Weeks Of Olanzapine Treatment Research Articles

Effects of 6-week olanzapine treatment on serum IL-2, IL-4, IL-8, IL-10, and TNF-α levels in drug-naive individuals with first-episode schizophrenia

BackgroundSchizophrenia is a complex neuropsychiatric disorder. Growing evidence indicates that the activation of the inflammatory response system with interleukin (IL)-2, IL-4, IL-8, IL-10, and tumor necrosis factor-alpha (TNF-α) plays an important role in the pathogenesis of schizophrenia,. However, clinical data on cytokine levels in patients with schizophrenia treated with antipsychotics are inconsistent or inconclusive. In this study, we have examined inflammatory factors’ alterations and their relationship to changes in clinical symptoms before and after olanzapine treatment of drug-naive patients with first-episode schizophrenia.MethodsWe recruited 142 hospitalized patients with first-episode schizophrenia as a study group; blood samples were collected, and the patients were assessed for clinical symptoms at baseline and after 6 weeks of olanzapine treatment. One hundred individuals with no history of mental illness were also recruited as healthy controls. Blood samples were collected, and the serum levels of IL-2, IL-4, IL-8, IL-10, and TNF-α were determined using an enzyme cycling assay. The severity of clinical symptoms was assessed according to the Positive and Negative Syndrome Scale (PANSS).ResultsIndividuals with schizophrenia had lower IL-8 levels and higher IL-10 levels than healthy controls (P < 0.001). Positive correlations were detected between serum IL-2 and IL-10 concentrations and each subscale of the PANSS (all P < 0.05). Moreover, a negative correlation existed between the serum IL-8 concentration and the PANSS negative score (r = − 0.172, P = 0.040). After 6 weeks of treatment, serum IL-8 levels in the patient group were lower than at baseline (P < 0.001), whereas serum IL-10 and TNF-α levels were higher than at baseline (all P < 0.05). Therefore, serum IL-10 can be determined as an independent risk factor for outcome in patients with first-episode schizophrenia (P = 0.02, OR = 2.327). Furthermore, serum IL-2, IL-10, and TNF-α levels were significantly lower, whereas the serum IL-8 level was significantly higher (P < 0.001) in the healthy control group than in the “response” and “no-response” treatment groups respectively.ConclusionsOur results indicate that serum IL-2, IL-8, IL-10, and TNF-α levels may be involved in the pathophysiological mechanisms of schizophrenia and correlate with the effects of olanzapine.

Chronic olanzapine treatment leads to increased opioid receptor expression and changes in feeding regulating neurons in the female rat hypothalamus

Opioid receptor antagonists have shown increasing promise as an adjunct therapy to psychotropic medication. The goal is to reduce the weight gain and metabolic adverse effects that are associated with certain second-generation antipsychotics, such as olanzapine and clozapine. In this study, female rats were treated for 4 weeks with a long-acting injectable formulation of olanzapine to assess effects on hypothalamic feeding regulation. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the mu, kappa and delta opioid receptors were defined in the five hypothalamic areas: paraventricular nucleus (PVN), arcuate nucleus (ARC), ventromedial nucleus (VMN), dorsomedial nucleus (DMN) and lateral hypothalamus (LH). In addition, hypothalamic neuron number and size were estimated using the unbiased optical fractionator and spatial rotator methods. Hyperphagia was observed after only 24hours of olanzapine treatment, with continued weight gain throughout the duration of the study. In contrast, the observed food intake reversed to control levels after 2 weeks of olanzapine treatment. Chronic olanzapine treatment increased expression of kappa opioid receptor mRNA and receptor availability in the PVN, as well as increased mu opioid receptor availability in the PVN, ARC and VMN. These changes were accompanied by fewer anorexigenic proopiomelanocortin-expressing neurons of the ARC and corticotropin-releasing hormone expressing neurons of the PVN. This study links olanzapine-driven metabolic effects to increased opioid receptor expression in the hypothalamus, thus providing a rationale for the positive effects of using opioid receptor antagonists to relieve olanzapine adverse effects.

Gamma-aminobutyric acid supplementation improves olanzapine-induced insulin resistance by inhibiting macrophage infiltration in mice subcutaneous adipose tissue.

