Effects of olanzapine on hippocampal CA3 and the prefrontal cortex local field potentials.

Olanzapine is an antipsychotic drug applied in psychiatry to treat psychoses, especially schizophrenia and schizoaffective disorders with similar or better improvement than haloperidol and risperidone in the treatment of depressive and negative symptoms. The effect of olanzapine on neural synchrony remains to be explored. We investigated the effects of olanzapine on gamma oscillations in the CA3 region of the hippocampus and frontal association cortex. Olanzapine reduced carbachol (CCh)-induced gamma oscillation power in CA3 slice and gamma oscillation power in the frontal association cortex in vivo. The power of theta oscillations was increased in the presence of olanzapine. The phase amplitude coupling of theta and gamma wave was strengthened by the administration of olanzapine in the frontal association cortex in vivo. Taken together, these results show that olanzapine modulates local field potential and the neuronal activity.

Olanzapine's effects on hypothalamic transcriptomics and kinase activity.

Olanzapine is a second-generation antipsychotic that disrupts metabolism and is associated with an increased risk of type 2 diabetes. The hypothalamus is a key region in the control of whole-body metabolic homeostasis. The objective of the current study was to determine how acute peripheral olanzapine administration affects transcription and serine/threonine kinase activity in the hypothalamus. Hypothalamus samples from rats were collected following the pancreatic euglycemic clamp, thereby allowing us to study endpoints under steady state conditions for plasma glucose and insulin. Olanzapine stimulated pathways associated with inflammation, but diminished pathways associated with the capacity to combat endoplasmic reticulum stress and G protein-coupled receptor activity. These pathways represent potential targets to reduce the incidence of type 2 diabetes in patients taking antipsychotics.

Modulatory effect of olanzapine on neuronal nitric oxide synthase (nNOS) expression in the rat striatum.

Nitric oxide (NO) has been thought to be a novel factor involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about potential crosstalk between neuronal NO signaling and neuroleptics action. The present work was, therefore, focused on gene expression of neuronal NO synthase (nNOS) in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at dose 5 mg/kg daily). All individuals were killed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain, and for both descriptive and quantitative analysis of nNOS protein distribution in selected brain structures. Long-term treatment with olanzapine is reflected in different changes in the number of enzyme-expressing cells in the rat brain. Olanzapine decreased the number of nNOS-expressing cells and possibly reduced NO synthesis in the rat striatum. Olanzapine can be taken into account as a potential inhibitor of NO synthesis in the rat striatum.

Olanzapine, risperidone and ziprasidone differently affect lysosomal function and autophagy, reflecting their different metabolic risk in patients.

The metabolic effects induced by antipsychotics in vitro depend on their action on the trafficking and biosynthesis of sterols and lipids. Previous research showed that antipsychotics with different adverse effects in patients cause similar alterations in vitro, suggesting the low clinical usefulness of cellular studies. Moreover, the inhibition of peripheral AMPK was suggested as potential aetiopathogenic mechanisms of olanzapine, and different effects on autophagy were reported for several antipsychotics. We thus assessed, in clinically-relevant culture conditions, the aetiopathogenic mechanisms of olanzapine, risperidone and ziprasidone, antipsychotics with respectively high, medium, low metabolic risk in patients, finding relevant differences among them. We highlighted that: olanzapine impairs lysosomal function affecting autophagy and autophagosome clearance, and increasing intracellular lipids and sterols; ziprasidone activates AMPK increasing the autophagic flux and reducing intracellular lipids; risperidone increases lipid accumulation, while it does not affect lysosomal function. These in vitro differences align with their different impact on patients. We also provided evidence that metformin add-on improved autophagy in olanzapine-treated cells and reduced lipid accumulation induced by both risperidone and olanzapine in an AMPK-dependent way; metformin also increased the production of bile acids to eliminate cholesterol accumulations caused by olanzapine. These results have different clinical implications. We demonstrated that antipsychotics with different metabolic impacts on patients actually have different mechanisms of action, thus supporting the possibility of a personalised antipsychotic treatment. Moreover, we found that metformin can fully revert the phenotype caused by risperidone but not the one caused by olanzapine, that still activates SREBP2.

Activation of the PERK-CHOP signaling pathway during endoplasmic reticulum stress contributes to olanzapine-induced dyslipidemia.

