients (DSM-IV criteria for schizophrenia, n = 30, age 18-36) taking olanzapine or risperidone and from healthy volunteers (n = 30) were measured. METHODS: The level of TBARS in plasma from healthy volunteers after incubation with olanzapine or risperidone was also estimated. RESULTS: Significantly lower plasma TAC (P < 0.05) and significantly increased level of TBARS (P < 0.001) in schizophrenic patients were observed. The in vitro study showed that after olanzapine or risperidone (at final concentrations corresponding to doses used in acute episodes of schizophrenia treatment) no changes of plasma lipid peroxidation were found (P > 0.05). The obtained results indicate that the pro-oxidant disturbances occur in schizophrenic patients (acute episode) taking stable doses of olanzapine or risperidone. CONCLUSION: It seems that second-generation antipsychotics (olanzapine and risperidone) are not responsible for increase of plasma lipid peroxidation.

Oxidative/nitrative modifications of plasma proteins and thiols from patients with schizophrenia.

OBJECTIVE: The level of various specific biomarkers of oxidative stress in plasma from schizophrenic patients, as well as biomarkers (the level of isoprostanes) in urine in schizophrenic patients was described. The aim of our present study was to evaluate biomarkers of oxidative stress by oxidative/nitrative modifications of plasma proteins (by measuring the level of carbonyl groups and 3-nitrotyrosine in proteins) from patients with schizophrenic disorders and from control group. We also investigated the level of low-molecular-weight thiols [glutathione (GSH), cysteine (CSH), cysteinylglycine (CGSH) and homocysteine] in plasma obtained from schizophrenic patients and from healthy volunteers. Patients hospitalized in the 1st and 2nd Psychiatric Department of the Medical University in Lodz, Poland were interviewed with a special questionnaire (treatment, course of diseases, dyskinesis and other extrapyramidal syndromes). According to DSM-IV criteria, all patients had a diagnosis of paranoid type. They were treated with antipsychotic drugs (clozapine, risperidone, olanzapine). The mean duration of schizophrenia was about 5 years. METHODS: Levels of carbonyl groups and 3-nitrotyrosine residues in plasma proteins were measured by ELISA and a competition ELISA, respectively. High-performance liquid chromatography was used to analyze free thiols in plasma. RESULTS: We observed a statistically increased level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine in plasma proteins from schizophrenic patients. In schizophrenic patients the amount of homocysteine in plasma was higher compared with the control group; the level of GSH, CSH and CGSH was decreased. This indicates that reactive oxygen species and reactive nitrogen species may stimulate oxidative/nitrative modifications of plasma proteins in schizophrenic patients. CONCLUSION: Considering the data presented in this study, we suggest that the amount of carbonyl groups and 3-nitrotyrosine in plasma proteins may be important indicators of protein damage in vivo in schizophrenia.

Isoprostenes as indicators of oxidative stress in schizophrenia.

OBJECTIVE: Free radicals induce oxidative stress and damage to all types of biological molecules and may be involved in pathology of schizophrenia. A cell membrane dysfunction caused by lipid peroxidation can be secondary to a free radical-mediated pathology and may contribute to specific aspects of schizophrenic symptomatology and complications of its treatment. METHOD: The aim of our study was to estimate oxidative stress in a group of schizophrenic patients by using different biomarkers of free radicals-induced lipid peroxidation (isoprostanes, thiobarbituric acid reactive substances (TBARS)). We also determined the products of enzymatic peroxidation of arachidonic acid, such as thromboxane B2 (TXB2) and its metabolite 11-dehydrothromboxane B2. Isoprostanes (IPs) are a family of novel prostaglandin isomers and are produced in free radical-catalysed reactions from arachidonic acid. They are useful as a specific, sensitive, chemically stable, noninvasive index of free radical generation in vivo. We therefore assessed in schizophrenic patients and control subjects the level of urinary excretion of isoprostane--8-epi-prostaglandin F2 alpha, (8-isoPGF2 alpha)--a marker of lipid peroxidation induced by free radicals using an immunoassay kit. We also studied the level of the other marker of enzymatic arachidonic acid peroxidation--11-dehydrothromboxane B2--in urine from schizophrenic patients and healthy volunteers. Moreover, we estimated the production of TBARS and TXB2 in plasma from schizophrenic patients and the control group. Patients hospitalised in the II Psychiatric Department of Medical University in Lodz, Poland, were interviewed with a special questionnaire (treatment, course of diseases, dyskinesis and other EPS). According to DSM-IV criteria, all patients had diagnosis of paranoid type. All patients were treated with second-generation antipsychotic drugs (risperidone, clozapine, and olanzapine). Mean time of schizophrenia duration was about 2 years. RESULTS: We observed a statistically increased level of TBARS in plasma (P=0.000162) and isoprostanes (P=3.5 x 10(-12)) in urine of schizophrenic patients in comparison with the control group. The level of markers of enzymatic oxidation of arachidonic acid (TXB2 and its metabolite, 11-dehydrothromboxane B2) did not change. This indicates that free radicals induce peroxidation of unsaturated fatty acid in schizophrenic patients. CONCLUSION: Considering the data presented in this study, we suggest that non-invasive measurement of 8-isoPGF2 alpha, is a valuable and sensitive (contrary to TBARS) indicator of oxidative stress status in vivo in schizophrenia.