To investigate whether gamma-aminobutyric acid (GABA) supplementation improves insulin resistance during olanzapine treatment in mice and to explore the underlying mechanisms. Insulin resistance and body weight gain were induced in mice by 10 weeks of olanzapine treatment. Simultaneously, the mice were administered GABA after 4 weeks of olanzapine administration. We found that mice treated with olanzapine had lower GABA levels in serum and subcutaneous white adipose tissue (sWAT). GABA supplementation restored GABA levels and improved olanzapine-induced lipid metabolism disorders and insulin resistance. Chronic inflammation in adipose tissue is one of the main contributors to insulin resistance. We found that GABA supplementation inhibited olanzapine-induced adipose tissue macrophage infiltration and M1-like polarization, especially in sWAT. In vitro studies showed that stromal vascular cells, rather than adipocytes, were sensitive to GABA. Furthermore, the results suggested that GABA improves olanzapine-induced insulin resistance at least in part through a GABAB receptor-dependent pathway. These findings suggest that targeting GABA may be a potential therapeutic approach for olanzapine-induced metabolic disorders.

Alteration in the mRNA expression profile of the autophagy-related mTOR pathway in schizophrenia patients treated with olanzapine

BackgroundThe mammalian target of rapamycin protein (mTOR) signaling pathway is involved in the pathogenesis of schizophrenia and the mechanism of extrapyramidal adverse reactions to antipsychotic drugs, which might be mediated by an mTOR-dependent autophagy impairment. This study aimed to examine the expression of mTOR pathway genes in patients with schizophrenia treated with olanzapine, which is considered an mTOR inhibitor and autophagy inducer.MethodsThirty-two patients with acute schizophrenia who had been treated with olanzapine for four weeks (average dose 14.24 ± 4.35 mg/d) and 32 healthy volunteers were recruited. Before and after olanzapine treatment, the Positive and Negative Syndrome Scale (PANSS) was used to evaluate the symptoms of patients with schizophrenia, and the mRNA expression levels of mTOR pathway-related genes, including MTOR, RICTOR, RAPTOR, and DEPTOR, were detected in fasting venous blood samples from all subjects using real-time quantitative PCR.ResultsThe MTOR and RICTOR mRNA expression levels in patients with acute schizophrenia were significantly decreased compared with those of healthy controls and further significantly decreased after four weeks of olanzapine treatment. The DEPTOR mRNA expression levels in patients with acute schizophrenia were not significantly different from those of healthy controls but were significantly increased after treatment. The expression levels of the RAPTOR mRNA were not significantly different among the three groups. The pairwise correlations of MTOR, DEPTOR, RAPTOR, and RICTOR mRNA expression levels in patients with acute schizophrenia and healthy controls were significant. After olanzapine treatment, the correlations between the expression levels of the DEPTOR and MTOR mRNAs and between the DEPTOR and RICTOR mRNAs disappeared.ConclusionsAbnormalities in the mTOR pathway, especially DEPTOR and mTORC2, might play important roles in the autophagy mechanism underlying the pathophysiology of schizophrenia and effects of olanzapine treatment.

Altered mRNA expression levels of autophagy- and apoptosis-related genes in the FOXO pathway in schizophrenia patients treated with olanzapine

This study attempted to analyze the alterations in the mRNA expression levels of autophagy- and apoptosis-related genes in the forkhead box transcription factor O (FOXO) pathway in schizophrenia patients before and after olanzapine treatment. For a total of 32 acute schizophrenic inpatients, clinical data with PANSS were obtained before and after four weeks of olanzapine treatment (mean dose 14.24 ± 4.35 mg/d) along with data from 32 healthy volunteers. The mRNA expression levels of the FOXO pathway genes were measured by real-time qPCR after fasting venous blood was collected and analyzed. The mRNA expression levels of FOXO1, FOXO3A, FASLG, and BCL2L11 were observed to be significantly decreased in acute schizophrenia patients. After four weeks of olanzapine treatment, the expression levels of the first three genes were further reduced, but BCL2L11 expression levels were not significantly changed. The pairwise correlations between the mRNA expression level of FASLG and those of the other three genes were not observed in acute schizophrenia patients, while these relationships were observed in healthy controls. After olanzapine treatment, the FASLG mRNA expression level was restored and exhibited a pairwise correlation with the FOXO3A and BCL2L11 mRNA expression levels but not with the FOXO1 mRNA expression level, and FASLG mRNA expression was also correlated with the duration of the disease. The statuses and correlations of the mRNA expression levels of FOXO pathway-related genes were altered in schizophrenia patients and were affected by olanzapine treatment and the duration of the disease.