Olanzapine (OLZ) is a widely prescribed antipsychotic drug with a relatively ideal effect in the treatment of schizophrenia (SCZ). However, its severe metabolic side effects often deteriorate clinical therapeutic compliance and mental rehabilitation. The peripheral mechanism of OLZ-induced metabolic disorders remains abstruse for its muti-target activities. Endoplasmic reticulum (ER) stress is implicated in cellular energy metabolism and the progression of psychiatric disorders. In this study, we investigated the role of ER stress in the development of OLZ-induced dyslipidemia. A cohort of 146 SCZ patients receiving OLZ monotherapy was recruited, and blood samples and clinical data were collected at baseline, and in the 4th week, 12th week, and 24th week of the treatment. This case-control study revealed that OLZ treatment significantly elevated serum levels of endoplasmic reticulum (ER) stress markers GRP78, ATF4, and CHOP in SCZ patients with dyslipidemia. In HepG2 cells, treatment with OLZ (25, 50 µM) dose-dependently enhanced hepatic de novo lipogenesis accompanied by SREBPs activation, and simultaneously triggered ER stress. Inhibition of ER stress by tauroursodeoxycholate (TUDCA) and 4-phenyl butyric acid (4-PBA) attenuated OLZ-induced lipid dysregulation in vitro and in vivo. Moreover, we demonstrated that activation of PERK-CHOP signaling during ER stress was a major contributor to OLZ-triggered abnormal lipid metabolism in the liver, suggesting that PERK could be a potential target for ameliorating the development of OLZ-mediated lipid dysfunction. Taken together, ER stress inhibitors could be a potentially effective intervention against OLZ-induced dyslipidemia in SCZ.

Brain metabolite levels in remitted psychotic depression with consideration of effects of antipsychotic medication.

BACKGROUND: The neurobiology of psychotic depression is not well understood and can be confounded by antipsychotics. Magnetic resonance spectroscopy (MRS) is an ideal tool to measure brain metabolites non-invasively. We cross-sectionally assessed brain metabolites in patients with remitted psychotic depression and controls. We also longitudinally assessed the effects of olanzapine versus placebo on brain metabolites. METHODS: Following remission, patients with psychotic depression were randomized to continue sertraline + olanzapine (n = 15) or switched to sertraline + placebo (n = 18), at which point they completed an MRS scan. Patients completed a second scan either 36 weeks later, relapse, or discontinuation. Where water-scaled metabolite levels were obtained and a Point-RESolved Spectroscopy sequence was utilized, choline, myo-inositol, glutamate + glutamine (Glx), N-acetylaspartate, and creatine were measured in the left dorsolateral prefrontal cortex (L-DLPFC) and dorsal anterior cingulate cortex (dACC). An ANCOVA was used to compare metabolites between patients (n = 40) and controls (n = 46). A linear mixed-model was used to compare olanzapine versus placebo groups. RESULTS: Cross-sectionally, patients (compared to controls) had higher myo-inositol (standardized mean difference [SMD] = 0.84; 95%CI = 0.25-1.44; p = 0.005) in the dACC but not different Glx, choline, N-acetylaspartate, and creatine. Longitudinally, patients randomized to placebo (compared to olanzapine) showed a significantly greater change with a reduction of creatine (SMD = 1.51; 95%CI = 0.71-2.31; p = 0.0002) in the dACC but not glutamate + glutamine, choline, myo-inositol, and N-acetylaspartate. CONCLUSIONS: Patients with remitted psychotic depression have higher myo-inositol than controls. Olanzapine may maintain creatine levels. Future studies are needed to further disentangle the mechanisms of action of olanzapine.

Olanzapine Effects on Parvalbumin/GAD67 Cell Numbers in Layers/Subregions of Dorsal Hippocampus of Chronically Socially Isolated Rats.

