Influence Of Clozapine Research Articles

Proteome Analysis of PC12 Cells Reveals Alterations in Translation Regulation and Actin Signaling Induced by Clozapine

Although antipsychotics are routinely used in the treatment of schizophrenia for the last decades, their precise mechanism of action is still unclear. In this study, we investigated changes in the PC12 cells’ proteome under the influence of clozapine, risperidone, and haloperidol to identify protein pathways regulated by antipsychotics. Analysis of the protein profiles in two time points: after 12 and 24 h of incubation with drugs revealed significant alterations in 510 proteins. Further canonical pathway analysis revealed an inhibition of ciliary trophic factor signaling after treatment with haloperidol and showed a decrease in acute phase response signaling in the risperidone group. Interestingly, all tested drugs have caused changes in PC12 proteome which correspond to inhibition of cytokines: tumor necrosis factor (TNF) and transforming growth factor beta 1 (TGF-β1). We also found that the 12-h incubation with clozapine caused up-regulation of protein kinase A signaling and translation machinery. After 24 h of treatment with clozapine, the inhibition of the actin cytoskeleton signaling and Rho proteins signaling was revealed. The obtained results suggest that the mammalian target of rapamycin complex 1 (mTORC1) and 2 (mTORC2) play a central role in the signal transduction of clozapine.

Influence of clozapine on neurodevelopmental protein expression and behavioral patterns in animal model of psychiatric disorder induced by low-level of lead.

Exposure to lead during pregnancy is a risk factor for the development of psychiatric disorders in the offspring. In this study, we investigated whether exposure to low levels of lead acetate (0.2%) in drinking water during pregnancy and lactation causes behavioral impairment and affects the expression of proteins associated with neurodevelopment. Lead exposure altered several parameters in rat offspring compared with those unexposed in open-field, social interaction, and pre-pulse inhibition tests. These parameters were restored to normal levels after clozapine treatment. Western blot and immunohistochemical analyses of the hippocampus revealed that several neurodevelopmental proteins were downregulated in lead-exposed rats. The expression was normalized after clozapine treatment (5 mg/kg/day, postnatal day 35–56). These findings demonstrate that downregulation of several proteins in lead-exposed rats affected subsequent behavioral changes. Our results suggest that lead exposure in early life may induce psychiatric disorders and treatment with antipsychotics such as clozapine may reduce their incidence.

Should we be targeting sleep architecture to more effectively treat schizophrenia?

The sleep architecture (or sleep kinetics) of schizophrenia is different from that of other mental illnesses, including major depressive disorder. However, clinicians rarely consider these parameters in clinical settings during treatment. This article discusses the use of polysomnography to characterize the sleeping patterns of patients diagnosed with schizophrenia and the positive influence of clozapine on sleep in patients with schizophrenia.

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

ABSTRACTAtypical 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.

Influence of clozapine to modified electroconvulsive therapy in the treatment resistant schizophrenia

IntroductionClozapine is one of the most effective drugs for the treatment resistant schizophrenia (TRS). It was reported that modified electroconvulsive therapy (mECT) may be an effective clozapine augmentation strategy in TRS.ObjectiveThe objective of this study was to investigate the influence of clozapine to mECT in the TRS.MethodsForty-seven patients were recruited in this study, but eight patients were excluded because clozapine was discontinued by reason of side effects. Ultimately, 39 patients were enrolled.ResultsSeventeen patients received mECT before clozapine therapy. Two patients continued mECT after starting clozapine therapy. There was a significant difference between before–after clozapine therapy (χ2 test, P< 0.01). Intermittent mECT was performed for 3 patients before clozapine and for one patient after starting clozapine.DiscussionThis result suggests that clozapine therapy reduces mECT. In Japan, the first-line treatment for TRS is CLO. mECT is recommended for clozapine resistant schizophrenia patients. Prescription of CLO is limited in the part of medical facility because all physicians who prescribe clozapine must be registered with the clozaril patient monitoring service in Japan. It is considered that mECT is more readily selected than clozapine therapy. Therefore, the number of mECT is not reduced generally.ConclusionClozapine therapy reduces the necessity of mECT.Disclosure of interestThe authors have not supplied their declaration of competing interest.

MicroRNA Microarray Analysis Combined with Interaction Network Analysis to Investigate the Influence of Clozapine to Metabolic Syndrome

MicroRNA Microarray Analysis Combined with Interaction Network Analysis to Investigate the Influence of Clozapine to Metabolic Syndrome

Dissociation of acute and chronic intermittent phencyclidine-induced performance deficits in the 5-choice serial reaction time task: influence of clozapine