Effects of olanzapine treatment on lipid profiles in patients with schizophrenia: a systematic review and meta-analysis

Olanzapine-induced dyslipidemia significantly increases the risk of cardiovascular disease in patients with schizophrenia. However, the clinical features of olanzapine-induced dyslipidemia remain hitherto unclear because of inconsistencies in the literature. This meta-analysis thus investigated the effects of olanzapine treatment on lipid profiles among patients with schizophrenia. Studies of the effects of olanzapine on lipids were obtained through the PubMed, Web of science, The Cochrane Library and Embase databases (up to January 1, 2020). Twenty-one studies and 1790 schizophrenia patients who received olanzapine therapy were included in our analysis. An olanzapine-induced increase was observed in plasma triglyceride (TG), total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C) levels in patients with schizophrenia (all P < 0.05). Moreover, the time points analyzed included the following: baseline, 4 weeks, 6 weeks, 8 weeks, 12 weeks, and ≥ 24 weeks (data of ≥ 24 weeks were integrated). The significant elevation of TG, TC, and LDL-C was observed in patients with schizophrenia already by 4 weeks of olanzapine therapy (all P < 0.05), with no obvious changes observed in high-density lipoprotein cholesterol (HDL-C) (P > 0.05). In conclusion, olanzapine-induced dyslipidemia, characterized by increased TG, TC, and LDL-C levels, was observed in patients with schizophrenia already by 4 weeks of olanzapine treatment.

Effects of long-term antipsychotics treatment on body weight: A population-based cohort study.

Background:Antipsychotics are often prescribed for long-term periods, however, most evidence of their impact on body weight comes from short-term clinical trials. Particularly, impact associated with dosage has been barely studied.Aims:The aim of this study was to describe the short- and long-term change in body weight of people initiated on high or low doses of the three most commonly prescribed second-generation antipsychotics.Methods:Retrospective cohorts of individuals with a diagnosed psychotic disorder observed from 2005 to 2015 in the UK primary care. The exposure was the first prescription of olanzapine, quetiapine or risperidone. The main outcome was change in body weight four years before and four years after initiation of antipsychotic treatment, stratified on sex and ‘low’ or ‘high’ dose.Results:In total, 22,306 women and 16,559 men were observed. Olanzapine treatment was associated with the highest change in weight, with higher doses resulting in more weight gain. After 4 years, given a high dose of olanzapine (> 5 mg), women gained on average +6.1 kg; whereas given a low dose (⩽ 5 mg), they gained +4.4 kg. During the first six weeks of olanzapine treatment, they gained on average +3.2 kg on high dose and +1.9 kg on low dose. The trends were similar for men. Individuals prescribed risperidone and quetiapine experienced less weight gain in both the short- and long-term.Conclusions:Olanzapine treatment was associated with the highest increase in weight. Higher doses were associated with more weight gain. Doctors should prescribe the lowest effective dose to balance mental-health benefits, weight gain and other adverse effects.

Reduced connectivity in anterior cingulate cortex as an early predictor for treatment response in drug-naive, first-episode schizophrenia: A global-brain functional connectivity analysis