Depression is linked to changes in GABAergic inhibitory neurons, especially parvalbumin (PV) interneurons, which are susceptible to redox dysregulation. Olanzapine (Olz) is an atypical antipsychotic whose mode of action remains unclear. We determined the effect of Olz on PV-positive (+) and glutamate decarboxylase 67 (GAD67) + cell numbers in the layers of dorsal hippocampus (dHIPP) cornu ammonis (CA1-CA3) and dentate gyrus (DG) subregions in rats exposed to chronic social isolation (CSIS), which is an animal model of depression. Antioxidative enzymes and proinflammatory cytokine levels were also examined. CSIS decreased the PV+ cell numbers in the Stratum Oriens (SO) and Stratum Pyramidale (SP) of dCA1 and dDG. It increased interleukin-6 (IL-6), suppressor of cytokine signaling 3 (SOCS3), and copper-zinc superoxide dismutase (CuZnSOD) levels, and it decreased catalase (CAT) protein levels. Olz in CSIS increased the number of GAD67+ cells in the SO and SP layers of dCA1 with no effect on PV+ cells. It reduced the PV+ and GAD67+ cell numbers in the Stratum Radiatum of dCA3 in CSIS. Olz antagonizes the CSIS-induced increase in CuZnSOD, CAT and SOCS3 protein levels with no effect on IL-6. Data suggest that the protective Olz effects in CSIS may be mediated by altering the number of PV+ and GAD67+ cells in dHIPP subregional layers.

Olanzapine alters the expression of gasotransmitter-related enzymes: CBS and HO-2 in the rat hippocampus and striatum.

BACKGROUND: Gaseous neurotransmitters have been thought to be novel factors involved in the mechanisms of mental disorders pathogenesis for quite some time. However, little is known about the potential crosstalk between neuronal gasotransmitter signaling and neuroleptics action. The present work was, therefore, focused on gene expression of H2S and CO-producing enzymes in the brains of rats chronically treated with olanzapine, an atypical antipsychotic drug. METHODS: Studies were carried out on adult, male Sprague-Dawley rats that were divided into 2 groups: control and experimental animals treated with olanzapine (28-day-long intraperitoneal injection, at a dose of 5 mg/kg daily). All individuals were sacrificed under anesthesia and the whole brains excised. Immunohistochemical procedure was used for histological assessment of the whole brain and for quantitative analysis of cystathionine ß-synthase (CBS) and heme oxygenase 2 (HO-2) protein distribution in selected brain structures. RESULTS: Long-term treatment with olanzapine is reflected in different changes in the number of enzymes-expressing cells in the rat brain. Olanzapine decreased the number of CBS-expressing cells and possibly reduced H2S synthesis in the hippocampus and striatum. The antipsychotic administration increased the number of HO-2 immunopositive cells and probably stimulated the CO production in the hippocampus. CONCLUSIONS: Modulatory effect of olanzapine on cellular mechanisms of gasotransmitter synthesis may be an alternative way of their pharmacological action.

Impaired mitophagosome-lysosome fusion mediates olanzapine-induced aging.

The lifespan of schizophrenia patients is significantly shorter than the general population. Olanzapine is one of the most commonly used antipsychotic drugs (APDs) for treating patients with psychosis, including schizophrenia and bipolar disorder. Despite their effectiveness in treating positive and negative symptoms, prolonged exposure to APDs may lead to accelerated aging and cognitive decline, among other side effects. Here we report that dysfunctional mitophagy is a fundamental mechanism underlying accelerated aging induced by olanzapine, using in vitro and in vivo (Caenorhabditis elegans) models. We showed that the aberrant mitophagy caused by olanzapine was via blocking mitophagosome-lysosome fusion. Furthermore, olanzapine can induce mitochondrial damage and hyperfragmentation of the mitochondrial network. The mitophagosome-lysosome fusion in olanzapine-induced aging models can be restored by a mitophagy inducer, urolithin A, which alleviates defective mitophagy, mitochondrial damage, and fragmentation of the mitochondrial network. Moreover, the mitophagy inducer ameliorated behavioral changes induced by olanzapine, including shortened lifespan, and impaired health span, learning, and memory. These data indicate that olanzapine impairs mitophagy, leading to the shortened lifespan, impaired health span, and cognitive deficits. Furthermore, this study suggests the potential application of mitophagy inducers as therapeutic strategies to reverse APD-induced adverse effects associated with accelerated aging.

Vitamin D Receptor Activation Attenuates Olanzapine-Induced Dyslipidemia in Mice Through Alleviating Hepatic Endoplasmic Reticulum Stress.