Cognitive deficits are a core feature of schizophrenia that respond minimally to existing drugs. PCP is commonly used to model schizophrenia-like deficits preclinically although different dosing protocols may affect different domains. Here we characterise the acute, and chronic intermittent effects of PCP in the 5-choice serial reaction time task (5-CSRTT) in rats, and assess the effects of clozapine. In a novel approach, we also assess the effects of increased inhibitory load and conduct clinically relevant signal detection analysis (SDA). The effects of acute and repeated PCP (2.58 mg/kg) treatment on attentional processes and inhibitory control were assessed during and following the chronic treatment regime in the presence or absence of chronic clozapine (20 mg/kg/day). Thirty minutes post-PCP injection, there was an increase in anticipatory responding which disappeared after 24 h. Although, acute PCP did not change accuracy of responding or processing speed, repeated PCP revealed delayed deficits in cognitive processing speed which were partly ameliorated by clozapine. Extended inter-trial intervals increased premature responding, while SDA revealed that clozapine modified persistent PCP-induced deficits in lnBeta (a composite measure of risk taking versus caution). Acute NMDA receptor antagonism impairs inhibitory control, whereas repeated treatment produces delayed deficits in cognitive processing speed. The ability of clozapine partially to restore persistent PCP-induced deficits in processing speed and in lnBeta is consistent with clinical findings. This suggests that the enduring effects of repeated PCP treatment, combined with SDA, offers a useful, translational, approach to evaluate novel cognitive enhancers in the 5-CSRTT.

P.3.016 The influence of clozapine on platelet serotonin, monoamine oxidase and plasma serotonin levels: relationship with symptoms and cognition

P.3.016 The influence of clozapine on platelet serotonin, monoamine oxidase and plasma serotonin levels: relationship with symptoms and cognition

P.3.038 The influence of clozapine on cognitive functions and catalepsy in rats after single and chronic administration

P.3.038 The influence of clozapine on cognitive functions and catalepsy in rats after single and chronic administration

Insulin and leptin levels in patients with schizophrenia or related psychoses--a comparison between different antipsychotic agents.

Conventional as well as newer antipsychotics cause weight gain, and, in the regulation of body weight, both insulin and leptin are hormones involved. The aim of the present study was to compare these hormonal levels in patients on treatment with different antipsychotics. Nineteen patients receiving conventional antipsychotics, 14 patients receiving clozapine and 14 patients receiving olanzapine, were studied. Fasting blood samples for insulin, leptin, glucose, and drug serum concentrations were analyzed. In addition, body mass index (BMI) was calculated. The median insulin level was significantly higher in the patients receiving olanzapine than in those receiving conventional agents, whereas there was no significant difference in insulin between the clozapine and the other two groups. However, in the clozapine group, insulin levels were positively correlated to the drug serum concentration. BMI was elevated in about half of the patients, with no difference being found between the groups. The leptin level was significantly higher in the women than in the men in the conventional agent group, but not in the olanzapine or clozapine groups. The higher insulin level in the patients receiving olanzapine than in those receiving conventional antipsychotics, despite similar BMI, points to a probable influence of olanzapine on insulin secretion. The correlation between the insulin levels and the clozapine concentration indicates, in addition, an influence of clozapine on insulin secretion. The gender difference in leptin, i.e. females normally having higher leptin levels than males, was found in the conventional agent group, but not in the olanzapine or clozapine groups, suggesting that also leptin regulation is altered during olanzapine or clozapine treatments. Moreover, it was mainly due to an increase of leptin in the males that leptin levels were equalized between sexes in the olanzapine group. We conclude that the influence of olanzapine and clozapine on both insulin and leptin levels might be associated with their weight-gain-inducing ability, while other mechanisms may be involved in the weight gain caused by conventional antipsychotics.

The Influence of Clozapine and Typical Neuroleptics on Information Processing ofthe Central Nervous System under Clinical Conditions in Schizophrenic Disorders: Implications for Fitness to Drive

The present study investigates the psychomotor performance of schizophrenic inpatients receiving neuroleptic medication and comedication according to their clinical demands in regard to their fitness to drive. The hypothesis was tested that even under polydrug medication, the clozapine-treated patients (n = 10) would have a superior performance compared to the patients taking classical neuroleptics (n = 18). The data were collected by technical equipment (Act and React Testsystem) measuring reaction time, vigilance, visual perception and stress tolerance. The patients’ driving ability turned out to be equally impaired in both treatment groups; 11% of the patients passed all tests without major impairment; 32% of the patients showed some impairments that required individual evaluation of their driving ability; 57% were considered to be severely impaired and driving could not be recommended. Except for one test, no significant group differences in psychomotor reaction performance were obtained. These results are discussed concerning limitations and consequences.

The influence of clozapine on the cytokine system

The influence of clozapine on the cytokine system

Long-term experience with clozapine in Denmark: research and clinical practice.

In Denmark, the use of clozapine has increased markedly (15-25% per year) since 1983, when the drug was relaunched--after its withdrawal in 1975. Several factors have contributed to this development: 1) the interesting pharmacology of clozapine, especially the atypical influence on dopamine transmission, including a relatively high D-1/D-2 receptor affinity ratio, 2) the potent anti-anxiety and anti-psychotic effect in severe and otherwise therapy-resistant psychotic patients, and 3) the lack of extrapyramidal side effects. A special monitoring form (for registration of total and differential leucocyte counts, ECG, body weight, drugs, doses and reason for possible withdrawal of the clozapine) is used in most Danish psychiatric institutions. This form secures the regular control of vital parameters and serves as an instrument for surveys of the use of clozapine in Denmark. Also, more selective studies are being carried out, e.g., on the effect of clozapine monotherapy versus combined therapy, and on the influence of clozapine on cardiovascular functions, including left ventricular output (echocardiography).