BackgroundAntipsychotic medications may have acute effect on brain functional connectivity (FC) after only a few days of treatment. It is unclear if early changes in FC can predict treatment response in patients with schizophrenia. MethodsThe study included 32 patients with drug-naive, first-episode schizophrenia and 32 healthy controls. Resting-state functional magnetic resonance imaging was obtained from the patients at two time-points (pre-treatment baseline and 1 week after treatment) and healthy controls at baseline. Patients were treated with olanzapine for 8 weeks, and clinical symptoms were assessed using the Positive and Negative Syndrome Scale (PANSS) at three time points (baseline, 1 week and 8 weeks after treatment). Imaging data were analyzed using global-brain FC (GFC) and support vector regression (SVR). ResultsAt baseline, an increased GFC was observed in bilateral anterior cingulate cortex (ACC) in patients compared with healthy controls. After 1 week of olanzapine treatment, patients showed decreased GFC in bilateral ACC compared to the baseline values. SVR analysis suggested a positive relationship between GFC changes in bilateral ACC at week 1 and improvement in negative symptoms at week 8 (r = 0.957, p < 0.001). ConclusionAn early decrease in GFC in bilateral ACC may serve as a predictor for treatment response in patients with schizophrenia. If further confirmed, our finding may be able to help clinicians decide, during the early treatment course, whether the patient should stay on the chosen antipsychotic medication or switch to a different one.

Disrupted asymmetry of inter- and intra-hemispheric functional connectivity in patients with drug-naive, first-episode schizophrenia and their unaffected siblings.

BackgroundLack of normal asymmetry in the brain has been reported in patients with schizophrenia. However, it remains unclear whether disrupted asymmetry originates from inter-hemispheric functional connectivity (FC) and/or intra-hemispheric FC in this patient population.MethodsForty-four patients with drug-naive, first-episode schizophrenia, 42 unaffected siblings, and 44 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The parameter of asymmetry (PAS) and support vector machine (SVM) were used to analyze the data. Patients were treated with olanzapine for 8 weeks.FindingsCompared with healthy controls, patients showed lower PAS scores in the left middle temporal gyrus (MTG)/inferior temporal gyrus (ITG), left posterior cingulate cortex (PCC)/precuneus and left angular gyrus, and higher PAS scores in the left precentral gyrus/postcentral gyrus. Unaffected siblings also showed lower PAS scores in the left MTG/ITG and left PCC/precuneus relative to healthy controls. Further, SVM analysis showed that a combination of the PAS scores in these two clusters in patients at baseline was able to predict clinical response after 8 weeks of olanzapine treatment with 77.27% sensitivity, 72.73% specificity, and 75.00% accuracy.InterpretationThe present study suggests disrupted asymmetry of inter- and intra-hemispheric FC in drug-naive, first-episode schizophrenia; in addition, a reduced asymmetry of inter-hemispheric FC in the left MTG/ITG and left PCC/precuneus may serve as an endophenotype for schizophrenia, and may have clinical utility to predict response to olanzapine treatment.FundThe National Key R&D Program of China and the National Natural Science Foundation of China.

Disrupted Asymmetry of Inter- and Intra-Hemispheric Functional Connectivity in Patients with Drug-Naive, First-Episode Schizophrenia and Their Unaffected Siblings

Background: Lack of normal asymmetry in the brain has been implicated in schizophrenia. However, it remains unclear whether disrupted asymmetry originates from inter-hemispheric functional connectivity (FC) and/or intra-hemispheric FC in patients with schizophrenia. Methods: Forty-four patients with drug-naive, first-episode schizophrenia, 42 unaffected siblings, and 44 healthy controls underwent resting-state functional magnetic resonance imaging (fMRI) scan. The parameter of asymmetry (PAS) and support vector machine (SVM) were used to analyze the data. Patients were treated with olanzapine for 8 weeks. Findings: Compared with healthy controls, patients showed lower PAS scores in the left middle temporal gyrus (MTG)/inferior temporal gyrus (ITG), left posterior cingulate cortex (PCC)/precuneus and left angular gyrus, and higher PAS scores in the left precentral gyrus/postcentral gyrus. Unaffected siblings also showed lower PAS scores in the left MTG/ITG and left PCC/precuneus relative to healthy controls. Further, SVM analysis showed that a combination of the PAS scores in these two clusters in patients at baseline was able to predict clinical response after 8 weeks of olanzapine treatment with 77.27% sensitivity, 72.73% specificity, and 75.00% accuracy. Interpretation: The present study suggests disrupted asymmetry of inter- and intra-hemispheric FC in drug-naive, first-episode schizophrenia; in addition, a reduced asymmetry of inter-hemispheric FC in the left MTG/ITG and left PCC/precuneus may serve as an endophenotype for schizophrenia, and may have clinical utility to predict response to olanzapine treatment. Funding: National Key R&D Program of China and National Natural Science Foundation of China. Conflict of Interest: Dr Fan reports receiving research support from the National Institute on Alcohol Abuse and Alcoholism, National Institute on Drug Abuse, the Stanley Medical Research Institute, the Baer Foundation, the Shine Foundation, the Vanguard Group, Janssen, Avanir Pharmaceuticals, Neurocrine, and Alkermes, and reports receiving honoraria for serving on an advisory board for Allergen. Other authors have nothing to disclose. Ethical approval statement: The study was approved by the ethics committees of the Second Affiliated Hospital of Guangxi Medical University. All subjects signed a written informed consent.