The involvement of vitamin D (VD) signaling in atypical antipsychotics (AAPs)-induced metabolic disturbances has been previously established. This study aims to elucidate the role of VD in maintaining endoplasmic reticulum (ER) homeostasis and its impact on AAPs-induced metabolic adverse effects. Female C57BL/6 mice receive either calcitriol or vehicle one week prior to co-treatment with olanzapine (OLZ) for an additional four weeks. Metabolic parameters, hepatic ER homeostasis, and the SREBPs pathway are assessed through biochemical assays and protein expression profiling. HepG2 cells are transfected with vitamin D receptor (VDR) siRNA for VDR knockdown. OLZ-treated HepG2 cells are exposed to calcitriol to examine its effects on SREBPs and the unfolded protein response (UPR) pathways. VDR activation by calcitriol reduces OLZ-induced hepatic ER stress, leading to decreased SREBPs activity and lipid accumulation. Conversely, the knockdown of VDR in HepG2 cells diminishes the protective effects of calcitriol against OLZ-induced ER stress and SREBPs activation. This resulted in sustained UPR activation, elevated cleaved SREBPs levels, and increased lipid accumulation. These findings highlight an essential role of VDR signaling in the beneficial effects of VD on OLZ-induced metabolic side effects. Targeting VDR to resolve ER stress is likely an applicable therapeutic strategy for AAPs-induced metabolic disturbances.

Sex-specific differences and similarities of olanzapine and risperidone on avoidance suppression in rats in the conditioned avoidance response test.

It is well known that antipsychotic drugs (APDs) are more effective in reducing symptoms in women than in men, and that women are more sensitive to the side effects of APDs. Therefore, it is of great importance that sex differences in drug responses are considered already in the early stages of drug development. In this study, we investigated whether sex-specific differences could be observed in response to the commonly prescribed APDs olanzapine and risperidone using the conditioned avoidance response (CAR) test. To this end we tested the effect of 1.25 and 2.5 mg/kg olanzapine and 0.25 and 0.4 mg/kg risperidone using female and male Wistar rats in the CAR test. Whereas there were no significant differences between the female and male rats in response to either dose of olanzapine administration, an injection of 0.4 mg/kg risperidone significantly suppressed avoidance more in female rats than in male rats. In addition, we found that the estrous cycle of the female rats did not have a significant effect on the avoidance response. In conclusion, we show that there are sex-specific differences as well as similarities between female and male rats in the CAR test and novel APDs should be tested on female and male rats in the future.

Prefrontal cortex-specific Dcc deletion induces schizophrenia-related behavioral phenotypes and fail to be rescued by olanzapine treatment.

Multiple genome studies have discovered that variation in deleted in colorectal carcinoma (Dcc) at transcription and translation level were associated with the occurrences of psychiatric disorders. Yet, little is known about the function of Dcc in schizophrenia (SCZ)-related behavioral abnormalities and the efficacy of antipsychotic drugs in vivo. Here, we used an animal model of prefrontal cortex-specific knockdown (KD) of Dcc in adult C57BL/6 mice to study the attention deficits and impaired locomotor activity. Our results supported a critical role of Dcc deletion in SCZ-related behaviors. Notably, olanzapine rescued the SCZ-related behaviors in the MK801-treated mice but not in the cortex-specific Dcc KD mice, indicating that Dcc play a critical in the mechanism of antipsychotic effects of olanzapine. Knockdown of Dcc in prefrontal cortex results in glutamatergic dysfunction, including defects in glutamine synthetase and postsynaptic maturation. As one of the major risk factors of the degree of antipsychotic response, Dcc deletion-induced glutamatergic dysfunction may be involved in the underlying mechanism of treatment resistance of olanzapine. Our findings identified Dcc deletion-mediated SCZ-related behavioral defects, which serve as a valuable animal model for study of SCZ and amenable to targeted investigations in mechanistic hypotheses of the mechanism underlying glutamatergic dysfunction-induced antipsychotic treatment resistance.

NU-1223, a simplified analog of alstonine, with 5-HT2cR agonist-like activity, rescues memory deficit and positive and negative symptoms in subchronic phencyclidine mouse model of schizophrenia.

The serotonin (5-HT)2 C receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HT2 CR agonism. Based on alstonine, we developed NU-1223, a simplified ß carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HT2 CR agonists, Ro-60-0175 and lorcaserin. The 5-HT2 CR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HT2 CR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HT2 CR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HT2 CR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.