The changes of aggregability of blood platelets in schizophrenia.

OBJECTIVE: Oxidative stress in schizophrenia may be responsible for the changes of platelet function and reactivity. Therefore, the aim of our present study was to evaluate the response of platelets from patients with schizophrenia to platelet agonists such as ADP and collagen. RESULTS: Platelet aggregation of schizophrenic patients and healthy subjects stimulated by collagen or ADP showed significant differences. Aggregation of platelets stimulated by collagen was significantly lower in schizophrenic patients (about 86%) than in healthy subjects (P=0.022), but when this process was induced by ADP, aggregation of platelets was significantly higher in schizophrenic patients (increase to about 112%) than in healthy subjects (P=0.018). We also observed that antipsychotic drugs (clozapine, risperidone, olanzapine, haloperidol) reduce aggregation of platelets of schizophrenic patients and healthy group in vitro. CONCLUSION: The obtained results indicate that the response of platelets from schizophrenic patients to ADP and collagen is different than in healthy subjects.

Modifications of blood platelet proteins of patients with schizophrenia.

Oxidative damage to lipids in plasma, blood platelets and neurons in patients with schizophrenia was described. The aim of our present study was to evaluate oxidative/nitrative modifications of blood platelets proteins by measurement the level of biomarkers of oxidative stress such as carbonyl groups, thiol groups and 3-nitrotyrosine in proteins in patients with schizophrenia and compare with a control group. Levels of carbonyl groups and 3-nitrotyrosine residues in platelet proteins were measured by ELISA and competition ELISA, respectively. The method with 5,5'-dithio-bis(2-nitro-benzoic acid) has been used to analyse thiol groups in platelet proteins. We demonstrated for the first time in platelet proteins from patients with schizophrenia a statistically significant increase of the level of biomarkers of oxidative/nitrative stress such as carbonyl groups or 3-nitrotyrosine; in schizophrenic patients the amount of thiol groups in platelet proteins was lower than in platelets from healthy subjects. Our results strongly indicate that in patients with schizophrenia reactive oxygen species and reactive nitrogen species induce not only peroxidation of lipids, but also may stimulate oxidative/nitrative modifications of platelet proteins. The consequence of these modifications may be the alteration of platelet protein structure and function.

Platelet haemostatic function in psychiatric disorders: Effects of antidepressants and antipsychotic drugs.

Objectives Platelets, the smallest anucleated blood cells, play an essential role in the first step of complex haemostatic process. This review presents the haemostatic function of blood platelets related to their activation in psychiatric disorders (schizophrenia, depression), the role of antipsychotic and antidepressant medication, and introduces the mechanisms by which activated platelets may be involved in the pathophysiology of these disorders. Methods Platelets are interesting and easily accessible blood cells to study biochemical pathways related to schizophrenia and other psychiatric disorders, and their complex activation process might be useful as a diagnostic peripheral marker for studying psychiatric disorders and haemostatic complications. Results The excessive activation of platelets observed in patients with depression and schizophrenia is involved in cardiovascular diseases, stroke and increased risk of thrombotic complications that may be major causes of morbidity and mortality of patients. The use of antidepressants or antipsychotic drugs in depression and schizophrenia treatment is often associated with haematological side effects such as bleeding, venous thromboembolism and impaired platelet function. Conclusions Understanding the role of platelet activation in psychiatric disorders such as schizophrenia or depression and medication may improve therapies in the future.