Serum IL-1ra, a novel biomarker predicting olanzapine-induced hypercholesterolemia and hyperleptinemia in schizophrenia

Olanzapine (OLZ) is efficacious whereas leads to adverse metabolic effects thus lead to higher risk of cardiovascular diseases (CVD) on schizophrenia. Cytokines have been found associated with metabolic disorders. Therefore, pretreatment prediction of OLZ-induced adverse metabolic effects is urgently needed.To investigate if baseline cytokine levels could become biomarkers for pathogenesis of schizophrenia or prediction for OLZ-induced adverse metabolic effects, we recruited 75 participants, including 23 schizophrenia inpatients, who were antipsychotic-free over the past 6 months or first episode and drug-naive and 52 matched health controls, in our prospective cohort study and cross-sectional study. We simultaneously examined 7 serum cytokine levels (IFN-γ, IL-1ra, IL-1β, IL-8, TNF-α, MCP-1, VEGF) before OLZ treatment by using liquid suspension array technique and obtained clinical correlates at 4-week intervals in total 8 weeks. The psychopathology was assessed with the Positive and Negative Symptom Scale (PANSS). The metabolic parameters were BMI, TG, total cholesterol, LDL, HDL, ApoA1, ApoB, lipoprotein a, fasting glucose, HbA1c, insulin, and leptin.At baseline, IL-1ra and MCP-1 levels in schizophrenia were significantly higher than health controls (t = 4.55, P = 0.0001, t = 3.08 P = 0.003). BMI, fasting insulin, cholesterol, triglyceride, LDL, ApoB and leptin were significantly increased in patients with schizophrenia after 8 weeks of olanzapine treatment. Correlation analysis showed that the baseline IL-1ra level were significantly correlated with the increased levels of cholesterol (P = 0.004), LDL (P = 0.005), ApoB (P = 0.018) and leptin (P = 0.010), but not with the increased BMI, insulin or triglycerides. Further stepwise multiple linear regression analysis indicated that IL-1ra levels prior to treatment remained significantly associated with increased levels of cholesterol, LDL, ApoB and leptin.Above all, higher IL-1ra and MCP-1 levels may be biomarkers indicating pathogenesis of schizophrenia. Higher serum levels of IL-1ra may predict subsequent higher possibility of hypercholesterolemia and hyperleptinemia following OLZ treatment in schizophrenia patients.

Effect of Olanzapine on Clinical and Polysomnography Profiles in Patients with Schizophrenia.

Acute and short-term administration of olanzapine has a favorable effect on sleep in schizophrenia patients. This study aimed to clarify the effect of olanzapine on polysomnographic profiles of schizophrenia patients during the acute phase of illness after controlling for previous drug exposure. Twenty-five drug-naïve or drug-free schizophrenia patients were assessed at baseline and after six weeks of olanzapine treatment on Brief Psychiatric Rating Scale (BPRS), Positive and Negative Syndrome Scale (PANSS), and Udvalg for Kliniske Undersogelser (UKU) side-effect rating scale and a whole-night polysomnography; fifteen patients completed the study. There was a significant reduction in all psychopathological variables with maximum reduction in PANSS total, BPRS total, and PANSS positive scores. A significant increase in total sleep time (TST), sleep efficiency (SE), nonrapid eye movement (NREM) stage 1 duration, stage 3 duration, stage 4 duration, and stage 4 percentage of TST, number of rapid eye movement (REM) periods, REM duration, and REM percentage of TST was observed. REM latency at baseline inversely predicted the reduction in BPRS total and PANSS total and positive scores. In summary, short-term treatment with olanzapine produced significant improvement in clinical and polysomnography profiles of patients with schizophrenia with shorter REM latency predicting a good clinical response.