Effects of antipsychotics, haloperidol and olanzapine, on the expression of apoptosis-related genes in mouse mHippoE-2 cells and rat hippocampus.

Objective. Modified levels of pro- (caspase3, Bax) and anti-apoptotic (Bcl-2) regulatory proteins have been detected in certain brain areas of schizophrenic patients indicating a possible dysregulation of apoptosis. In the present study, effects of antipsychotics, haloperidol (HAL) and olanzapine (OLA), on the gene expression of caspase3 (casp3), Bax and Bcl-2 were studied in vitro in mouse hippocampal mHippoE-2 cell line and in vivo in the hippocampus of MK-801 animal schizophrenia model with the aim to provide evidence that antipsychotics may affect the activity of apoptosis-related markers. Methods. mHippoE-2 cells were incubated with MK-801 (20 µM), HAL (10 µM), and OLA (10 µM) alone or combined, MK-801+HAL/OLA, for 24, 48, and 72 h. Male Sprague Dawley rats were injected with saline or MK-801 (0.5 mg/kg) for 6 days and since the 7th day, they were treated with vehicle (VEH), HAL (1 mg/kg) or OLA (2 mg/kg) for the next 7 days. The casp3, Bax and Bcl-2 gene expression in mHippoE-2 cells and rat hippocampus was measured by RT-PCR. Results. In mHippoE-2 cells, casp3 gene expression was increased by MK-801 and OLA treatments alone for 48 h, HAL treatment alone for 24 and 72 h, and co-treatment with MK-801+OLA for 24 and 72 h compared to controls. HAL and OLA suppressed the stimulatory effect of MK-801 on casp3 mRNA levels in cells after 48 h of incubation. Bax mRNA levels in mHippoE-2 cells were decreased after HAL treatment for 24 and 48 h, and also after co-treatment with MK-801+HAL for 72 h. In vivo, MK-801 decreased mRNA levels of both pro-apoptotic markers, casp3 and Bax, in hippocampus of VEH-treated rats and Bax mRNA levels in hippocampus of HAL-treated animals. OLA reversed the inhibitory effect of MK-801 on casp3 expression in the VEH-treated animals. Neither MK-801 nor antipsychotics induced changes in the gene expression of anti-apoptotic marker Bcl-2 in mHippoE-2 cells as well as hippocampus of rats. Conclusions. The results of the present study demonstrate that antipsychotics, HAL and OLA, may affect mRNA levels of pro-apoptotic markers in hippocampal cells in vitro, but not in vivo. The obtained data do not clearly support the assumed potentiating role of MK-801 in inducing apoptosis in specific brain areas and a possible protective role of antipsychotics against induction of apoptosis. The obtained data may contribute to a deeper insight into the neurodevelopmental changes connected with schizophrenia.

Changes in hypothalamic mu-opioid receptor expression following acute olanzapine treatment in female rats: Implications for feeding behavior.

Advances have been made in recent years in using opioid receptor antagonists as an adjunct therapy to psychotropic medication to reduce debilitating weight gain and metabolic adverse effects associated with in particular second generation antipsychotics. However, it is unknown whether second generation antipsychotics produce a change in opioid receptor expression in the brain. The present study investigated early changes in opioid receptor expression in the female rat hypothalamus, a master controller of hunger and metabolic regulation, after acute treatment with olanzapine, a commonly used second generation antipsychotic. Using quantitative spatial in situ hybridization and receptor autoradiography, expression levels of the three opioid receptors; kappa, mu and delta, were determined at mRNA and protein level, respectively, in the five hypothalamic areas: paraventricular nucleus, arcuate nucleus, ventromedial nucleus, dorsomedial nucleus and lateral hypothalamus. After 48 h of olanzapine treatment at clinically relevant plasma concentration weight gain and food intake changes, and increased plasma glucose were observed in female rats. Olanzapine treatment also led to a significant increase in mu opioid receptor availability in the arcuate nucleus, which contains both satiety and hunger controlling neurons. No other areas showed any opioid receptor expressional changes with olanzapine treatment on neither at mRNA nor protein level. Technical difficulties made it impossible to analyze mRNA levels in the lateral hypothalamus and overall binding of delta opioid receptors. Thus, the present study provided insights in to how olanzapine at clinically relevant plasma levels already at an early stage modulated the opioid system in the hypothalamus.