Antioxidant properties of atypical antipsychotic drugs used in the treatment of schizophrenia.

The aim of this study was to compare the antioxidant activities of six atypical antipsychotic drugs: clozapine (CLZ), quetiapine, olanzapine (OLA), risperidone, ziprasidone, aripiprazole (ARI), as well as a typical antipsychotic drug, haloperidol. Several tests of antioxidant activity were used: protection of thiol groups against oxidation by peroxynitrite (PN) and 3-morpholinosydnonimine (SIN-1, generator of PN), oxidation of dihydrorhodamine 123 by PN, SIN-1 and hypochlorite (NaOCl), bleaching of fluorescein fluorescence by PN, 2,2'-azobis(2-amidinopropane) dihydrochloride (AAPH, generator of peroxyl radicals) and NaOCl, radical-scavenging activity with respect to 2,2'-azinobis(3-ethylbenzthiazoline-6-sulfonic acid) radical, 2,2-diphenyl-1-picrylhydrazyl free radical and the Ferric Reducing Antioxidant Potential. In most of the tests, OLA showed the highest antioxidant activity, followed by CLZ and in some cases ARI, other compounds being much less active or not active. OLA and CLZ exerted limited toxicity on mouse neuroblastoma Neuro-2A (N2A) cells and protected the cells against the toxic action of SIN-1, AAPH and NaOCl in the physiologically relevant concentration range of these oxidants. Both drugs reduced the PN-induced nitration of intracellular proteins. Given that schizophrenia is associated with oxidative and nitrosative stress, the direct antioxidant activity OLA and CLZ may contribute to the therapeutic action of these compounds.

[The prevalence od social phobia in representative group of adolescents from Lodz]. / Wystepowanie leku spolecznego wsród reprezentatywnej grupy mlodziezy z Lodzi.

AIM: Recent epidemiological studies have produced a remarkable variation in the estimated life-time prevalence of social phobia, ranking from 0.5% to 22.6%. About 95% of social phobia occurs prior to the age of 20, approximately 40% prior to the age of 10. Studies of mainly patient samples report a mean age of onset of 14.6 to 20 years. METHOD: In co-operation with GUS, the year 2000 we assessed with a specially prepared questionnaire including DSM-IV criteria for social phobia and CIDI, the prevalence of specific and generalised type of social phobia in a representative group of adolescent population from Lódz. Subjects of the study (n = 1929) were chosen from 36450 adolescents. RESULTS: We found, that generalised social phobia was present in 7% of subjects, specific subtype in 17% of subjects, more frequently in women than in men (p < 0.05), with the same prevalence in adolescents from various type of schools. 15% of adolescents with social phobia were alcohol or psychoactive drug abusers, 5% attempted suicide. CONCLUSION: Only 1/4th of adolescents with social phobia was in psychological or psychiatric therapy. Subjects with social phobia have a high risk of other comorbid psychiatric disorders and significant worsening of social functioning.

Generation of superoxide anion radicals and platelet glutathione peroxidase activity in patients with schizophrenia.

Blood platelets are considered to be a peripheral marker in schizophrenia and other psychiatric disorders. Oxidative stress in schizophrenia may be responsible for changes in platelet metabolism and function; therefore, the aim of this study was to examine and compare the generation of superoxide anions and activity of an antioxidant enzyme (glutathione peroxidase [GPx]) in blood platelets in patients with schizophrenia and healthy subjects. The level of superoxide anions generated in platelets after thrombin and platelet-activating factor stimulation and activity of GPx in patients with schizophrenia and healthy volunteers was estimated. The results obtained from the study indicate that the generation of superoxide anions in platelets as a response of platelets in patients with schizophrenia to such activating factors as thrombin or platelet-activating factor is higher than in the response of platelets of healthy subjects. In platelets from schizophrenic patients, suppressed GPx activity of about 67% was observed.

Polyphenols from Berries of Aronia melanocarpa Reduce the Plasma Lipid Peroxidation Induced by Ziprasidone.