Olanzapine alleviates oxidative stress in the liver of socially isolated rats.

Olanzapine, an antipsychotic drug, is used to treat depressive disorder, but its effects on the liver, the main site of drug metabolism, still remain elusive. We studied the effects of 3 weeks of olanzapine treatment (7.5 mg/kg per day) on the malondialdehyde (MDA) and protein carbonyl (PCO) contents, protein expression of copper/zinc superoxide dismutase (CuZnSOD), and activity of total superoxide dismutase (SOD), as well as catalase (CAT) protein expression and activity levels in the liver cytosol of rats exposed to 6 weeks of chronic social isolation (CSIS), which causes depressive- and anxiety-like behaviors. Increased cytosolic MDA in CSIS rats (vehicle- or olanzapine-treated) indicated hepatic oxidative stress. Increase in PCO and CAT activity associated with unchanged total SOD activity following CSIS also confirm the presence of oxidative stress. Chronic olanzapine treatment in CSIS prevented increase in PCO without an effect on MDA content. Increased SOD activity in olanzapine-treated (controls and CSIS) groups compared with corresponding vehicle-treated groups and decreased CAT activity in olanzapine-treated CSIS rats compared with vehicle-treated CSIS group was found. The data suggest that chronic olanzapine treatment has a protective effect on hepatic protein oxidation and improves antioxidant defense. The beneficial effects of olanzapine may be due to its free radical scavenging properties and antioxidant activity.

The effects of blood serum from schizophrenia patients under olanzapine monotherapy on the ultrastructure of astrocytes in human fetal brain organotypic culture

To study effects of blood serum (BS) from schizophrenia patients under olanzapine monotherapy on astrocytes in the human fetal brain organotypic culture. Authors studied the human fetal brain organotypic culture after the application of BS from 20 normals and 33 patients (ICD-10 schizophrenia, paranoid type, F20.02; F20.22) taken before and after 8 and 28 weeks of olanzapine treatment. A qualitative electron microscopic study of glial cells, neurons and neuropil as well as morphometric study of the ultrastructure of astrocytes were performed. Authors found no effects of BS from the patients with schizophrenia on neurons and synaptic contacts. The qualitative and morphometric studies revealed different effects of BS from the patients on the astrocyte ultrastructure before and after olanzapine treatment. The application of BS from untreated schizophrenia patients induced dystrophic alterations of astrocytes, BS from patients who received olanzapine during 8 weeks did not influence the astrocyte ultrastructure. After 28 weeks of olanzapine treatment,a hypertrophy of astrocytes (an increase (р≤0.05) of the area of cells and the number of mitochondria (p=0,015) and unaltered volume density of mitochondria) was found as compared to normal control cultures. BS from patients with schizophrenia before and after olanzapine treatment induced opposite types of ultrastructural changes of astrocytes in the human fetal brain organotypic culture. The differences might be due to the previously reported changes of the level of circulating immune complexes and interleukins in blood serum of schizophrenia patients and due to the effects of olanzapine on these parameters.

Effects of olanzapine on serum protein phosphorylation patterns in patients with schizophrenia.