Prediction of treatment response to antipsychotic drugs for precision medicine approach to schizophrenia: randomized trials and multiomics analysis.

BACKGROUND: Choosing the appropriate antipsychotic drug (APD) treatment for patients with schizophrenia (SCZ) can be challenging, as the treatment response to APD is highly variable and difficult to predict due to the lack of effective biomarkers. Previous studies have indicated the association between treatment response and genetic and epigenetic factors, but no effective biomarkers have been identified. Hence, further research is imperative to enhance precision medicine in SCZ treatment. METHODS: Participants with SCZ were recruited from two randomized trials. The discovery cohort was recruited from the CAPOC trial (n = 2307) involved 6 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, Quetiapine, Aripiprazole, Ziprasidone, and Haloperidol/Perphenazine (subsequently equally assigned to one or the other) groups. The external validation cohort was recruited from the CAPEC trial (n = 1379), which involved 8 weeks of treatment and equally randomized the participants to the Olanzapine, Risperidone, and Aripiprazole groups. Additionally, healthy controls (n = 275) from the local community were utilized as a genetic/epigenetic reference. The genetic and epigenetic (DNA methylation) risks of SCZ were assessed using the polygenic risk score (PRS) and polymethylation score, respectively. The study also examined the genetic-epigenetic interactions with treatment response through differential methylation analysis, methylation quantitative trait loci, colocalization, and promoter-anchored chromatin interaction. Machine learning was used to develop a prediction model for treatment response, which was evaluated for accuracy and clinical benefit using the area under curve (AUC) for classification, R2 for regression, and decision curve analysis. RESULTS: Six risk genes for SCZ (LINC01795, DDHD2, SBNO1, KCNG2, SEMA7A, and RUFY1) involved in cortical morphology were identified as having a genetic-epigenetic interaction associated with treatment response. The developed and externally validated prediction model, which incorporated clinical information, PRS, genetic risk score (GRS), and proxy methylation level (proxyDNAm), demonstrated positive benefits for a wide range of patients receiving different APDs, regardless of sex [discovery cohort: AUC = 0.874 (95% CI 0.867-0.881), R2 = 0.478; external validation cohort: AUC = 0.851 (95% CI 0.841-0.861), R2 = 0.507]. CONCLUSIONS: This study presents a promising precision medicine approach to evaluate treatment response, which has the potential to aid clinicians in making informed decisions about APD treatment for patients with SCZ. Trial registration Chinese Clinical Trial Registry ( https://www.chictr.org.cn/ ), 18. Aug 2009 retrospectively registered: CAPOC-ChiCTR-RNC-09000521 ( https://www.chictr.org.cn/showproj.aspx?proj=9014 ), CAPEC-ChiCTR-RNC-09000522 ( https://www.chictr.org.cn/showproj.aspx?proj=9013 ).

Increased levels of lipid and protein oxidation in rat prefrontal cortex after treatment by lithium, valproic acid, and olanzapine.

Oxidative stress is widely accepted to contribute to the pathogenesis of several psychiatric diseases. Many antipsychotic drugs and mood stabilizers act through restoration of the dysregulated oxidative homeostasis in the brain. However, the long-term effect of these drugs per se in terms of their potential to interfere with the oxidative status in the brain remains largely controversial. The present study aimed to investigate the sole effect of three commonly used psychoactive drugs, lithium, valproic acid, and olanzapine, on lipid and protein oxidation status in the prefrontal cortex of healthy rats. A total of 80 adult male albino Wistar rats were used, and groups were treated with saline (control), lithium, valproic acid, or olanzapine daily for 30 days. Following sacrification, right prefrontal cortexes were dissected and homogenized. Lipid peroxidation (LPO) and protein oxidation (AOPP) assays were performed by ELISA. LPO levels were significantly higher in lithium and valproic acid-treated rats by 45% and 40%, respectively. Olanzapine treatment caused a mild 26% increase in LPO levels, but the effect was non-significant. Lithium, valproic acid, and olanzapine treatments significantly increased AOPP levels by 58%, 54%, and 36.5%, respectively. There was a strong positive correlation between the lipid peroxidation and protein oxidation levels. Our results call attention to the need to consider the pro-oxidative capacity of antipsychotic drugs per se and their potential to disturb the oxidative homeostasis in the brain during long-term medication for psychiatric diseases.