Background. Oxidative stress in schizophrenia may be caused partially by the treatment of patients with antipsychotics. The aim of the study was to establish the effects of polyphenol compounds derived from berries of Aronia melanocarpa (Aronox) on the plasma lipid peroxidation induced by ziprasidone in vitro. Methods. Lipid peroxidation was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) alone and with Aronox (5 ug/ml; 50 ug/ml). Results. We observed a statistically significant increase of TBARS level after incubation of plasma with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) (after 24 h incubation: P = 7.0 × 10(-4), P = 1.6 × 10(-3), and P = 2.7 × 10(-3), resp.) and Aronox lipid peroxidation caused by ziprasidone was significantly reduced. After 24-hour incubation of plasma with ziprasidone (40 ng/ml; 139 ng/ml; and 250 ng/ml) in the presence of 50 ug/ml Aronox, the level of TBARS was significantly decreased: P = 6.5 × 10(-8), P = 7.0 × 10(-6), and P = 3.0 × 10(-5), respectively. Conclusion. Aronox causes a distinct reduction of lipid peroxidation induced by ziprasidone.

Beta-glucan from Saccharomyces cerevisiae reduces plasma lipid peroxidation induced by haloperidol.

Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to establish the effects of beta-d-glucan, polysaccharide derived from the yeast cell walls of species such as Saccharomyces cerevisiae, and the antipsychotics (the first generation antipsychotic (FGA) - haloperidol and the second generation antipsychotic (SGA) - amisulpride) action on plasma lipid peroxidation in vitro. Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of beta-glucan (4 µg/ml). The action of beta-d-glucan was also compared with the properties of a well characterized commercial monomeric polyphenol - resveratrol (3,4',5-trihydroxystilbene, the final concentration - 4 µg/ml). The two-way analysis variance showed that the differences in TBARS levels were depended on the type of tested drugs (p=7.9 × 10(-6)). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24h incubation of plasma with haloperidol compared to the control samples (p<0.01, p<0.02, respectively). Amisulpride, contrary to haloperidol (after 1 and 24h) did not cause plasma lipid peroxidation (p>0.05). We showed that in the presence of beta-glucan, lipid peroxidation in plasma samples treated with haloperidol was significantly decreased. Moreover, we did not observe the synergistic action of beta-glucan and amisulpride on the inhibition of plasma lipid peroxidation. However, the beta-d-glucan was found to be more effective antioxidant, than the solution of pure resveratrol. The presented results indicate that beta-glucan seems to have distinctly protective effects against the impairment of plasma lipid molecules induced by haloperidol.

Inhibitory effects of polyphenol compounds on lipid peroxidation caused by antipsychotics (haloperidol and amisulpride) in human plasma in vitro.

OBJECTIVE: Plant antioxidants protect cells against oxidative stress. Since oxidative stress observed in schizophrenia may be caused partially by the treatment of patients with various antipsychotics, the aim of the study was to assess whether there is a difference between a first-generation antipsychotic (FGA; haloperidol) and a second-generation antipsychotic (SGA; amisulpride (4-amino-N-[(1-ethylpyrrolidin-2-yl)methyl]-5-ethysufonyl-2-methoxy-benzamide)) action on peroxidation of plasma lipids, and to establish the effects of polyphenol compounds (resveratrol (3,4',5-trihydroxystilbene) and quercetin (3,5,7,3',4'- pentahydroxyflavone)) and the antipsychotics action on this process in vitro. METHODS: Lipid peroxidation in human plasma was measured by the level of thiobarbituric acid reactive species (TBARS). The samples of plasma from healthy subjects were incubated with haloperidol or amisulpride in the presence of polyphenols: resveratrol and quercetin. RESULTS: The two-way analysis variance (ANOVA II test) showed that the differences in TBARS levels were depended on the type of tested drugs (P = 8.35 x 10(-6)). We observed a statistically increase of the level of biomarker of lipid peroxidation such as TBARS after 1 and 24 h incubation of plasma with haloperidol compared to the control samples (P<0.03, P<0.0002, respectively). Amisulpride, contrary to haloperidol (after 1 h) does not significantly influence the increase of plasma TBARS level in comparison with control samples. Amisulpride induced significantly decrease of plasma TBARS level after 24 h (P=0.03). We showed that in the presence of polyphenols: resveratrol and quercetin, lipid peroxidation in plasma samples treated with tested drugs was significantly decreased. After incubation (24 h) of plasma with haloperidol in the presence of resveratrol or quercetin we observed a significantly decreased the level of TBARS (P = 3.9 x 10(-4), P = 2.1 x 10(-3), respectively). CONCLUSION: Considering the data presented in this study, we showed that haloperidol, contrary to amisulpride caused a distinct increase of lipid peroxidation. Polyphenols reduced significantly lipid peroxidation caused by haloperidol.