Previous studies have shown that blood serum phosphoproteins are altered in schizophrenia patients in comparison to controls. However, it is not known whether phosphoproteins are also changed in response to treatment with antipsychotics. Blood samples were taken from patients (n = 23) at baseline and after 6 weeks of olanzapine treatment. Immobilized metal ion affinity chromatography (IMAC) was used for enrichment of serum phosphoproteins and these were analyzed by label-free LC-MS in expression mode (LC-MS(E) ). We identified 11 proteins that were changed significantly in overall abundance and 45 proteins that showed changes in phosphorylation after the antipsychotic treatment. The altered phosphoproteins were mainly involved in the acute phase response, lipid and glucose homeostasis (LXR), retinoic acid signaling (RXR), and complement pathways. Some of the proteins showed a marked increase in phosphorylation, including apolipoprotein A-I (3.4-fold), alpha-1-anti-chymotrypsin (3.1-fold), and apolipoprotein B-100 (2.2-fold). In addition, several proteins showed either decreased phosphorylation (e.g. complement C4A, collagen alpha-1 chain, complement factor H) or a mixture of increased and decreased phoshphorylation (e.g. afamin, complement C5, complement factor B). Finally, 24 of the altered phosphoproteins showed opposite directional changes in a comparison of baseline schizophrenia patients before and after treatment with olanzapine. These included alpha-1B-glycoprotein, apolipoprotein A-IV, vitamin D-binding protein, and prothrombin. These data demonstrate the potential for future studies of serum phosphoproteins as a readout of physiological function and might have utility in studies aimed at identification of biomarkers for drug response prediction or monitoring.

Neuroprotective Effects of Olanzapine inN-Methyl-d-Aspartate-Induced Retinal Injury

The aim of this study was to investigate the neuroprotective effect of olanzapine (OLA), an atypical antipsychotic drug, on N-methyl-d-aspartate (NMDA)-induced retinal injury. Retinal neuronal ischemia was induced by NMDA in Wistar rats. OLA was administered intraperitoneally in 2 different dosages: 2 and 12 mg/kg. At the end of 2 weeks of OLA treatment, 1 eye of each animal was enucleated for histopathologic examination. We also measured malondialdehyde (MDA) levels in retinal homogenates as a marker of ischemic injury. The retinal ganglion cell (RGC) count was significantly higher in cases where we used OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0032 and P=0.0005, respectively). We also found that MDA was significantly reduced by OLA 2 mg/kg or OLA 12 mg/kg compared to the control group (P=0.0001 and P=0.0001, respectively). There was no statistically significant difference between OLA 2 mg/kg or OLA 12 mg/kg groups in terms of RGC count and MDA levels (P>0.05 for all). Our data showed that OLA preserved RGCs from NMDA-induced retinal injury; thus, it may have potential neuroprotective effects.

Neural Correlates of Weight Gain With Olanzapine

CONTEXT Iatrogenic obesity caused by atypical antipsychotics increases the rate of death from all causes. Olanzapine is a commonly prescribed atypical antipsychotic medication that frequently causes weight gain. To our knowledge, the neural correlates of this weight gain have not been adequately studied in humans. OBJECTIVE To test the hypothesis that olanzapine treatment disrupts the neural activity associated with the anticipation and receipt (consumption) of food rewards (chocolate milk and tomato juice). DESIGN Event-related functional magnetic resonance imaging study, before and after a 1-week treatment with olanzapine. SETTING A university neuroimaging center. PARTICIPANTS Twenty-five healthy individuals. MAIN OUTCOME MEASURES Changes in blood oxygen level-dependent activations to the anticipation and receipt of food rewards after olanzapine treatment. RESULTS One week of olanzapine treatment caused significant increases in weight, food consumption, and disinhibited eating. Our imaging data showed enhanced activations in the inferior frontal cortex, striatum, and anterior cingulate cortex to the anticipation of a food reward. Activation in the caudate and putamen were enhanced to the receipt of the rewarding food. We also found a decrease in reward responsivity to receipt of the rewarding food in the lateral orbital frontal cortex, an area of the brain thought to exercise inhibitory control on feeding. CONCLUSIONS Olanzapine treatment enhanced both the anticipatory and consummatory reward responses to food rewards in the brain reward circuitry that is known to respond to food rewards in healthy individuals. We also noted a decrease in responsivity to food consumption in a brain area thought to inhibit feeding behavior.