Intranasal administration of olanzapine has beneficial outcome in a rat activity-based anorexia model.

The atypical antipsychotic drug olanzapine is prescribed despite clinical studies on olanzapine treatment showing mixed results on treatment efficacy in anorexia nervosa. We investigated the effect of systemic and intranasal administration of olanzapine in the activity-based anorexia (ABA) model. Rats were habituated to a running wheel and exposed to the ABA model while treated with olanzapine. During ABA rats had 1.5 h of daily access to food and ad libitum access to a running wheel for seven consecutive days. Olanzapine was administered via an osmotic minipump (1, 2.75, and 7.5 mg/kg) or intranasally 2 h before dark onset (1 and 2.75 mg/kg). We monitored body weight, food intake, wheel revolutions, body temperature, and adipose tissue. We found 2.75 and 7.5 mg/kg systemic olanzapine decreased wheel revolutions during ABA. Relative adipose tissue mass was increased in the 7.5 mg/kg olanzapine-treated group while body weight, food intake, and body temperature were unaltered by the systemic olanzapine. 1 and 2.75 mg/kg intranasal olanzapine diminished wheel revolutions and body temperature during the first 2 h after administration. The intranasal olanzapine-treated rats had a higher body weight at the end of ABA. We find that olanzapine has beneficial outcomes in the ABA via two administration routes by acting mainly on running wheel activity. Intranasal olanzapine showed a rapid effect in the first hours after administration in reducing locomotor activity. We recommend further exploring intranasal administration of olanzapine in anorectic patients to assist them in coping with restlessness.

Interhemispheric differences of pyramidal cells in the primary motor cortices of schizophrenia patients investigated postmortem.

Motor disturbances are observed in schizophrenia patients, but the neuroanatomical background is unknown. Our aim was to investigate the pyramidal cells of the primary motor cortex (BA 4) in both hemispheres of postmortem control and schizophrenia subjects-8 subjects in each group-with 2.5-5.5 h postmortem interval. The density and size of the Sternberger monoclonal incorporated antibody 32 (SMI32)-immunostained pyramidal cells in layer 3 and 5 showed no change; however, the proportion of larger pyramidal cells is decreased in layer 5. Giant pyramidal neurons (Betz cells) were investigated distinctively with SMI32- and parvalbumin (PV) immunostainings. In the right hemisphere of schizophrenia subjects, the density of Betz cells was decreased and their PV-immunopositive perisomatic input showed impairment. Part of the Betz cells contained PV in both groups, but the proportion of PV-positive cells has declined with age. The rat model of antipsychotic treatment with haloperidol and olanzapine showed no differences in size and density of SMI32-immunopositive pyramidal cells. Our results suggest that motor impairment of schizophrenia patients may have a morphological basis involving the Betz cells in the right hemisphere. These alterations can have neurodevelopmental and neurodegenerative explanations, but antipsychotic treatment does not explain them.

Discovery and optimization of olanzapine derivatives as new ferroptosis inhibitors.

Ferroptosis is a new type of cell death associated with many human diseases. It is a new strategy to discover ferroptosis inhibitors for the treatment of ferroptosis-related diseases. Here the FDA-approved drug library containing 1160 molecules was screened for ferroptosis inhibitors in RSL3-induced HT22 mouse hippocampal neuronal cells. As a result, olanzapine showed potent ferroptosis inhibitory activity (EC50 = 1.18 µM). Structural optimization and the structure-activity relationships (SARs) analysis led to the synthesis of 41 new derivatives (4-44) and one known compound 45. Comparing with olanzapine, its derivative 36 showed nearly sixteen-folds improved ferroptosis inhibition and low cytotoxicity (EC50 = 0.074 µM, CC50 = 18.8 µM). Further mechanistic studies revealed that compound 36 specifically inhibited ferroptosis by its antioxidative ability. This work demonstrates that olanzapine protected RSL3-induced ferroptosis in HT22 cell, and its derivative 36 having nanomolar ferroptosis inhibitory activity merit to be developed for drugs against ferroptosis-related neurological diseases.