The effects of the second generation antipsychotics and a typical neuroleptic on collagen-induced platelet aggregation in vitro.

OBJECTIVE: Antipsychotics are widely used in psychiatry, and consequently a lot of their side effects have been reported. One of them is cardiovascular disease leading to increased risk of stroke, thrombosis, pulmonary, embolism, in which hyperactivation of blood platelets is involved. The purpose of the present study was to examine the effects of the second generation antipsychotics (SGAs) such as clozapine, risperidone, and olanzapine, and a typical neuroleptic - haloperidol - on the one step of platelet activation-platelet aggregation induced by collagen in vitro. Blood was collected into buffered sodium citrate (3.8%) and centrifuged to get platelet-rich plasma (PRP). In PRP (2x10(8) platelets/ml) obtained from healthy volunteers that was incubated with antipsychotics (clozapine, risperidone, olanzapine, haloperidol; 30 min) aggregation of blood platelets was measured using a Chrono-Log Lumi-aggregometer. Aggregation of platelets was measured after stimulation of platelets with 1 microl of collagen (2 microg/ml). RESULTS: Clozapine, like haloperidol reduced platelet aggregation induced by collagen (inhibition of platelet aggregation reached about 20%) (P=1x10(-5) and P=0.003, respectively). Risperidone had also a weak antiaggregatory effect (P=0.05). Among tested antipsychotics only olanzapine had no effect on collagen-stimulated platelet aggregation (P>0.05). CONCLUSION: The obtained results indicate that the difference in action of tested drugs on platelet aggregation may dependent on the various chemical structures of these drugs. Clozapine, risperidone and haloperidol are structurally diverse, and they all significantly reduce platelet aggregability induced by collagen. On the other hand, a close structural analog of clozapine - olanzapine - did not inhibit platelet aggregation. However, mechanism of antipsychotics action on blood platelets is not clear. Moreover, it seems that clozapine, risperidone and haloperidol treatment due to antiaggregatory action may have even some antithrombotic effects.

The first- and second-generation antipsychotic drugs affect ADP-induced platelet aggregation.

OBJECTIVE: Blood platelets play an important role in haemostasis and their hyperaggregability may lead to thrombosis and cardiovascular diseases. Increased incidence of mortality, caused by cardiovascular disease, and the increased risk of thrombotic complication in schizophrenic patients treated with antipsychotics have been reported. The effects of antipsychotic drugs on blood platelet function are not fully explained, therefore the purpose of the present study was to examine and compare the effects of the second-generation antipsychotic drugs used in schizophrenia (clozapine, risperidone and olanzapine), with the effects of the first generation antipsychotic, haloperidol, on the platelet aggregation induced by ADP in vitro. METHODS: Blood obtained from healthy volunteers (n=25) collected into sodium citrate was centrifuged (250xg, 10 min) at room temperature to obtain platelet-rich plasma. Aggregation of blood platelets (10 microM ADP) was recorded (Chrono-log aggregometer) in platelet-rich plasma preincubated with antipsychotic drugs (final concentration: clozapine 420 ng/ml, risperidone 65 ng/ml, olanzapine 40 ng/ml, haloperidol 20 ng/ml) for 30 min. RESULTS: Our results showed that all tested drugs inhibit platelet aggregation induced by ADP in vitro. Among studied antipsychotic drugs clozapine and olanzapine significantly reduced platelet aggregability in vitro. In comparison with control platelets (without the drug), clozapine inhibited ADP-induced platelet aggregation by 21% (P=3.7x10(-6)) and olanzapine by 18% (P=2.8x10(-4)), respectively. CONCLUSION: The obtained results indicate that antipsychotic drugs, especially clozapine and olanzapine, contrary to haloperidol, reduced response of blood platelets to ADP measured as platelet aggregation. This suggests that therapy with such antipsychotics, particularly with second-generation antipsychotics, may partly reduce prothrombotic events associated with the increased platelet activation observed in schizophrenic patients. The mechanism of antiaggregatory influence of antipsychotics requires further studies.