Pharmacogenomic Associations With Weight Gain in Olanzapine Treatment of Patients Without Schizophrenia

Pharmacogenomic analyses of weight gain during treatment with second-generation antipsychotics have resulted in a number of associations with variants in ankyrin repeat and kinase domain containing 1 (ANKK1)/dopamine D2 receptor (DRD2) and serotonin 2C receptor (HTR2C) genes. These studies primarily assessed subjects with schizophrenia who had prior antipsychotic exposure that may have influenced the amount of weight gained from subsequent therapies. We assessed the relationships between single-nucleotide polymorphisms (SNPs) in these genes with weight gain during treatment with olanzapine in a predominantly antipsychotic-naive population. The association between 5 ANKK1, 54 DRD2, and 11 HTR2C SNPs and weight change during 8 weeks of olanzapine treatment was assessed in 4 pooled studies of 205 white patients with diagnoses other than schizophrenia who were generally likely to have had limited previous antipsychotic exposure. The A allele of DRD2 rs2440390(A/G) was associated with greater weight gain in the entire study sample (P = .0473). Three HTR2C SNPs in strong linkage disequilibrium, rs6318, rs2497538, and rs1414334, were associated with greater weight gain in women but not in men (P = .0032, .0012, and .0031, respectively). A significant association with weight gain for 2 HTR2C SNPs previously reported associated with weight gain, -759C/T (rs3813929) and -697G/C (rs518147), was not found. Associations between weight gain and HTR2C and DRD2 variants in whites newly exposed to olanzapine may present opportunities for the individualization of medication selection and development based on differences in adverse events observed across genotype groups.

The investigation of leptin and hypothalamic neuropeptides role in first attack psychotic male patients: Olanzapine monotherapy

The mechanism underlying the weight gain due to treatment with olanzapine and other second generation antipsychotics has not been fully understood. To examine olanzapine's weight gain effects, we accepted first attack psychotic patients with no medication (pre-treatment) (n=22) and the healthy control group (n=26) in this study. After patientś diagnosis, they were hospitalized and then treated for four weeks with olanzapine (post-treatment). We used case-control association design to test body mass index (BMI) and biochemical changes in each group. We also investigated peripheral leptin and neuropeptides/hormones namely, pro-opiomelanocortin (POMC), cocaine and amphetaime regulated transcript (CART), and neuropeptide Y (NPY) levels. These neuropeptides which are synthesized/secreted from arcuate nucleus of hypothalamus affect food intake and therefore, body weight. After 4 weeks of olanzapine treatment; BMI (body mass index), waist circumference, blood triglyceride, total cholesterol, and very low density lipoprotein (VLDL) levels were increased significantly in patients compared to their pre-treatment baseline. In pre-treatment, patients' NPY levels were significantly lower while α-MSH, the anorexigenic product of POMC levels were significantly higher vs. control. Both leptin and NPY levels were significantly increased in patients after the treatment but the NPY levels were also significantly lower in post-treatment vs. the control group. The CART levels did not change after the treatment. We may presume that the antagonist effect of olanzapine on the serotonin (5HT2CR and 5HT1BR) receptors of the arcuate hypothalamic neurons may be a basis for a deregulation of the neurohormones secretion.

Neural changes associated with appetite information processing in schizophrenic patients after 16 weeks of olanzapine treatment

There is evidence that some atypical antipsychotics, including olanzapine, can produce unwanted metabolic side effects, weight gain and diabetes. However, neuronal correlates of change related to food information processing have not been investigated with these medications. We studied the effect of a pharmacological manipulation with an antipsychotic known to cause weight gain on metabolites, cognitive tasks and neural correlates related to food regulation. We used functional magnetic resonance imaging in conjunction with a task requiring visual processing of appetitive stimuli in schizophrenic patients and healthy controls before and after 16 weeks of antipsychotic medication with olanzapine. In patients, the psychological and neuronal changes associated following the treatment correlated with appetite control measures and metabolite levels in fasting blood samples. After 16 weeks of olanzapine treatment, the patients gained weight, increased their waist circumference, had fewer positive schizophrenia symptoms, a reduced ghrelin plasma concentration and an increased concentration of triglycerides, insulin and leptin. In premotor area, somatosensory cortices as well as bilaterally in the fusiform gyri, the olanzapine treatment increased the neural activity related to appetitive information in schizophrenic patients to similar levels relative to healthy individuals. However, a higher increase in sensitivity to appetitive stimuli after the treatment was observed in insular cortices, amygdala and cerebellum in schizophrenic patients as compared with healthy controls. Furthermore, these changes in neuronal activity correlated with changes in some metabolites and cognitive measurements related to appetite regulation.